FIRST: Study to Determine Efficacy and Safety of Lenalidomide Plus Low-dose Dexamethasone Versus Melphalan, Prednisone, Thalidomide in Patients With Previously Untreated Multiple Myeloma

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00689936
• Collaborator: (none)
• Enrollment: 1,623
• Locations: 288
• Arms: 3
• Actual Duration (Months): 94.8
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the safety and efficacy of Lenalidomide plus low dose dexamethasone to that of the combination of melphalan, prednisone and thalidomide.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Lenalidomide and low-dose dexamethasone; Drug: Lenalidomide plus low-dose dexamethasone given for 18 four-week cycles; Drug: Melphalan, Prednisone and Thalidomide	Phase 3

Detailed Description

CC-5013-MM020/IFM 07-01 is a Phase III, multicenter, randomized, open-label, 3-arm study that will compare the efficacy and safety of two Lenalidomide plus low-dose dexamethasone regimens given for two different durations of time (i.e., until progressive disease [PD] or for up to a maximum of 18 four-week cycles) to that of MPT given for a maximum of 12 six-week cycles.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1623 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Open-label, 3-arm Study to Determine the Efficacy and Safety of Lenalidomide(REVLIMID) Plus Low-dose Dexamethasone When Given Until Progressive Disease or for 18 Four-week Cycles Versus the Combination of Melphalan, Prednisone, and Thalidomide Given for 12 Six-week Cycles in Patients With Previously Untreated Multiple Myeloma Who Are Either 65 Years of Age or Older or Not Candidates for Stem Cell Transplantation.
• Actual Study Start Date: Aug 21, 2008
• Actual Primary Completion Date: Jul 14, 2016
• Actual Study Completion Date: Jul 14, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lenalidomide / Dexamethasone until disease progression Lenalidomide plus low-dose dexamethasone given until disease progression	Drug: Lenalidomide and low-dose dexamethasone; Lenalidomide - oral, 2.5mg, 5mg, 10mg, 15mg 20mg, or 25 mg capsules, given either days 1-21 of each 28 day cycles or given every other day for 21 days until documentation of PD. Dexamethasone - oral 4mg tablets for a total dose of 20mg or 40 mg given days 1,8,15 and 22 of each 28 day cycle up to disease progression; Other Names: Revlimid
Experimental: Lenalidomide / Dexamethasone for 18 cycles Lenalidomide plus low-dose dexamethasone given for 18 four-week cycles	Drug: Lenalidomide plus low-dose dexamethasone given for 18 four-week cycles; lenalidomide - oral, 2.5mg, 5mg, 10mg, 15mg, 20 mg or 25 mg capsules given on days 1-21 of each 28 day cycle or every other day for 21 days for 18 cycles. Dexamethasone - oral 4mg tablets for a total dose of 20mg or 40 mg given days 1,8,15 and 22 of each 28 day cycle for 18 cycles; Other Names: Revlimid
Active Comparator: Melphalan, Prednisone, and Thalidomide (MPT) for 12 cycles Combination of Melphalan, Prednisone and Thalidomide given for 12 six-week cycles	Drug: Melphalan, Prednisone and Thalidomide; Melphalan - oral, 2mg tablets dosed at either 0.25mg/kg, 0.125 mg/kg, 0.20mg/kg or 0.10mg/kg on days 1-4 of each 42 day cycle up to 12 cycles Prednisone - oral, 5mg, 10mg, 20 mg and 50 mg tablets dosed at 2mg/kg daily days 1-4 of each 42 day cycle for up to 12 cycles Thalidomide - oral, 50mg, 100mg and 200 mg capsules dosed at either 100mg or 200 mg daily on days 1-41 of each 42 day cycle for up to 12 cycles; Other Names: Prednisone Thalomid

Outcome Measures

Primary Outcome Measures

1. Kaplan-Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC) [From date of randomization until the data cut-off date of 24 May 2013. Median follow-up time for all participants was 17.1 months.]

   PFS was calculated as the time from randomization to the first documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy without documented PD were censored on the date of their last response assessment, prior to receiving any other anti-myeloma therapy. Censoring rules for PFS: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any adequate response assessment; Progression documented between scheduled assessments; Death between adequate assessments; no progression; study discontinuations for reasons other than PD or death; new anti-myeloma started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's).

2. Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator At the Time of Final Analysis [From date of randomization to date of data cut-off date of 21 January 2016; median follow-up for all participants was 17.7 months]

   PFS was calculated as the time from randomization to the first documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy without documented PD were censored on the date of their last response assessment, prior to receiving any other anti-myeloma therapy. Censoring rules for PFS: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any adequate response assessment; Progression documented between scheduled assessments; Death between adequate assessments; no progression; study discontinuations for reasons other than PD or death; new anti-myeloma started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's).

Secondary Outcome Measures

1. Kaplan Meier Estimates of Overall Survival at the Time of Final Analysis (OS) [From date of randomization to date of data cut-off date of 21 January 2016; median follow-up for all participants was 48.3 months]

   Overall survival was defined as the time between randomization and death. Participants, who died, regardless of the cause of death, were considered to have had an event. All participants who were lost to follow-up prior to the end of the trial or who were withdrawn from the trial were censored at the time of last contact. Participants who were still being treated were censored at the last available date the participant was known to be alive.

2. Percentage of Participants With an Objective Response Based on IRAC Review [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

   Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

3. Percentage of Participants With an Objective Response Based on Investigator Assessment at Time of Final Analysis [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

   Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined s: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

4. Kaplan Meier Estimates of Duration of Myeloma Response as Determined by the IRAC [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median follow-up for responders was 20.1 months]

   Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first.

5. Kaplan Meier Estimates of Duration of Myeloma Response as Determined by an Investigator Assessment at Time of Final Analysis [Disease response was assessed every 28 days until end of treatment; data cut-off date of 21 January 2016; median follow-up for responders was 19.9 months]

   Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first.

6. Time to First Response Based on the Review by the IRAC [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

   The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria.

7. Time to First Response Based on the Investigator Assessment at the Time of Final Analysis [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.]

   The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria assessed by the investigator.

8. Kaplan Meier Estimates of Time to Treatment Failure (TTF) [From date of randomization until the data cut-off of 24 May 2013; median follow-up for all participants was 16.1 months.]

   TTF is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by IRAC based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT) or death.

9. Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis [From date of randomization until the data cut-off date of 21 January 2016; median follow up for all participants was 16.1 months.]

   TTF is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by the investigators assessment based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT) or death.

10. Kaplan Meier Estimates for Time to Second-line Anti-myeloma Treatment (AMT) [From date of randomization until the data cut-off of 24 May 2013; median follow-up for all participants was 23.0 months]

    Time to second-line anti-myeloma therapy was defined as time from randomization to the start of another non-protocol anti-myeloma therapy.

11. Kaplan Meier Estimates of Time to Second Line Therapy AMT at the Time of Final Analysis [From date of randomization until the data cut-off of date 21 January 2016; median follow-up for all participants was 23.0 months]

    Time to second-line anti-myeloma therapy is defined as time from randomization to the start of another non-protocol anti-myeloma therapy. Those who do not receive another anti-myeloma therapy were censored at the last assessment or follow-up visit known to have received no new therapy.

12. Percentage of Participants With an Objective Response After Second-line Anti-myeloma Treatment at the Time of Final Analysis [Disease response was assessed every 28 days until end of treatment; data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined s: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

13. Percentage of Participants With a Myeloma Response by Adverse Risk Cytogenetic Risk Category Based on IRAC Review. [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

14. Percentage of Participants With a Myeloma Response by Favorable Hyperdiploidy Risk Cytogenetic Risk Category Based on IRAC Review [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

15. Percentage of Participants With a Myeloma Response by Normal Risk Cytogenetic Risk Category Based on IRAC Review [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

16. Percentage of Participants With a Myeloma Response by Uncertain Risk Cytogenetic Risk Category Based on IRAC Review [Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.

17. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement.

18. Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

19. Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Role Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

20. Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

21. Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain [Cycle 1 Day 1, (Baseline) then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Cognitive Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

22. Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Social Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

23. Change From Baseline in the EORTC QLQ-C30 Fatigue Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.

24. Change From Baseline in the EORTC QLQ-C30 Pain Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Pain Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.

25. Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Nausea/Vomiting Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.

26. Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnoea Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.

27. Change From Baseline in the EORTC QLQ-C30 Insomnia Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Insomnia Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.

28. Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Appetite Loss Scale is scored between 0 and 100, with a high score indicating a higher level of appetite loss. Negative change from Baseline values indicate improvement in appetite and positive values indicate worsening of appetite.

29. Change From Baseline in the EORTC QLQ-C30 Constipation Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Constipation Scale is scored between 0 and 100, with a high score indicating a higher level of constipation. Negative change from Baseline values indicate improvement in constipation and positive values indicate worsening of constipation.

30. Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Diarrhea Scale is scored between 0 and 100, with a high score indicating a higher level of diarrhea. Negative change from Baseline values indicate improvement in diarrhea and positive values indicate worsening of diarrhea.

31. Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Financial Difficulties Scale is scored between 0 and 100, with a high score indicating a higher level of financial difficulties. Negative change from Baseline values indicate improvement in financial difficulties and positive values indicate worsening of financial difficulties.

32. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates more severe disease symptom(s).

33. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score represents a more severe overall side effect of treatment.

34. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the future perspective scale, a higher score indicates a better perspective of the future.

35. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the body image scale, a higher score indicates a better body image.

36. Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Health Utility Index Score [Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit]

    EQ-5D is a self-administered questionnaire that assesses health-related quality of life. The EQ-5D descriptive health profile comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 levels of response: No problem (1), some problems (2), and extreme problems (3). A unique EQ-5D health state is defined by combining one level from each of the five dimensions into a single utility index score. EQ-5D index values range from -0.59 to 1.00 where higher EQ-5D scores represent better health status. A positive change from baseline score indicates improvement in health status and better health state.

37. Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year [Day 1 (randomization) up to last visit completed 25 July 2016]

    HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. The rate of inpatient hospitalizations per patient year was calculated as the total number of hospitalizations divided by the total number of patient-years followed in the study period. Patient-years (PY) were calculated as the duration from baseline to last available HRQL assessment for each patient.

38. Number of Participants With Adverse Events (AEs) During the Active Treatment Phase [From first dose of study drug through 28 days following the discontinuation visit from active treatment phase; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    A TEAE is any AE occurring or worsening on or after the first treatment of any study drug, and within 30 days after the last dose of the last study drug. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event.

39. Shift From Baseline to Most Extreme Postbaseline Value in Creatinine Clearance (CrCl) During the Active Treatment Phase [Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Renal function was assessed for participants from baseline to the most extreme value in creatinine clearance calculated using the Cockcroft-Gault estimation.

40. Shift From Baseline to Most Extreme Postbaseline Value in Absolute Neutrophil Count During the Active Treatment Phase [Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Neutrophil counts was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale.

41. Shift From Baseline to Most Extreme Postbaseline Value in Hemoglobin During the Active Treatment Phase [Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Hemoglobin was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale.

42. Shift From Baseline to Most Extreme Postbaseline Value in Platelet Count During the Active Treatment Phase. [Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm]

    Improvement in platelets was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale.

43. Improvement of Infection Rate by Observing the Historical Data Compared to the Clinical Data Base [From randomization to 24 May 2013]

    Improvement of infection rate by observing historical data compared to the data within clinical database as not analyzed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Must understand and voluntarily sign informed consent form

2. Age ≥ 18 years at the time of signing consent

3. Previously untreated, symptomatic multiple myeloma as defined by the 3 criteria below:

• MM diagnostic criteria (all 3 required):

• Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma

• Monoclonal protein present in the serum and/or urine

• Myeloma-related organ dysfunction (at least one of the following) [C] Calcium elevation in the blood (serum calcium >10.5 mg/dl or upper limit of normal) [R] Renal insufficiency (serum creatinine >2 mg/dl) [A] Anemia (hemoglobin <10 g/dl or 2 g < laboratory normal) [B] Lytic bone lesions or osteoporosis

AND have measurable disease by protein electrophoresis analyses as defined by the following:

• IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours

• IgA multiple myeloma: Serum M-protein level ≥ 0.5 g/dl or urine M-protein level ≥ 200 mg/24 hours

• IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200mg/24hours

• IgD multiple myeloma: Serum M-protein level ≥ 0.05 g/dl or urine M-protein level ≥ 200 mg/24 hours

• Light chain multiple myeloma: Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours

AND are at least 65 years of age or older or, if younger than 65 years of age, are not candidates for stem cell transplantation because:

• The patient declines to undergo stem cell transplantation or

• Stem cell transplantation is not available to the patient due to cost or other reasons

1. ECOG performance status of 0, 1, or 2

2. Able to adhere to the study visit schedule and other protocol requirements

3. Females of child-bearing potential (FCBP)^2:

4. Must agree to undergo two medically supervised pregnancy tests prior to starting study therapy with either Rd or MPT. The first pregnancy test will be performed within 10-14 days prior to the start of Rd or MPT and the second pregnancy test will be performed within 24 hours prior to the start of Rd or MPT. She must also agree to ongoing pregnancy testing during the course of the study and after the end of study therapy. This applies even if the patient practices complete and continued sexual abstinence.

5. Must commit to either continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use and be able to comply with effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including during periods of dose interruptions), and for 28 days after discontinuation of study therapy.

6. Male Patients:

7. Must agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy.

8. Must agree to not donate semen during study drug therapy and for a period after end of study drug therapy.

9. Must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy.

10. All patients must:

11. Have an understanding that the study drug could have a potential teratogenic risk.

12. Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy.

13. Agree not to share study medication with another person. All FCBP and male patients must be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [i.e., less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of randomization]).

2. Any serious medical condition that places the patient at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, patient with unstable cardiac disease as defined by: Cardiac events such as MI within the past 6 months, NYHA heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; patients with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.

3. Pregnant or lactating females.

4. Any of the following laboratory abnormalities:

• Absolute neutrophil count (ANC) < 1,000/µL (1.0 x 109/L)

• Untransfused platelet count < 50,000 cells/µL (50 x 10^9/L)

• Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)

1. Renal failure requiring hemodialysis or peritoneal dialysis.

2. Prior history of malignancies, other than multiple myeloma, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)

1. Patients who are unable or unwilling to undergo antithrombotic therapy.

2. Peripheral neuropathy of > grade 2 severity.

3. Known HIV positivity or active infectious hepatitis, type A, B, or C. Primary AL (immunoglobulin light chain) amyloidosis and myeloma complicated by amyloidosis.

• 1 A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma-related.

• 2 A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (i.e., amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of AL Birmingham	Birmingham	Alabama	United States	35294
2	Cedar Sinai Medical Center Dept of Medicine	Los Angeles	California	United States	90048
3	University of California, San Francisco- California	San Francisco	California	United States	94143
4	Stanford University Stanford	Stanford	California	United States	94305
5	Gainesville Heme Oncology Associates	Gainesville	Florida	United States	32607
6	Baptist Cancer Institute	Jacksonville	Florida	United States	32207
7	Integrated Community Oncology Network	Orange Park	Florida	United States	32073
8	Gulf Coast Oncology	Saint Petersburg	Florida	United States	33705
9	Palm Beach Cancer Institute, LLC	West Palm Beach	Florida	United States	33401
10	Southern Illinois Hematology Oncology	Centralia	Illinois	United States	62801
11	Orchard Healthcare Research, Inc.	Chicago	Illinois	United States	60611
12	John H Stroger Hospital of Cook County	Chicago	Illinois	United States	60612
13	Rush University Medical Center	Chicago	Illinois	United States	60612
14	Ingalls Cancer Institute	Harvey	Illinois	United States	60426-3558
15	Cancer Center of Kansas	Wichita	Kansas	United States	67124
16	Maine Center for Cancer Medicine Blood Disorders	Scarborough	Maine	United States	04074
17	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
18	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
19	Billings Clinic	Billings	Montana	United States	59107
20	Arena Oncology Associates, PC	Lake Success	New York	United States	11042
21	Dakota Cancer Institute	Fargo	North Dakota	United States	58103
22	Gabrail Cancer Center Research	Canton	Ohio	United States	44718
23	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
24	Cleveland Clinic	Cleveland	Ohio	United States	44195
25	Kaiser Permanente Northwest Oncology Hematology	Portland	Oregon	United States	97227
26	St. Luke's Hospital and Health Network	Allentown	Pennsylvania	United States	18104
27	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
28	The Cancer Center	Collierville	Tennessee	United States	38017
29	University of Tennessee Cancer Institute	Memphis	Tennessee	United States	38104
30	University of Texas Medical Branch	Galveston	Texas	United States	77555-0561
31	Swedish Cancer Institute	Seattle	Washington	United States	98104
32	Fred Hutchinson Cancer Center	Seattle	Washington	United States	98109
33	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
34	Peter MacCallum Cancer Centre Divsion of Haematology Medical Oncology	E. Melbourne	Victoria	Australia	3002
35	Western Hospital	Footscray	Victoria	Australia	3011
36	Frankston Hospital	Frankston	Victoria	Australia	3199
37	Flinders Medical Centre	Bedford Park		Australia	5042
38	Geelong Hospital	Geelong		Australia	3220
39	Gosford Hospital	Gosford		Australia	2250
40	Royal Brisbane and Women's Hospital	Herston		Australia	4029
41	Cabrini Hospital	Malvern		Australia	3144
42	The Royal Melbourne Hospital	Parkville		Australia	3050
43	Royal Perth Hospital	Perth		Australia	6000
44	Gold Coast Hospital	Southport		Australia	4215
45	Royal North Shore Hospital	St Leonards		Australia	2065
46	Westmead Hospital	Wentworthville		Australia	2145
47	Border Medical Oncology	Wodonga		Australia	3690
48	Wollongong Hospital	Wollongong		Australia	2500
49	Princess Alexandra Hospital	Woolloongabba		Australia	4102
50	Hospital Leoben	Leoben		Austria	8700
51	Hospital of Barmherzige Schwestern Linz	Linz		Austria	4010
52	Hospital of Elisabethinen Linz	Linz		Austria	4010
53	General Hospital Linz	Linz		Austria	4021
54	MM-015. Salzburger Landkliniken, St. Johanns-Spital, Universitätsklinik fur Innere Medizin III	Salzburg		Austria	5020
55	Hospital St. Polten	St. Pölten		Austria	3100
56	Hospital of the Barmherzigen Bruder Vienna	Vienna		Austria	1020
57	MM-015.Wihelminenspital	Vienna		Austria	1160
58	MM-015. Medizinische Universität Wien	Vienna		Austria	A-1090
59	Hospital Wels	Wels		Austria	4600
60	Hospital Wiener Neustadt	Wiener Neustadt		Austria
61	ZNA Stuivenberg Centrumziekenhuis	Antwerpen		Belgium	2069
62	Les Cliniques du Sud Luxembourg	Arlon		Belgium	6700
63	AZ St-Jan Brugge Oostende AV	Brugge		Belgium	8000
64	Hopital Erasme	Brussels		Belgium	1070
65	AZ-VUB	Brussels		Belgium	1090
66	Jules Bordet Institut	Brussel		Belgium	1000
67	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
68	Universitair Ziekenhuis Antwerpen	Edegem		Belgium	2650
69	UZ Gent	Gent		Belgium	9000
70	Virga Jesse Ziekenhuis	Hasselt		Belgium	3500
71	Universitair Ziekenhuis Leuven, Campus Gasthuisberg	Leuven		Belgium	3000
72	H. Hartziekenhuis Roeselare-Menen vzw campus Wilgenstraat	Roeselare		Belgium	8800
73	Cliniques Universitaires UCL de Mont-Godine	Yvoir		Belgium	5530
74	University of Calgary	Calgary	Alberta	Canada	T2N 2T9
75	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
76	British Columbia Cancer Agency	Kelowna	British Columbia	Canada	V1Y 5L3
77	Royal Columbian Hospital	New Westminster	British Columbia	Canada	V3M 1X4
78	BC Cancer Agency - Fraser Valley Centre	Surrey	British Columbia	Canada	V3V 1Z2
79	Leukemia/BMT Program of BCDiv of Hem, Vancouver Gen Hosp	Vancouver	British Columbia	Canada	V5Z 1M9
80	Vancouver Island Cancer Center	Victoria	British Columbia	Canada	V8R 6V5
81	Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 3L6
82	Queen Elizabeth II Health Sciences Center	Halifax	Nova Scotia	Canada	B3H2Y9
83	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
84	London Health Science Centre	London	Ontario	Canada	N6A 4G5
85	Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
86	Odette Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
87	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
88	Hospital Charles LeMoyne	Greenfield Park	Quebec	Canada	J4V 2H1
89	Hopital de la Cite-de-la-Sante	Laval	Quebec	Canada	H7M 3L9
90	Hotel-Dieu de Levis	Levis	Quebec	Canada	G5V 3Z1
91	Hopital du Sacre-Coeur de Montreal	Montreal	Quebec	Canada	G4H 1C5
92	Hospital Maisonneuve - Rosemont	Montreal	Quebec	Canada	H1T 2M4
93	CHUM- Hopital Notre-Dame	Montreal	Quebec	Canada	H2L4M1
94	McGill University	Montreal	Quebec	Canada	H2W 1S6
95	Sir Mortimer B. Davis - Jewish Genl	Montreal	Quebec	Canada	H3T 1E2
96	CHUQ - Hotel-Dieu de QuebecHematology - Oncology	Quebec		Canada	G1R 2J6
97	Chaoyang Hospital	Beijing		China	100020
98	Peking University People's Hospital	Beijing		China	100044
99	West China Hospital of Sichuan University	Chengdu		China	610041
100	Ruijin Hospital Shanghai Jiaotong University	Shanghai		China	200025
101	Blood Disease Hospital, Chinese Academy of Medical Science and Peking Union Medical College	Tianjin		China	300041
102	Clinique Claude BernardOncologie	Albi		France	81000
103	CHU Sud	Amiens		France	80054
104	CHRU Hopital du bocage	Angers cedex 01		France	49033
105	CH Argenteuil Victor Dupouy	Argenteuil		France	95100
106	Centre Hospitalier de la cote basque	Bayonne		France	64109
107	Centre Hospitalier	Blois cedex		France	41016
108	Hopital Avicenne	Bobigny Cedex		France	93009
109	Institut Bergonie Centre Regional de Lutte Contre Le Cancer de Bordeaux Et Sud Ouest	Bordeaux		France	33076
110	Polyclinique Bordeaux Nord Aquitaine	Bordeaux		France	33300
111	Hopital de Fleyriat	Bourg en Bresse cedex		France	01012
112	Hopital Augustin Morvan	Brest cedex		France	29609
113	Centre Francois Baclesse	Caen cedex 5		France	14076
114	CHU	Caen		France	14033
115	CH	Cannes Cedex		France	06401
116	CH Rene Dubois	Cergy-Pontoise		France	95303
117	Centre Hospitalier William Morey	Chalon/Saone Cedex		France	71321
118	Hopital dinstruction des armees Percy	Clamart Cedex		France	92141
119	Hopital Antoine Beclere	Clamart		France	92141
120	Chu Estaing	Clermont Ferrand		France	63000
121	CH Louis Pasteur	Colmar cedex		France	68024
122	Hopital Henri Mondor	Creteil		France	94010
123	CHRU Hopital du bocage	Dijon		France	21034
124	Centre Hospitalier General	Dunkerque		France	59385
125	CHRU	Grenoble cedex 09		France	38043
126	Institut Prive de Cancerologie	Grenoble		France	38034
127	Centre Hospitalier Departemental	La Roche -Sur-Yon cedex 9		France	85925
128	CH	Le Chesnay Cedex		France	78157
129	Hopital J MonodRhumato Nord	Le Havre		France	76000
130	Kremlin Bicetre	Le Kremlin bicetre CDX		France	942975
131	Centre Hospitalier	Le Mans cedex		France	72037
132	Centre Jean Bernard	Le Mans		France	72000
133	CHRU-Hopital Claude Huriez	Lille cedex		France	59037
134	GH de Institut Catholique St Vincent	Lille		France	59000
135	CH - Hôpital Dupuytren	Limoges Cedex 1		France	87042
136	CHU Hopital Edouard Herriot	Lyon cedex		France	69437
137	Centre Leon Berard	Lyon		France	69008
138	Centre Hospitalier de Valence	Lyon		France	69495
139	Institut Paoli-Calmettes	Marseille Cedex 9		France	13009
140	Hopital de Mercy	METZ cedex 3		France	57085
141	Clinique Pont de chaume Oncologie et Radiotherapie	Montauban cedex		France	82017
142	CHU Montpellier - Hôpital Lapeyronie	Montpellier Cedex 5		France	34295
143	Hopital Emile Muller	Mulhouse		France	68000
144	CHRU - Hotel Dieu	Nantes		France	44035
145	Centre Antoine Lacassagne Oncologie medicale et Hematologie	Nice cedex 1		France	06050
146	Hopital de lArchet 1	Nice cedex 3		France	06202
147	CH La Source	Orleans		France	45000
148	Hopital Cochin	Paris Cedex 14		France	75679
149	Hopital Saint Louis	Paris		France	75010
150	Hopital Necker	Paris		France	75015
151	CHU Hôpital St-Antoine	Paris		France	75571
152	CHRU - Hopital du Haut Leveque	Pessac		France	33604
153	CU CHU Clemenceau	Poitiers cedex		France	86021
154	Hopital R. Debre	Reims cedex		France	51032
155	CHU Reims - Hôpital Maison Blanche	Reims		France	51100
156	CHRU Hopital sud Medecine Interne	Rennes cedex 02		France	35056
157	CHRU Hôpital de Pontchaillou	Rennes Cedex		France	35033
158	CHG Rodez	Rodez		France	12027
159	Centre Henri Becquerel	Rouen cedex		France	76038
160	Centre Rene Huguenin	Saint Cloud		France	92210
161	Institut de Cancerologie de Loire	St Priest en Jarez		France	42270
162	Centre Hospitalier Yves Le Foll	St-Brieuc cedex 1		France	22027
163	CHRU Hôpital de Hautepierre	Strasbourg		France	67098
164	CHRU Hopital Purpan	Toulouse cedex 9		France	TSA 40031-31059
165	CHRU Hopital Bretonneau	Tours cedex		France	37044
166	CHRU Hopital Trousseau	Tours		France	37044
167	CHRU Hôpitaux de Brabois	Vandoeuvre Cedex		France	54511
168	CH P. Chubert	Vannes cedex		France	56017
169	Institut Gustave Roussy	Villejuif		France	94805
170	Medizinische Kinik und Poliklinik I	Dresden		Germany	D-01307
171	Universitaetsklinikum Dusseldorf Klinik fuer Haematologie	Dusseldorf		Germany	40225
172	Universitatsklinikum Essen-	Essen		Germany	45122
173	Staedtische Kliniken Frankfurt am Main Hochst	Frankfurt am Main		Germany	65929
174	Universitatsklinikum Giessen	Giessen		Germany	35385
175	Ernst-Moritz-Arndt-Universität Greifswald	Greifswald		Germany	17487
176	Askepios Klinik St. Georg	Hamburg		Germany	20099
177	Universitatsklinikum Jena	Jena		Germany	07740
178	Medizinische Klinik und Poliklinik II	Leipzig		Germany	04103
179	Universitatsklinikum schleswig-Holstein	Lübeck		Germany	23538
180	Poliklinik A	Muenster		Germany	48129
181	Klinikum der Johann-Wolfgang-Goethe-Universtat	München		Germany	81377
182	Medizinische Klinik III Klinikum der Universität München-Großhadern	München		Germany	81377
183	Medizinische Fakultat der Universitat Rostock	Rostock		Germany	18057
184	Zentrum F. Innere Medizin II Robert- Bosch-Krankenhaus GmBH	Stuttgart		Germany	D -70376
185	Medizinische Klinik - Abteilung II	Tübingen		Germany	72076
186	Klinik fur Innere Medizin III	Ulm		Germany	89081
187	Alexandra Hospital, University of Athens	Athens		Greece	11528
188	Attiko Hospital of Athens	Athens		Greece	124
189	Evangelismos Hospital of Athens	Athens		Greece
190	University of Athens	Athens		Greece
191	Metaxa Hospital Peiraias	Piraeus		Greece	18537
192	Theagenio Anticancer Hospital of Thessaloniki	Thessaloniki		Greece	540 07
193	Adelaide and Meath Hospital	Dublin		Ireland	24
194	Mater Misercordiae Hospital	Dublin		Ireland	7
195	University Hospital Galway	Galway		Ireland	ST46QG
196	Policlinico S. Orsola	Bologna		Italy	40138
197	Oncologia Medica, Università della Magna Grecia	Catanzaro		Italy	88100
198	Clinica Ematologica, A.O.U. San Martino di Genova	Genova		Italy	16132
199	Ematologia ed Immunologia, Azienda Ospedaliera Vito Fazzi di Lecce	Lecce		Italy	73100
200	Unità Operativa di Oncoematologia, Ospedale di Matera	Matera		Italy	75100
201	U.O. di Ematologia e Trapianto di Midollo Osseo	Milano		Italy	20132
202	Istituto Europeo di Oncologia - IEO	Milano		Italy	20141
203	Presidio Ospedaliero A. Perrino	Milano		Italy	20141
204	Policlinico di Modena	Modena		Italy	41100
205	Oncoematologia, Istituto Nazionale Tumori Fondazione G. Pascale	Napoli		Italy	80131
206	Casa di Cura La Maddalena, Divisione di Ematologia	Palermo		Italy	90146
207	Policlinico San Matteo Universita Di Pavia	Pavia 2		Italy	27100
208	Ospedale Civile	Piacenza		Italy	29100
209	A.O. Universitaria Ospedale S.Chiara Dip.Oncologia, Div. Ematologia	Pisa		Italy	56126
210	Arcispedale Santa Maria Nuova	Reggio Emilia		Italy	42100
211	Istituto Nazionale Tumori Regina Elena, Struttura Complessa Ematologia ed Unita di Cellule Staminali	Roma		Italy	00144
212	Azienda Policlinico Umberto I, Universita La Sapienzadi Roma	Rome		Italy	00161
213	Ospedale Molinette	Torino		Italy	10126
214	Hallym University Sacred Heart Hospital	Anyang		Korea, Republic of	431-070
215	Inje University Busan Paik Hospital	Busan		Korea, Republic of	614-735
216	Daegu Catholic University Medical Center 3056-6	Daegu		Korea, Republic of	705-718
217	Chungnam National University Hospital	Daejon		Korea, Republic of	301-721
218	National Cancer Center	Gyeonggi-do		Korea, Republic of	410-769
219	Hwasun Chonnam National University Hospital	Hwasun-goon		Korea, Republic of	519-803
220	Gachon University Gil Hospital	Incheon		Korea, Republic of	405-760
221	Chonbuk National University Hospital 42	Jeonju		Korea, Republic of	561-712
222	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of	463-707
223	Severance Hospital	Seongsanno		Korea, Republic of	120-752
224	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
225	Samsung Medical Center	Seoul		Korea, Republic of	135-710
226	The Catholic University of Korea Seoul - Saint Mary's Hospital	Seoul		Korea, Republic of	137-701
227	Asan Medical Center	Seoul		Korea, Republic of	138-736
228	Ewha Womans University Mokdong Hospital	Seoul		Korea, Republic of	158-710
229	Auckland City Hospital	Auckland		New Zealand	1023
230	Christchurch Hospital	Christchurch		New Zealand	8011
231	Wellington Hospital	Newtown		New Zealand	6021
232	Hospital de Sao Marcos	Braga		Portugal
233	Hospitais da Universidade de Coimbra	Coimbra		Portugal	3000-075
234	Instituto Portugues de Oncologia de Lisboa	Lisboa		Portugal	1099-023
235	Hospital de Santa Maria	Lisboa		Portugal	1649-035
236	Instituto Português de Oncologia Porto	Porto		Portugal	4200-072
237	Hospital de Santo Antonio- Porto	Porto		Portugal
238	Hospital Universitari Germans Trias i Pujol	Badalona (Barcelona)		Spain	8916
239	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08025
240	Instituto Catalan de Oncologia-Hospital Duran	Barcelona		Spain	08907
241	Hospital Reina Sofia	Cordoba		Spain	14004
242	Hospital Univ. Josep Trueta	Girona		Spain	17007
243	Hospital Clinico San Carlos	Madrid		Spain	28040
244	Hospital 12 de Octubre	Madrid		Spain	28041
245	Hospital Universitario La Paz	Madrid		Spain	28046
246	Hospital General Universitario Morales Messeguer	Murcia		Spain	30008
247	Hospital Clinico Virgen de la Victoria	Málaga		Spain	29010
248	Hospital Son Llatzer	Palma de Mallorca		Spain	7198
249	Clinica Universitaria de Navarra,	Pamplona		Spain	31008
250	Hospital Sant Pau	Reus		Spain	43201
251	Hospital de Donosti	San Sebastian		Spain	20014
252	Hospital Universtario Marques de Valdecilla	Santander		Spain	39008
253	Hospital Clinico Santiago de Compostela	Santiago de Compostela		Spain	15706
254	Hosptial La Fe	Valencia		Spain	46009
255	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
256	Hospital Clinico Universitario Lozano Blesa	Zaragoza		Spain	50009
257	Hospital Miguel Servet	Zaragoza		Spain	50009
258	Linkoping University Hospital	Linkoping		Sweden	SE 581 85
259	Karolinska University HospitalSolna	Stockholm		Sweden	SE 17176
260	St. Görans Hospital	Stockholm		Sweden	SE- 11281
261	Karolinska University Hospital Huddinge	Stockholm		Sweden	SE-14186
262	Abteilung Onkologie Haematologie des Kantonsspitals Aarau	Aarau		Switzerland	5001
263	UniversitatsSpital Basel	Basel		Switzerland	4031
264	Inselsspital Bern	Berne		Switzerland	3010
265	Kantonsspital Graubunden	Chur		Switzerland	7000
266	Centre Hospitalier Universitaire Vaudois CHUV	Lausanne		Switzerland	1011
267	Kantonsspital Munsterlingen	Münsterlingen (TG)		Switzerland	8596
268	Kantonsspital Winterthur	Winterthur		Switzerland	8400
269	China Medical University Hospital	Taichung City		Taiwan	40447
270	Veteran General Hospital - Taipei	Taipei		Taiwan	11217
271	National Taiwan University Hospital	Tapei		Taiwan	10002
272	Gwynedd Hospital	Bangor		United Kingdom	LL57 2PW
273	Royal United Hospital	Bath		United Kingdom	BA1 3NG
274	Belfast City Hospital Haematology Department	Belfast Northern Ireland		United Kingdom	BT9 7AB
275	Birminghman QE	Birmingham West Midlands		United Kingdom	B15 2TH
276	Royal Bournemouth Hosp	Bournemouth Dorset		United Kingdom	BH7 7DW
277	Bristol Haematology and Oncology Centre	Bristol		United Kingdom	BS2 8ED
278	Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 2QQ
279	University Hospital of Wales - Cardiff	Cardiff		United Kingdom	CF14 4XW
280	The Beatson West of Scotland Centre	Glasgow		United Kingdom	G12 0YN
281	Dept of Haematology St Bartholomews Hospital	London		United Kingdom	EC1A 7BE
282	Guy's and St Thomas' Hospital - London	London		United Kingdom	SE1 9RT
283	Royal Free Hospital	London		United Kingdom	W12 0HS
284	Churchhill Hospital	Oxford		United Kingdom	OX3 7LI
285	Derriford Hospital	Plymouth Crownhill Devon		United Kingdom	PL6 8DH
286	Royal Hallamshire Hospital Sheffield Teaching Hospitals NHS Trust	Sheffield		United Kingdom	S10 2JF
287	Pinderfields General Hospital	West Yorkshire		United Kingdom	WF1 4DG
288	New Cross Hospital- Wolverhampton	Wolverhampton		United Kingdom	WV10 OPQ

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Christian Jacques, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to CSR synopsis

Publications

• Ailawadhi S, DerSarkissian M, Duh MS, Lafeuille MH, Posner G, Ralston S, Zagadailov E, Ba-Mancini A, Rifkin R. Cost Offsets in the Treatment Journeys of Patients With Relapsed/Refractory Multiple Myeloma. Clin Ther. 2019 Mar;41(3):477-493.e7. doi: 10.1016/j.clinthera.2019.01.009. Epub 2019 Feb 14.
• Ailawadhi S, Jacobus S, Sexton R, Stewart AK, Dispenzieri A, Hussein MA, Zonder JA, Crowley J, Hoering A, Barlogie B, Orlowski RZ, Rajkumar SV. Disease and outcome disparities in multiple myeloma: exploring the role of race/ethnicity in the Cooperative Group clinical trials. Blood Cancer J. 2018 Jul 6;8(7):67. doi: 10.1038/s41408-018-0102-7.
• Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. doi: 10.1056/NEJMoa1402551.
• Delforge M, Minuk L, Eisenmann JC, Arnulf B, Canepa L, Fragasso A, Leyvraz S, Langer C, Ezaydi Y, Vogl DT, Giraldo-Castellano P, Yoon SS, Zarnitsky C, Escoffre-Barbe M, Lemieux B, Song K, Bahlis NJ, Guo S, Monzini MS, Ervin-Haynes A, Houck V, Facon T. Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide. Haematologica. 2015 Jun;100(6):826-33. doi: 10.3324/haematol.2014.120121. Epub 2015 Mar 13.
• Dimopoulos MA, Cheung MC, Roussel M, Liu T, Gamberi B, Kolb B, Derigs HG, Eom H, Belhadj K, Lenain P, Van der Jagt R, Rigaudeau S, Dib M, Hall R, Jardel H, Jaccard A, Tosikyan A, Karlin L, Bensinger W, Schots R, Leupin N, Chen G, Marek J, Ervin-Haynes A, Facon T. Impact of renal impairment on outcomes with lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 trial in transplant-ineligible patients with multiple myeloma. Haematologica. 2016 Mar;101(3):363-70. doi: 10.3324/haematol.2015.133629. Epub 2015 Dec 11.
• Dumontet C, Hulin C, Dimopoulos MA, Belch A, Dispenzieri A, Ludwig H, Rodon P, Van Droogenbroeck J, Qiu L, Cavo M, Van de Velde A, Lahuerta JJ, Allangba O, Lee JH, Boyle E, Perrot A, Moreau P, Manier S, Attal M, Roussel M, Mohty M, Mary JY, Civet A, Costa B, Tinel A, Gaston-Mathé Y, Facon T. A predictive model for risk of early grade ≥ 3 infection in patients with multiple myeloma not eligible for transplant: analysis of the FIRST trial. Leukemia. 2018 Jun;32(6):1404-1413. doi: 10.1038/s41375-018-0133-x. Epub 2018 Apr 26.
• Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. doi: 10.1182/blood-2017-07-795047. Epub 2017 Nov 17.
• Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial. J Clin Oncol. 2016 Oct 20;34(30):3609-3617. doi: 10.1200/JCO.2016.66.7295.
• Jain T, Sonbol MB, Firwana B, Kolla KR, Almader-Douglas D, Palmer J, Fonseca R. High-Dose Chemotherapy with Early Autologous Stem Cell Transplantation Compared to Standard Dose Chemotherapy or Delayed Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant. 2019 Feb;25(2):239-247. doi: 10.1016/j.bbmt.2018.09.021. Epub 2018 Sep 20.
• Pegourie B, Karlin L, Benboubker L, Orsini-Piocelle F, Tiab M, Auger-Quittet S, Rodon P, Royer B, Leleu X, Bareau B, Cliquennois M, Fuzibet JG, Voog E, Belhadj-Merzoug K, Decaux O, Rey P, Slama B, Leyronnas C, Zarnitsky C, Boyle E, Bosson JL, Pernod G; IFM Group. Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study. Am J Hematol. 2019 Jun;94(6):635-640. doi: 10.1002/ajh.25459. Epub 2019 Apr 1.
• Vogl DT, Delforge M, Song K, Guo S, Gibson CJ, Ervin-Haynes A, Facon T. Long-term health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma receiving lenalidomide and dexamethasone. Leuk Lymphoma. 2018 Feb;59(2):398-405. doi: 10.1080/10428194.2017.1334125. Epub 2017 Jun 22.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00689936
• Other Study ID Numbers: CC-5013-MM-020; 2007-004823-39
• First Posted: Jun 4, 2008
• Last Update Posted: Nov 20, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Celgene: newly diagnosed multiple myeloma; Lenalidomide; Revlimid; phase III
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Thalidomide; Dexamethasone; Dexamethasone acetate; Prednisone; Lenalidomide; Melphalan; BB 1101

Study Results

Participant Flow

Recruitment Details	This study was conducted in the Europe, Asia, North America and Pacific regions. Participants were randomized at 246 sites (165 in Europe, 23 in Asia, 39 in North America, and 19 in the Pacific). The study was co-sponsored by Intergroupe Francophone du Myélome (IFM) (for sites in France, Switzerland, and Belgium) and Celgene Corporation.
Pre-assignment Detail	Participants were stratified at randomization by 1) age (≤ 75 versus > 75 years), 2) stage (International Staging System Stages I or II versus Stage III), and 3) country.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Period Title: Active Treatment Phase
STARTED	535	541	547
Safety Population	532	540	541
Untreated	3	1	6
COMPLETED	0	0	0
NOT COMPLETED	535	541	547
Period Title: Active Treatment Phase
STARTED	87	300	273
COMPLETED	87	300	273
NOT COMPLETED	0	0	0
Period Title: Active Treatment Phase
STARTED	382	463	459
COMPLETED	255	275	315
NOT COMPLETED	127	188	144

Baseline Characteristics

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)	Total
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.	Total of all reporting groups
Overall Participants	535	541	547	1623
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.2 (6.57)	72.9 (6.50)	73.1 (6.32)	73.1 (6.46)
Sex: Female, Male (Count of Participants)
Female	241 45%	268 49.5%	260 47.5%	769 47.4%
Male	294 55%	273 50.5%	287 52.5%	854 52.6%
Race/Ethnicity, Customized (Number) [Number]
Asian	40 7.5%	43 7.9%	44 8%	127 7.8%
Black or African American	9 1.7%	6 1.1%	5 0.9%	20 1.2%
Native Hawaiian or other Pacific Islanders	1 0.2%	0 0%	1 0.2%	2 0.1%
White or Caucasian	474 88.6%	480 88.7%	491 89.8%	1445 89%
Other, Miscellaneous	6 1.1%	11 2%	3 0.5%	20 1.2%
Undisclosed	5 0.9%	1 0.2%	3 0.5%	9 0.6%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	37 6.9%	33 6.1%	36 6.6%	106 6.5%
Not Hispanic or Latino	493 92.1%	505 93.3%	508 92.9%	1506 92.8%
Undisclosed	5 0.9%	3 0.6%	3 0.5%	11 0.7%
International Staging System (ISS) (Number) [Number]
Stage I	106 19.8%	106 19.6%	103 18.8%	315 19.4%
Stage II	227 42.4%	229 42.3%	225 41.1%	681 42%
Stage III	202 37.8%	206 38.1%	219 40%	627 38.6%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Number) [Number]
0 (fully active)	155 29%	163 30.1%	156 28.5%	474 29.2%
1 (restrictive but ambulatory)	257 48%	263 48.6%	275 50.3%	795 49%
2 (ambulatory but unable to work)	119 22.2%	113 20.9%	111 20.3%	343 21.1%
3-4 (limited self-care, completely disabled)	2 0.4%	2 0.4%	2 0.4%	6 0.4%
Missing	2 0.4%	0 0%	3 0.5%	5 0.3%
Creatinine clearance (Number) [Number]
>=60 ml/min	269 50.3%	280 51.8%	285 52.1%	834 51.4%
<60 ml/min	266 49.7%	261 48.2%	261 47.7%	788 48.6%
Missing	0 0%	0 0%	1 0.2%	1 0.1%
Beta2 Microglobulin (Number) [Number]
>5.5 mg/L	224 41.9%	224 41.4%	234 42.8%	682 42%
<=5.5 mg/L	309 57.8%	316 58.4%	312 57%	937 57.7%
Missing	2 0.4%	1 0.2%	1 0.2%	4 0.2%
Albumin (Number) [Number]
<=35 g/L	192 35.9%	209 38.6%	223 40.8%	624 38.4%
> 35 g/L	343 64.1%	331 61.2%	324 59.2%	998 61.5%
Missing	0 0%	1 0.2%	0 0%	1 0.1%
Lactic Dehydrogenase (Number) [Number]
<200 U/L	448 83.7%	442 81.7%	434 79.3%	1324 81.6%
>=200 U/L	86 16.1%	99 18.3%	112 20.5%	297 18.3%
Missing	1 0.2%	0 0%	1 0.2%	2 0.1%
Multiple Myeloma Subtype (Number) [Number]
Immunoglobulin A	138 25.8%	142 26.2%	123 22.5%	403 24.8%
Immunoglobulin A and Immunoglobulin G	7 1.3%	6 1.1%	8 1.5%	21 1.3%
Immunoglobulin A and Immunoglobulin M	0 0%	0 0%	1 0.2%	1 0.1%
Immunoglobulin D	4 0.7%	7 1.3%	4 0.7%	15 0.9%
Immunoglobulin G	334 62.4%	331 61.2%	350 64%	1015 62.5%
Immunoglobulin M	3 0.6%	1 0.2%	1 0.2%	5 0.3%
Not available (includes light-chain disease)	49 9.2%	54 10%	60 11%	163 10%
Cytogenetic Risk (Number) [Number]
Adverse Risk	170 31.8%	185 34.2%	189 34.6%	544 33.5%
Favorable Hyperdiploidy	112 20.9%	103 19%	102 18.6%	317 19.5%
Normal	148 27.7%	131 24.2%	141 25.8%	420 25.9%
Uncertain Risk	38 7.1%	56 10.4%	40 7.3%	134 8.3%
Not evaluable	34 6.4%	35 6.5%	44 8%	113 7%
Missing	33 6.2%	31 5.7%	31 5.7%	95 5.9%

Outcome Measures

1. Primary Outcome

Title	Kaplan-Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)
Description	PFS was calculated as the time from randomization to the first documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy without documented PD were censored on the date of their last response assessment, prior to receiving any other anti-myeloma therapy. Censoring rules for PFS: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any adequate response assessment; Progression documented between scheduled assessments; Death between adequate assessments; no progression; study discontinuations for reasons other than PD or death; new anti-myeloma started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's).
Time Frame	From date of randomization until the data cut-off date of 24 May 2013. Median follow-up time for all participants was 17.1 months.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population included all participants who were randomized, independent of whether they received study treatment or not.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (95% Confidence Interval) [months]	25.5	20.7	21.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00006
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.70349
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

2. Primary Outcome

Title	Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator At the Time of Final Analysis
Description	PFS was calculated as the time from randomization to the first documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy without documented PD were censored on the date of their last response assessment, prior to receiving any other anti-myeloma therapy. Censoring rules for PFS: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any adequate response assessment; Progression documented between scheduled assessments; Death between adequate assessments; no progression; study discontinuations for reasons other than PD or death; new anti-myeloma started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's).
Time Frame	From date of randomization to date of data cut-off date of 21 January 2016; median follow-up for all participants was 17.7 months

Outcome Measure Data

Analysis Population Description

The intent to treat population included all participants who were randomized, independent of whether they received study treatment or not.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (95% Confidence Interval) [months]	26.0	21.0	21.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.91161
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

3. Secondary Outcome

Title	Kaplan Meier Estimates of Overall Survival at the Time of Final Analysis (OS)
Description	Overall survival was defined as the time between randomization and death. Participants, who died, regardless of the cause of death, were considered to have had an event. All participants who were lost to follow-up prior to the end of the trial or who were withdrawn from the trial were censored at the time of last contact. Participants who were still being treated were censored at the last available date the participant was known to be alive.
Time Frame	From date of randomization to date of data cut-off date of 21 January 2016; median follow-up for all participants was 48.3 months

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized, independent of whether they received study treatment or not.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (95% Confidence Interval) [months]	59.1	62.3	49.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00234
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.82903
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00119
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.66 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

4. Secondary Outcome

Title	Percentage of Participants With an Objective Response Based on IRAC Review
Description	Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population includes all participants who were randomized, independent of whether they received study treatment or not.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Number [percentage of participants]	75.1 14%	73.4 13.6%	62.3 11.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; 1.41 to 2.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.53065
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00010
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.67
	Confidence Interval	(2-Sided) 95%; 1.29 to 2.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With an Objective Response Based on Investigator Assessment at Time of Final Analysis
Description	Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined s: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population includes all participants who were randomized, independent of whether they received study treatment or not.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Number [percentage of participants]	80.7 15.1%	78.6 14.5%	67.5 12.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; 1.53 to 2.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.40500
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00004
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 1.35 to 2.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Kaplan Meier Estimates of Duration of Myeloma Response as Determined by the IRAC
Description	Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median follow-up for responders was 20.1 months

Outcome Measure Data

Analysis Population Description

Study participants with at least a PR

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	402	397	341
Median (95% Confidence Interval) [months]	35.0	22.1	22.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on unstratified Cox proportional hazards model.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on unstratified Cox proportional hazards model.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.76740
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on unstratified Cox proportional hazards model.

7. Secondary Outcome

Title	Kaplan Meier Estimates of Duration of Myeloma Response as Determined by an Investigator Assessment at Time of Final Analysis
Description	Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first.
Time Frame	Disease response was assessed every 28 days until end of treatment; data cut-off date of 21 January 2016; median follow-up for responders was 19.9 months

Outcome Measure Data

Analysis Population Description

Study participants with at least a PR

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	432	425	369
Median (95% Confidence Interval) [months]	31.5	21.5	22.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.99537
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

8. Secondary Outcome

Title	Time to First Response Based on the Review by the IRAC
Description	The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

Participants who had at least a PR.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	402	397	341
Median (Full Range) [months]	1.8	1.8	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.46672
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Time to First Response Based on the Investigator Assessment at the Time of Final Analysis
Description	The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria assessed by the investigator.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

Outcome Measure Data

Analysis Population Description

Participants who had at least a PR.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	430	425	368
Median (Full Range) [months]	1.8	1.8	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.46987
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Kaplan Meier Estimates of Time to Treatment Failure (TTF)
Description	TTF is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by IRAC based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT) or death.
Time Frame	From date of randomization until the data cut-off of 24 May 2013; median follow-up for all participants was 16.1 months.

Outcome Measure Data

Analysis Population Description

ITT population includes participants who were randomized, independent of whether they received study treatment or not

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (95% Confidence Interval) [months]	16.9	17.2	14.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00012
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.68 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00187
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.71 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.45973
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

11. Secondary Outcome

Title	Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis
Description	TTF is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by the investigators assessment based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT) or death.
Time Frame	From date of randomization until the data cut-off date of 21 January 2016; median follow up for all participants was 16.1 months.

Outcome Measure Data

Analysis Population Description

ITT population includes participants who were randomized, independent of whether they received study treatment or not

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (95% Confidence Interval) [months]	16.9	17.2	14.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00002
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00126
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.72 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.27704
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

12. Secondary Outcome

Title	Kaplan Meier Estimates for Time to Second-line Anti-myeloma Treatment (AMT)
Description	Time to second-line anti-myeloma therapy was defined as time from randomization to the start of another non-protocol anti-myeloma therapy.
Time Frame	From date of randomization until the data cut-off of 24 May 2013; median follow-up for all participants was 23.0 months

Outcome Measure Data

Analysis Population Description

ITT population includes all participants who were randomized, independent of whether they received study treatment or not

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (95% Confidence Interval) [months]	39.1	28.5	26.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.56 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00067
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.63 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.12333
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a stratified Cox proportional hazards model

13. Secondary Outcome

Title	Kaplan Meier Estimates of Time to Second Line Therapy AMT at the Time of Final Analysis
Description	Time to second-line anti-myeloma therapy is defined as time from randomization to the start of another non-protocol anti-myeloma therapy. Those who do not receive another anti-myeloma therapy were censored at the last assessment or follow-up visit known to have received no new therapy.
Time Frame	From date of randomization until the data cut-off of date 21 January 2016; median follow-up for all participants was 23.0 months

Outcome Measure Data

Analysis Population Description

ITT population includes all participants who were randomized, independent of whether they received study treatment or not.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	535	541	547
Median (Full Range) [months]	36.7	28.5	26.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.54 to .73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on unstratified Cox proportional hazards model.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00001
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on unstratified Cox proportional hazards model.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.05821
	Comments	The p-value is based on the unstratified log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on unstratified Cox proportional hazards model.

14. Secondary Outcome

Title	Percentage of Participants With an Objective Response After Second-line Anti-myeloma Treatment at the Time of Final Analysis
Description	Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined s: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment; data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population; Participants with second line AMT.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	299	377	381
Number [percentage of participants]	46.2 8.6%	53.1 9.8%	45.7 8.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.93824
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.08836
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.04974
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants With a Myeloma Response by Adverse Risk Cytogenetic Risk Category Based on IRAC Review.
Description	Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population with Cytogenetic risk of Adverse Risk

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	170	185	189
Number [Percentage of participants]	70.0 13.1%	69.7 12.9%	58.2 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.02134
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95%; 1.08 to 2.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	1.00000
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.02374
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 95%; 1.08 to 2.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Percentage of Participants With a Myeloma Response by Favorable Hyperdiploidy Risk Cytogenetic Risk Category Based on IRAC Review
Description	Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population with a Cytogenetic Risk of Favorable Hyperploidy

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	112	103	102
Number [percentage of participants]	80.4 15%	81.6 15.1%	70.6 12.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.11152
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.70
	Confidence Interval	(2-Sided) 95%; 0.91 to 3.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.86336
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.07321
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.84
	Confidence Interval	(2-Sided) 95%; 0.96 to 3.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Percentage of Participants With a Myeloma Response by Normal Risk Cytogenetic Risk Category Based on IRAC Review
Description	Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population with a cytogenetic risk of normal

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	148	131	141
Number [percentage of particpants]	80.4	74.8	61.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.00043
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.62
	Confidence Interval	(2-Sided) 95%; 1.55 to 4.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.31274
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 0.78 to 2.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.01936
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.90
	Confidence Interval	(2-Sided) 95%; 1.13 to 3.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Percentage of Participants With a Myeloma Response by Uncertain Risk Cytogenetic Risk Category Based on IRAC Review
Description	Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR based on the IRAC Review; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPRis serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas.
Time Frame	Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

ITT population with a Cytogenetic Risk of Uncertain Risk

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	38	56	40
Number [percentage of participants]	60.5 11.3%	76.8 14.2%	57.5 10.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.82128
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.46 to 2.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Low-Dose Dexamethasone (Rd), Lenalidomide and Dexamethasone Rd18
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.11041
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.19 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone Rd18, Melphalan + Prednisone + Thalidomide (MPT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.07302
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.44
	Confidence Interval	(2-Sided) 95%; 1.01 to 5.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	508	507	508
Month 1	0.4 (23.98)	-1.3 (23.93)	1.0 (23.68)
Month 3	4.8 (24.15)	4.7 (25.15)	4.3 (26.04)
Month 6	5.9 (25.93)	5.4 (23.88)	6.1 (25.98)
Month 12	4.8 (26.42)	3.2 (25.38)	6.5 (25.90)
Month 18	6.4 (28.02)	5.7 (24.86)	4.8 (27.05)
Study discontinuation	-0.1 (27.07)	5.0 (27.33)	0.3 (28.07)

20. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	511	514	509
Month 1	-1.7 (21.11)	-1.4 (19.56)	-0.9 (21.28)
Month 3	3.4 (23.33)	4.7 (22.94)	2.2 (23.68)
Month 6	4.7 (25.09)	7.6 (22.85)	5.3 (24.52)
Month 12	5.0 (25.65)	7.4 (23.40)	6.9 (27.22)
Month 18	6.9 (26.71)	6.8 (23.58)	8.3 (27.10)
Discontinuation Visit	-0.1 (29.70)	3.0 (27.32)	-0.1 (27.58)

21. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Role Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	509	508	508
Month 1	-2.7 (29.94)	-4.6 (28.20)	-2.4 (30.48)
Month 3	2.4 (33.32)	6.3 (32.43)	4.1 (34.23)
Month 6	6.3 (35.44)	8.6 (32.42)	8.2 (36.09)
Month 12	7.8 (36.60)	9.4 (34.15)	11.8 (38.94)
Month 18	8.0 (35.34)	9.1 (34.35)	14.5 (39.03)
Discontinuation Visit	-0.3 (39.58)	3.8 (36.34)	-1.0 (38.41)

22. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	509	510	510
Month 1	0.6 (22.13)	0.1 (20.73)	1.0 (21.52)
Month 3	3.8 (22.29)	3.9 (22.11)	2.1 (22.27)
Month 6	4.6 (24.36)	5.8 (22.39)	5.5 (22.55)
Month 12	4.6 (24.08)	4.9 (22.23)	5.1 (22.37)
Month 18	5.8 (25.61)	3.1 (23.31)	5.1 (22.99)
Discontinuation Visit	2.6 (24.30)	3.7 (23.77)	-0.0 (24.72)

23. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Cognitive Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Time Frame	Cycle 1 Day 1, (Baseline) then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	509	510	510
Month 1	-1.2 (21.73)	-1.7 (19.08)	-1.8 (24.07)
Month 3	-0.7 (22.89)	1.8 (20.94)	-1.5 (24.02)
Month 6	-0.9 (22.57)	0.9 (19.77)	-0.3 (23.55)
Month 12	-1.6 (25.05)	-1.2 (20.19)	-0.6 (22.97)
Month 18	-2.2 (25.61)	-2.8 (20.97)	-0.7 (23.99)
Discontinuation Visit	-4.9 (27.57)	-2.6 (22.34)	-7.1 (25.15)

24. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Social Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	505	503	503
Month 1	-4.3 (29.10)	-2.2 (27.44)	-1.4 (30.52)
Month 3	0.7 (29.36)	2.0 (30.93)	2.4 (30.70)
Month 6	4.0 (32.48)	5.2 (28.50)	3.4 (35.24)
Month 12	2.9 (34.96)	3.8 (32.29)	5.8 (33.68)
Month 18	4.2 (34.99)	3.2 (31.67)	6.0 (35.20)
Discontinuation Visit	-1.2 (33.50)	2.7 (33.37)	-3.5 (33.20)

25. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Fatigue Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	511	514	512
Month 1	2.6 (25.32)	4.4 (24.03)	2.8 (25.44)
Month 3	-2.5 (28.15)	-3.4 (25.16)	-1.8 (28.53)
Month 6	-3.7 (28.54)	-5.9 (26.37)	-4.5 (29.09)
Month 12	-4.3 (29.47)	-2.3 (26.63)	-3.9 (29.56)
Month 18	-3.1 (29.82)	0.1 (29.12)	-4.3 (30.05)
Discontinuation Visit	0.3 (29.75)	-1.6 (29.11)	2.7 (30.15)

26. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Pain Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Pain Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	511	514	512
Month 1	-5.4 (31.89)	-4.4 (30.70)	-7.8 (30.93)
Month 3	-13.4 (34.28)	-13.1 (32.32)	-12.1 (31.98)
Month 6	-14.4 (35.64)	-16.1 (33.44)	-13.4 (34.45)
Month 12	-14.0 (36.05)	-14.7 (32.34)	-14.3 (32.85)
Month 18	-14.4 (35.03)	-12.4 (35.28)	-14.7 (32.81)
Discontinuation Visit	-8.0 (39.37)	-7.9 (37.65)	-6.0 (37.09)

27. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Nausea/Vomiting Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	511	513	512
Month 1	1.8 (20.05)	-0.5 (23.19)	4.0 (22.91)
Month 3	-1.1 (19.42)	-2.5 (21.92)	-1.2 (19.89)
Month 6	-1.3 (18.53)	-4.0 (21.52)	-3.9 (19.57)
Month 12	-2.2 (17.16)	-3.6 (18.86)	-3.9 (19.09)
Month 18	-2.3 (19.20)	-2.7 (18.92)	-3.9 (19.44)
Discontinuation Visit	0.4 (21.43)	-4.2 (24.37)	1.0 (21.46)

28. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnoea Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population includes all participants with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	509	508	506
Month 1	0.9 (30.87)	3.6 (29.85)	4.2 (32.04)
Month 3	-0.8 (31.87)	-1.9 (29.45)	2.0 (32.49)
Month 6	-2.3 (33.12)	-2.9 (29.66)	0.1 (30.29)
Month 12	-3.5 (30.97)	-1.6 (29.23)	-1.6 (32.76)
Month 18	-1.8 (32.73)	2.9 (28.33)	0.4 (32.68)
Discontinuation Visit	-1.0 (37.42)	0.8 (31.01)	7.8 (33.72)

29. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Insomnia Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Insomnia Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	510	513	511
Month 1	2.1 (33.34)	3.2 (34.32)	-10.5 (30.47)
Month 3	0.2 (35.11)	-1.3 (33.54)	-8.9 (35.28)
Month 6	-1.2 (34.84)	-1.9 (31.43)	-11.6 (32.96)
Month 12	-1.0 (34.78)	1.1 (32.47)	-9.6 (31.00)
Month 18	-0.5 (37.11)	1.4 (35.72)	-6.0 (34.42)
Discontinuation Visit	-5.2 (36.47)	-1.6 (31.27)	-4.5 (36.98)

30. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Appetite Loss Scale is scored between 0 and 100, with a high score indicating a higher level of appetite loss. Negative change from Baseline values indicate improvement in appetite and positive values indicate worsening of appetite.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	509	512	510
Month 1	1.3 (33.46)	2.9 (31.87)	1.0 (32.35)
Month 3	-5.9 (38.34)	-3.3 (35.25)	-6.2 (35.03)
Month 6	-9.8 (40.02)	-8.6 (33.98)	-13.5 (35.98)
Month 12	-7.3 (37.07)	-6.4 (35.30)	-10.5 (34.16)
Month 18	-8.1 (35.97)	-5.1 (33.29)	-12.2 (31.88)
Discontinuation Visit	-1.0 (36.77)	-7.5 (37.49)	-2.6 (37.18)

31. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Constipation Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Constipation Scale is scored between 0 and 100, with a high score indicating a higher level of constipation. Negative change from Baseline values indicate improvement in constipation and positive values indicate worsening of constipation.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	508	511	510
Month 1	8.3 (36.74)	6.3 (36.18)	18.4 (41.23)
Month 3	1.8 (37.53)	0.0 (37.02)	13.9 (39.30)
Month 6	-2.4 (37.51)	-5.1 (37.39)	6.8 (40.41)
Month 12	-2.4 (38.79)	-5.2 (38.09)	3.7 (38.28)
Month 18	-4.5 (35.42)	-5.9 (36.65)	0.0 (37.06)
Discontinuation Visit	-7.9 (39.98)	-7.5 (39.20)	-2.2 (38.86)

32. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Diarrhea Scale is scored between 0 and 100, with a high score indicating a higher level of diarrhea. Negative change from Baseline values indicate improvement in diarrhea and positive values indicate worsening of diarrhea.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	508	509	510
Month 1	3.8 (25.53)	2.3 (24.94)	-0.6 (18.79)
Month 3	3.7 (24.99)	3.4 (27.27)	-2.4 (18.61)
Month 6	8.2 (28.36)	6.0 (27.95)	-2.2 (21.19)
Month 12	11.8 (31.35)	9.1 (28.74)	-2.5 (17.26)
Month 18	14.8 (31.20)	10.9 (30.96)	-1.7 (17.46)
Discontinuation Visit	10.8 (29.56)	6.4 (31.38)	-0.5 (19.39)

33. Secondary Outcome

Title	Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain
Description	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Financial Difficulties Scale is scored between 0 and 100, with a high score indicating a higher level of financial difficulties. Negative change from Baseline values indicate improvement in financial difficulties and positive values indicate worsening of financial difficulties.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	501	504	502
Month 1	2.1 (21.43)	-0.3 (20.59)	0.5 (22.98)
Month 3	1.9 (23.09)	-0.4 (21.88)	1.9 (21.48)
Month 6	1.4 (22.92)	-0.3 (21.24)	0.7 (24.57)
Month 12	0.4 (23.99)	1.6 (23.28)	1.1 (23.16)
Month 18	2.0 (22.23)	1.8 (23.30)	0.4 (21.20)
Discontinuation Visit	1.9 (27.19)	0.5 (23.84)	5.0 (24.82)

34. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale
Description	EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates more severe disease symptom(s).
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	510	512	511
Month 1	-4.0 (18.75)	-4.1 (19.37)	-4.4 (19.04)
Month 3	-9.1 (21.66)	-10.0 (19.97)	-7.0 (20.43)
Month 6	-8.8 (20.89)	-9.9 (20.94)	-7.9 (21.94)
Month 12	-7.8 (21.74)	-8.7 (20.29)	-6.5 (21.58)
Month 18	-8.7 (23.50)	-6.2 (23.30)	-7.9 (21.26)
Discontinuation Visit	-3.5 (24.82)	-4.5 (24.90)	-3.7 (23.54)

35. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale
Description	EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score represents a more severe overall side effect of treatment.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	509	511	510
Month 1	2.5 (13.72)	4.0 (14.89)	5.6 (15.00)
Month 3	1.0 (15.23)	1.2 (14.67)	3.5 (15.40)
Month 6	1.7 (15.58)	-0.4 (14.39)	2.9 (17.28)
Month 12	1.9 (14.49)	1.2 (16.20)	4.7 (17.17)
Month 18	2.2 (15.63)	2.3 (17.36)	4.3 (16.37)
Discontinuation Visit	0.6 (15.85)	-1.0 (15.81)	3.8 (16.52)

36. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale
Description	EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the future perspective scale, a higher score indicates a better perspective of the future.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	504	508	509
Month 1	4.7 (22.17)	3.9 (20.94)	3.3 (23.20)
Month 3	8.5 (23.28)	9.2 (22.95)	6.3 (25.06)
Month 6	9.8 (23.67)	12.3 (24.84)	8.0 (25.26)
Month 12	10.8 (21.90)	12.1 (24.41)	10.0 (26.30)
Month 18	12.7 (23.96)	11.7 (24.76)	9.5 (21.75)
Discontinuation Visit	5.8 (25.91)	8.8 (26.71)	3.2 (27.13)

37. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale
Description	EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the body image scale, a higher score indicates a better body image.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	492	498	504
Month 1	-4.5 (29.44)	-1.5 (27.19)	-1.6 (29.97)
Month 3	-1.7 (27.54)	0.8 (26.23)	-3.0 (29.38)
Month 6	-1.4 (27.84)	1.5 (29.72)	-2.8 (33.07)
Month 12	-1.4 (29.60)	-0.4 (31.64)	-2.6 (31.96)
Month 18	-2.3 (28.09)	-0.3 (31.04)	-1.1 (33.60)
Discontinuation Visit	-5.6 (34.29)	1.8 (30.66)	-5.6 (33.73)

38. Secondary Outcome

Title	Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Health Utility Index Score
Description	EQ-5D is a self-administered questionnaire that assesses health-related quality of life. The EQ-5D descriptive health profile comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 levels of response: No problem (1), some problems (2), and extreme problems (3). A unique EQ-5D health state is defined by combining one level from each of the five dimensions into a single utility index score. EQ-5D index values range from -0.59 to 1.00 where higher EQ-5D scores represent better health status. A positive change from baseline score indicates improvement in health status and better health state.
Time Frame	Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

Outcome Measure Data

Analysis Population Description

ITT population with available data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	490	492	490
Month 1	0.0 (0.29)	-0.0 (0.31)	0.0 (0.28)
Month 3	0.1 (0.33)	0.1 (0.32)	0.1 (0.32)
Month 6	0.1 (0.32)	0.1 (0.31)	0.1 (0.34)
Month 12	0.1 (0.33)	0.1 (0.31)	0.1 (0.35)
Month 18	0.1 (0.36)	0.1 (0.32)	0.1 (0.35)
Discontinuation Visit	0.0 (0.40)	0.0 (0.35)	0.0 (0.39)

39. Secondary Outcome

Title	Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year
Description	HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. The rate of inpatient hospitalizations per patient year was calculated as the total number of hospitalizations divided by the total number of patient-years followed in the study period. Patient-years (PY) were calculated as the duration from baseline to last available HRQL assessment for each patient.
Time Frame	Day 1 (randomization) up to last visit completed 25 July 2016

Outcome Measure Data

Analysis Population Description

Healthcare Resource Utilization not analyzed.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	0	0	0

40. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) During the Active Treatment Phase
Description	A TEAE is any AE occurring or worsening on or after the first treatment of any study drug, and within 30 days after the last dose of the last study drug. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event.
Time Frame	From first dose of study drug through 28 days following the discontinuation visit from active treatment phase; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose treatment dose of treatment in any arm

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	532	540	541
≥ 1 adverse event (AE)	529 98.9%	536 99.1%	539 98.5%
≥ 1 grade (Gr) 3 or 4 AE	453 84.7%	433 80%	480 87.8%
≥ 1 grade (Gr) 5 AE	50 9.3%	36 6.7%	38 6.9%
≥ 1 serious adverse event (SAE)	359 67.1%	308 56.9%	270 49.4%
≥ 1 AE related to Lenalidomide/Dex/Mel/Pred/Thal	506 94.6%	501 92.6%	527 96.3%
≥ 1 AE related to Lenalidomide	482 90.1%	481 88.9%	0 0%
≥ 1 AE related to dexamethasone	429 80.2%	410 75.8%	0 0%
≥ 1 AE related to melphalan	0 0%	0 0%	441 80.6%
≥ 1 AE related to prednisone	0 0%	0 0%	326 59.6%
≥ 1 AE related to thalidomide	0 0%	0 0%	493 90.1%
≥1 AE related to Lenalidomide/Dex or Mel/Pred/Thal	269 50.3%	269 49.7%	145 26.5%
≥ 1 Gr 3 or 4 AE related to Len/Dex/Mel/Pred/Thal	373 69.7%	326 60.3%	423 77.3%
≥ 1 grade 3 or 4 AE related to Lenalidomide	342 63.9%	290 53.6%	0 0%
≥ 1 grade 3 or 4 AE related to dexamethasone	229 42.8%	177 32.7%	0 0%
≥ 1 grade 3 or 4 AE related to melphalan	0 0%	0 0%	307 56.1%
≥ 1 grade 3 or 4 AE related to prednisone	0 0%	0 0%	118 21.6%
≥ 1 grade 3 or 4 AE related to Thalidomide	0 0%	0 0%	316 57.8%
≥1Gr 3 or 4 AE related to Len/Dex or Mel/Pred/Thal	131 24.5%	104 19.2%	49 9%
≥ 1 Grade 5 AE related to Len/Dex/Mel/Pred/Thal	17 3.2%	11 2%	10 1.8%
≥ 1 Grade 5 AE related to Lenalidomide	12 2.2%	9 1.7%	0 0%
≥ 1 Grade 5 AE related to Dexamethasone	16 3%	7 1.3%	0 0%
≥ 1 Grade 5 AE related to melphalan	0 0%	0 0%	6 1.1%
≥ 1 Grade 5 AE related to prednisone	0 0%	0 0%	5 0.9%
≥ 1 Grade 5 AE related to Thalidomide	0 0%	0 0%	5 0.9%
≥1 Grade 5 AE related to Len/Dex or Mel/Pred/Thal	11 2.1%	5 0.9%	2 0.4%
≥1 SAE related to Len/Dex/Mel/Pred/Thal	195 36.4%	158 29.2%	142 26%
≥1 SAE related to Lenalidomide	165 30.8%	130 24%	0 0%
≥1 SAE related to dexamethasone	130 24.3%	97 17.9%	0 0%
≥1 SAE related to melphalan	0 0%	0 0%	75 13.7%
≥1 SAE related to prednisone	0 0%	0 0%	62 11.3%
≥1 SAE related to thalidomide	0 0%	0 0%	94 17.2%
≥1 SAE related to Len/Dex or Mel/Pred/Thal	95 17.8%	64 11.8%	27 4.9%
≥1AE leading to Len/Dex/Mel/Pred/Thal Withdrawal	157 29.3%	109 20.1%	153 28%
≥1 AE leading to Lenalidomide withdrawal	109 20.4%	93 17.2%	0 0%
≥1 AE leading to dexamethasone withdrawal	152 28.4%	104 19.2%	0 0%
≥1 AE leading to melphalan withdrawal	0 0%	0 0%	83 15.2%
≥1 AE leading to prednisone withdrawal	0 0%	0 0%	78 14.3%
≥1 AE leading to Thalidomide withdrawal	0 0%	0 0%	146 26.7%
≥1AE leading to Len/DexOR Mel/Pred/Thal Withdrawal	96 17.9%	84 15.5%	71 13%
≥1AE leading to Len/Dex/Mel/Pred/Thal reduction	279 52.1%	214 39.6%	348 63.6%
≥1 AE leading to Lenalidomide reduction	203 37.9%	155 28.7%	0 0%
≥1 AE leading to dexamethasone reduction	170 31.8%	118 21.8%	0 0%
≥1 AE leading to melphalan reduction	0 0%	0 0%	199 36.4%
≥1 AE leading to prednisone reduction	0 0%	0 0%	47 8.6%
≥1 AE leading to thalidomide reduction	0 0%	0 0%	254 46.4%
≥1AE leading to Len/Dex or Mel/Pred/Thal reduction	30 5.6%	20 3.7%	2 0.4%
≥1 AE leading to Rd or MPT interruption	368 68.8%	321 59.3%	419 76.6%
≥1 AE leading to Lenalidomide interruption	353 66%	301 55.6%	0 0%
≥1 AE leading to dexamethasone interruption	319 59.6%	280 51.8%	0 0%
≥1 AE leading to melphalan interruption	0 0%	0 0%	328 60%
≥1 AE leading to prednisone interruption	0 0%	0 0%	324 59.2%
≥1 AE leading to Thalidomide interruption	0 0%	0 0%	388 70.9%
≥1 AE leading to Len and Dex or MPT interruption	290 54.2%	241 44.5%	249 45.5%

41. Secondary Outcome

Title	Shift From Baseline to Most Extreme Postbaseline Value in Creatinine Clearance (CrCl) During the Active Treatment Phase
Description	Renal function was assessed for participants from baseline to the most extreme value in creatinine clearance calculated using the Cockcroft-Gault estimation.
Time Frame	Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

Safety Population with baseline and postbaseline CrCl data.

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	494	506	484
CrCl< 30 mL/min to CrCl< 30 mL/min	15 2.8%	17 3.1%	19 3.5%
CrCl < 30 mL/min to CrCl ≥ 30 but < 50 mL/min	18 3.4%	14 2.6%	19 3.5%
CrCl < 30 mL/min to CrCl ≥ 50 but < 80 mL/min	7 1.3%	8 1.5%	5 0.9%
CrCl< 30 mL/min to ≥ 80 mL/min	2 0.4%	2 0.4%	0 0%
CrCl≥ 30 but < 50 mL/min to < 30 mL/min	1 0.2%	2 0.4%	0 0%
CrCl ≥ 30 but < 50 mL/min to CrCl ≥ 30 but < 50 mL	37 6.9%	41 7.6%	41 7.5%
CrCl ≥ 30 but < 50 mL/min to CrCl ≥ 50 but < 80 mL	67 12.5%	55 10.2%	65 11.9%
CrCl ≥ 30 but < 50 mL/min to ≥ 80 mL/min	9 1.7%	12 2.2%	2 0.4%
CrCl ≥ 50 but < 80 mL to CrCl< 30 mL/min	0 0%	0 0%	0 0%
CrCl ≥ 50 but < 80 mL to CrCl ≥ 30 but < 50 mL/min	4 0.7%	1 0.2%	4 0.7%
CrCl ≥ 50 but < 80 mL to CrCl ≥ 50 but < 80 mL/min	112 20.9%	130 24%	102 18.6%
CrCl ≥ 50 but < 80 mL to ≥ 80 mL/min	107 20%	99 18.3%	97 17.7%
CrCl ≥ 80 mL/min to CrCl< 30 mL/min	0 0%	1 0.2%	0 0%
CrCl ≥ 80 mL/min to CrCl ≥ 30 but < 50 mL/min	0 0%	0 0%	0 0%
CrCl ≥ 80 mL/min to CrCl ≥ 50 but < 80 mL/min	6 1.1%	10 1.8%	9 1.6%
CrCl ≥ 80 mL/min to CrCl ≥ 80 mL/min	109 20.4%	114 21.1%	121 22.1%

42. Secondary Outcome

Title	Shift From Baseline to Most Extreme Postbaseline Value in Absolute Neutrophil Count During the Active Treatment Phase
Description	Neutrophil counts was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale.
Time Frame	Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

Safety Population; includes participants with baseline and postbaseline absolute neutrophil laboratory test grade information

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	525	534	526
Normal Baseline Grade to Normal Postbaseline Grade	103 19.3%	133 24.6%	37 6.8%
Normal Baseline Grade to Grade 1 postbaseline	96 17.9%	85 15.7%	79 14.4%
Normal Baseline Grade to Grade 2 postbaseline	121 22.6%	109 20.1%	128 23.4%
Normal Baseline Grade to Grade 3 postbaseline	70 13.1%	71 13.1%	141 25.8%
Normal Baseline Grade to Grade 4 postbaseline	21 3.9%	30 5.5%	45 8.2%
Grade 1 Baseline to Normal postbaseline	7 1.3%	6 1.1%	2 0.4%
Grade1 Baseline to Grade 1 postbaseline	8 1.5%	11 2%	2 0.4%
Grade 1 Baseline to Grade 2 postbaseline	17 3.2%	15 2.8%	11 2%
Grade 1 Baseline to Grade 3 postbaseline	25 4.7%	30 5.5%	20 3.7%
Grade 1 Baseline to Grade 4 postbaseline	9 1.7%	4 0.7%	21 3.8%
Grade 2 Baseline to normal postbaseline	1 0.2%	0 0%	0 0%
Grade 2 Baseline to Grade 1 postbaseline	1 0.2%	1 0.2%	1 0.2%
Grade 2 Baseline to Grade 2 postbaseline	14 2.6%	11 2%	7 1.3%
Grade 2 Baseline to Grade 3 postbaseline	18 3.4%	18 3.3%	21 3.8%
Grade 2 Baseline to Grade 4 postbaseline	9 1.7%	5 0.9%	10 1.8%
Grade 3 Baseline to Normal postbaseline	0 0%	0 0%	0 0%
Grade 3 Baseline to Grade 1 postbaseline	0 0%	0 0%	0 0%
Grade 3 Baseline to Grade 2 postbaseline	2 0.4%	1 0.2%	0 0%
Grade 3 Baseline to Grade 3 postbaseline	2 0.4%	2 0.4%	0 0%
Grade3 Baseline to Grade 4 postbaseline	0 0%	2 0.4%	1 0.2%
Grade 4 Baseline to Normal postbaseline Grade	0 0%	0 0%	0 0%
Grade 4 Baseline to Grade 1 postbaseline Grade	1 0.2%	0 0%	0 0%
Grade 4 Baseline to Grade 2 postbaseline	0 0%	0 0%	0 0%
Grade 4 Baseline Grade to Grade 3 postbaseline	0 0%	0 0%	0 0%
Grade 4 Baseline to Grade 4 postbaseline	0 0%	0 0%	0 0%

43. Secondary Outcome

Title	Shift From Baseline to Most Extreme Postbaseline Value in Hemoglobin During the Active Treatment Phase
Description	Hemoglobin was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale.
Time Frame	Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

Safety Population; Includes participants with baseline and postbaseline hemoglobin laboratory test grade information

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	527	535	526
Normal Baseline Grade to Normal Postbaseline Grade	6 1.1%	10 1.8%	9 1.6%
Normal Baseline Grade to Grade 1 postbaseline	39 7.3%	30 5.5%	25 4.6%
Normal Baseline Grade to Grade 2 postbaseline	8 1.5%	8 1.5%	4 0.7%
Normal Baseline Grade to Grade 3 postbaseline	0 0%	1 0.2%	1 0.2%
Normal Baseline Grade to Grade 4 postbaseline	0 0%	0 0%	0 0%
Grade 1 Baseline to Normal postbaseline	0 0%	0 0%	0 0%
Grade 1 Baseline to Grade 1 postbaseline	106 19.8%	126 23.3%	110 20.1%
Grade1 Baseline to Grade 2 postbaseline	128 23.9%	123 22.7%	123 22.5%
Grade 1 Baseline to Grade 3 postbaseline	25 4.7%	17 3.1%	20 3.7%
Grade 1 Baseline to Grade 4 postbaseline	2 0.4%	5 0.9%	4 0.7%
Grade 2 Baseline to normal postbaseline	0 0%	0 0%	0 0%
Grade 2 Baseline to Grade 1 postbaseline	8 1.5%	12 2.2%	14 2.6%
Grade 2 Baseline to Grade 2 postbaseline	125 23.4%	135 25%	133 24.3%
Grade 2 Baseline to Grade 3 postbaseline	48 9%	41 7.6%	47 8.6%
Grade 2 Baseline to Grade 4 postbaseline	4 0.7%	9 1.7%	11 2%
Grade 3 Baseline to Normal postbaseline	0 0%	0 0%	0 0%
Grade 3 Baseline to Grade 1 postbaseline	0 0%	1 0.2%	0 0%
Grade 3 Baseline to Grade 2 postbaseline	12 2.2%	4 0.7%	10 1.8%
Grade 3 Baseline to Grade 3 postbaseline	10 1.9%	8 1.5%	10 1.8%
Grade 3 Baseline to Grade 4 postbaseline	5 0.9%	3 0.6%	2 0.4%
Grade 4 Baseline to Normal postbaseline	0 0%	0 0%	0 0%
Grade 4 Baseline to Grade 1 postbaseline	0 0%	0 0%	0 0%
Grade 4 Baseline to Grade 2 postbaseline	0 0%	0 0%	1 0.2%
Grade 4 Baseline to Grade 3 postbaseline	0 0%	1 0.2%	0 0%
Grade 4 Baseline to Grade 4 postbaseline	1 0.2%	1 0.2%	2 0.4%

44. Secondary Outcome

Title	Shift From Baseline to Most Extreme Postbaseline Value in Platelet Count During the Active Treatment Phase.
Description	Improvement in platelets was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale.
Time Frame	Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

Outcome Measure Data

Analysis Population Description

Safety population; Includes participants with baseline and postbaseline platelet laboratory test grade information

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	527	535	526
Normal Baseline Grade to Normal Postbaseline Grade	197 36.8%	197 36.4%	165 30.2%
Normal Baseline Grade to Grade 1 postbaseline	216 40.4%	211 39%	208 38%
Normal Baseline Grade to Grade 2 postbaseline	24 4.5%	30 5.5%	27 4.9%
Normal Baseline Grade to Grade 3 postbaseline	15 2.8%	12 2.2%	31 5.7%
Normal Baseline Grade to Grade 4 postbaseline	4 0.7%	5 0.9%	11 2%
Grade1 Baseline to Normal postbaseline Grade	1 0.2%	3 0.6%	6 1.1%
Grade 1 Baseline to Grade 1 postbaseline	34 6.4%	38 7%	51 9.3%
Grade 1 Baseline to Grade 2 postbaseline	15 2.8%	19 3.5%	7 1.3%
Grade 1 Baseline to Grade 3 postbaseline	10 1.9%	12 2.2%	10 1.8%
Grade 1 Baseline to Grade 4 postbaseline	2 0.4%	1 0.2%	1 0.2%
Grade 2 Baseline to normal postbaseline Grade	0 0%	0 0%	0 0%
Grade 2 Baseline to Grade 1 postbaseline	0 0%	1 0.2%	2 0.4%
Grade 2 Baseline to Grade 2 postbaseline	3 0.6%	3 0.6%	1 0.2%
Grade 2 Baseline to Grade 3 postbaseline	3 0.6%	2 0.4%	2 0.4%
Grade 2 Baseline to Grade 4 postbaseline	1 0.2%	0 0%	2 0.4%
Grade 3 Baseline to Normal postbaseline Grade	0 0%	0 0%	0 0%
Grade 3 Baseline to Grade 1 postbaseline	0 0%	0 0%	0 0%
Grade 3 Baseline to Grade 2 postbaseline	0 0%	0 0%	1 0.2%
Grade 3 Baseline to Grade 3 postbaseline	0 0%	0 0%	1 0.2%
Grade 3 Baseline to Grade 4 postbaseline	2 0.4%	1 0.2%	0 0%

45. Secondary Outcome

Title	Improvement of Infection Rate by Observing the Historical Data Compared to the Clinical Data Base
Description	Improvement of infection rate by observing historical data compared to the data within clinical database as not analyzed.
Time Frame	From randomization to 24 May 2013

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.	Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.	Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
Measure Participants	0	0	0

Adverse Events

Time Frame	From the first dose of treatment to at least 28 days after discontinuation of active treatment for those not continuing in the PFS phase; median duration of treatment was 80.2 weeks in the Rd arm, 72.0 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
Arm/Group Title	Lenalidomide and Low-Dose Dexamethasone (Rd)		Lenalidomide and Dexamethasone (Rd18)		Melphalan + Prednisone + Thalidomide (MPT)
Arm/Group Description	Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.		Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity occurred. Those > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity.		Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity occurred.
All Cause Mortality
	Lenalidomide and Low-Dose Dexamethasone (Rd)		Lenalidomide and Dexamethasone (Rd18)		Melphalan + Prednisone + Thalidomide (MPT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lenalidomide and Low-Dose Dexamethasone (Rd)		Lenalidomide and Dexamethasone (Rd18)		Melphalan + Prednisone + Thalidomide (MPT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	378/532 (71.1%)		308/540 (57%)		270/541 (49.9%)
Blood and lymphatic system disorders
ANAEMIA	24/532 (4.5%)		15/540 (2.8%)		23/541 (4.3%)
ANAEMIA HAEMOLYTIC AUTOIMMUNE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
DISSEMINATED INTRAVASCULAR COAGULATION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
FEBRILE BONE MARROW APLASIA	0/532 (0%)		2/540 (0.4%)		1/541 (0.2%)
FEBRILE NEUTROPENIA	5/532 (0.9%)		8/540 (1.5%)		13/541 (2.4%)
HAEMOLYSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPERVISCOSITY SYNDROME	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPOCOAGULABLE STATE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
IDIOPATHIC THROMBOCYTOPENIC PURPURA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
LEUKOPENIA	0/532 (0%)		3/540 (0.6%)		4/541 (0.7%)
LYMPHADENITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LYMPHOPENIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
NEUTROPENIA	9/532 (1.7%)		5/540 (0.9%)		7/541 (1.3%)
PANCYTOPENIA	1/532 (0.2%)		2/540 (0.4%)		4/541 (0.7%)
THROMBOCYTOPENIA	5/532 (0.9%)		6/540 (1.1%)		10/541 (1.8%)
Cardiac disorders
ACUTE CORONARY SYNDROME	5/532 (0.9%)		0/540 (0%)		1/541 (0.2%)
ACUTE MYOCARDIAL INFARCTION	6/532 (1.1%)		1/540 (0.2%)		4/541 (0.7%)
ANGINA PECTORIS	7/532 (1.3%)		2/540 (0.4%)		0/541 (0%)
ANGINA UNSTABLE	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
ARRHYTHMIA	0/532 (0%)		2/540 (0.4%)		2/541 (0.4%)
ARRHYTHMIA SUPRAVENTRICULAR	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ARTERIOSCLEROSIS CORONARY ARTERY	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
ATRIAL FIBRILLATION	18/532 (3.4%)		12/540 (2.2%)		9/541 (1.7%)
ATRIAL FLUTTER	3/532 (0.6%)		2/540 (0.4%)		2/541 (0.4%)
ATRIAL THROMBOSIS	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
ATRIOVENTRICULAR BLOCK	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ATRIOVENTRICULAR BLOCK COMPLETE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
BRADYARRHYTHMIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
BRADYCARDIA	2/532 (0.4%)		2/540 (0.4%)		2/541 (0.4%)
CARDIAC AMYLOIDOSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
CARDIAC ARREST	5/532 (0.9%)		3/540 (0.6%)		1/541 (0.2%)
CARDIAC FAILURE	13/532 (2.4%)		11/540 (2%)		8/541 (1.5%)
CARDIAC FAILURE CONGESTIVE	7/532 (1.3%)		5/540 (0.9%)		5/541 (0.9%)
CARDIAC FLUTTER	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
CARDIO-RESPIRATORY ARREST	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
CARDIOGENIC SHOCK	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
CARDIOMYOPATHY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CARDIOPULMONARY FAILURE	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
CONGESTIVE CARDIOMYOPATHY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
COR PULMONALE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CORONARY ARTERY DISEASE	5/532 (0.9%)		0/540 (0%)		0/541 (0%)
CORONARY ARTERY INSUFFICIENCY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
CORONARY ARTERY STENOSIS	1/532 (0.2%)		1/540 (0.2%)		2/541 (0.4%)
DIASTOLIC DYSFUNCTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPERTENSIVE HEART DISEASE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LEFT VENTRICULAR DYSFUNCTION	1/532 (0.2%)		2/540 (0.4%)		0/541 (0%)
LEFT VENTRICULAR FAILURE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
MITRAL VALVE INCOMPETENCE	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
MYOCARDIAL INFARCTION	7/532 (1.3%)		2/540 (0.4%)		2/541 (0.4%)
MYOCARDIAL ISCHAEMIA	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
NODAL ARRHYTHMIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PALPITATIONS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
PERICARDIAL EFFUSION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PERICARDITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
RIGHT VENTRICULAR FAILURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SICK SINUS SYNDROME	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SINOATRIAL BLOCK	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
SINUS ARREST	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SINUS BRADYCARDIA	2/532 (0.4%)		0/540 (0%)		2/541 (0.4%)
SUPRAVENTRICULAR TACHYCARDIA	1/532 (0.2%)		2/540 (0.4%)		2/541 (0.4%)
TACHYARRHYTHMIA	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
TACHYCARDIA	1/532 (0.2%)		4/540 (0.7%)		0/541 (0%)
VENTRICULAR FLUTTER	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
VENTRICULAR TACHYCARDIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
Congenital, familial and genetic disorders
LEFT VENTRICLE OUTFLOW TRACT OBSTRUCTION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
THALASSAEMIA BETA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
Ear and labyrinth disorders
VERTIGO	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
Endocrine disorders
HYPERTHYROIDISM	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
THYROID CYST	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
Eye disorders
BLINDNESS UNILATERAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CATARACT	5/532 (0.9%)		0/540 (0%)		1/541 (0.2%)
CHOROIDAL DETACHMENT	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
CONJUNCTIVAL OEDEMA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
DIABETIC RETINOPATHY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DIPLOPIA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
GLAUCOMA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
OCULAR HYPERTENSION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
UVEITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
VISION BLURRED	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ABDOMINAL PAIN	5/532 (0.9%)		1/540 (0.2%)		2/541 (0.4%)
ABDOMINAL PAIN UPPER	0/532 (0%)		3/540 (0.6%)		0/541 (0%)
ABDOMINAL WALL HAEMATOMA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
COLITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
COLITIS ISCHAEMIC	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
COLONIC POLYP	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
CONSTIPATION	5/532 (0.9%)		3/540 (0.6%)		5/541 (0.9%)
DIARRHOEA	9/532 (1.7%)		8/540 (1.5%)		4/541 (0.7%)
DIVERTICULAR PERFORATION	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
DIVERTICULUM	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
DYSPHAGIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ENTERITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ENTEROCOLITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ENTEROCUTANEOUS FISTULA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ENTEROVESICAL FISTULA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
FAECALOMA	0/532 (0%)		3/540 (0.6%)		0/541 (0%)
GASTRIC DISORDER	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
GASTRIC ULCER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GASTRIC ULCER HAEMORRHAGE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GASTRITIS	3/532 (0.6%)		0/540 (0%)		0/541 (0%)
GASTROINTESTINAL HAEMORRHAGE	3/532 (0.6%)		0/540 (0%)		0/541 (0%)
GASTROINTESTINAL MOTILITY DISORDER	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
GASTROINTESTINAL NECROSIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
GASTROINTESTINAL STENOSIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
GINGIVAL BLEEDING	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HAEMATEMESIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HAEMORRHAGIC EROSIVE GASTRITIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
HIATUS HERNIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ILEUS	0/532 (0%)		0/540 (0%)		3/541 (0.6%)
ILEUS PARALYTIC	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INGUINAL HERNIA	3/532 (0.6%)		2/540 (0.4%)		1/541 (0.2%)
INGUINAL HERNIA STRANGULATED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INGUINAL HERNIA, OBSTRUCTIVE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
INTESTINAL ISCHAEMIA	1/532 (0.2%)		1/540 (0.2%)		1/541 (0.2%)
INTESTINAL OBSTRUCTION	4/532 (0.8%)		3/540 (0.6%)		1/541 (0.2%)
INTESTINAL PERFORATION	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
LARGE INTESTINE PERFORATION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
NAUSEA	6/532 (1.1%)		2/540 (0.4%)		7/541 (1.3%)
NECROTISING COLITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OBSTRUCTION GASTRIC	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OESOPHAGEAL STENOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OESOPHAGITIS	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
ORAL DISORDER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PANCREATITIS	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
PEPTIC ULCER HAEMORRHAGE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
RECTAL HAEMORRHAGE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
RECTAL PERFORATION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
REFLUX GASTRITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SIGMOIDITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SMALL INTESTINAL OBSTRUCTION	1/532 (0.2%)		1/540 (0.2%)		2/541 (0.4%)
SUBILEUS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
TONGUE HAEMATOMA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
UMBILICAL HERNIA, OBSTRUCTIVE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
UPPER GASTROINTESTINAL HAEMORRHAGE	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
VOMITING	8/532 (1.5%)		4/540 (0.7%)		8/541 (1.5%)
General disorders
ASTHENIA	12/532 (2.3%)		2/540 (0.4%)		5/541 (0.9%)
CHEST DISCOMFORT	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CHEST PAIN	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
CHILLS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
DEATH	3/532 (0.6%)		3/540 (0.6%)		1/541 (0.2%)
FATIGUE	3/532 (0.6%)		3/540 (0.6%)		3/541 (0.6%)
GENERAL PHYSICAL HEALTH DETERIORATION	16/532 (3%)		13/540 (2.4%)		12/541 (2.2%)
GENERALISED OEDEMA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
HYPERPYREXIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HYPERTHERMIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HYPOTHERMIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
INFLAMMATION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INFLUENZA LIKE ILLNESS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INJECTION SITE HAEMORRHAGE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MALAISE	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
MUCOSAL INFLAMMATION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MULTI-ORGAN FAILURE	0/532 (0%)		3/540 (0.6%)		3/541 (0.6%)
NON-CARDIAC CHEST PAIN	4/532 (0.8%)		4/540 (0.7%)		1/541 (0.2%)
OEDEMA PERIPHERAL	5/532 (0.9%)		2/540 (0.4%)		3/541 (0.6%)
PAIN	5/532 (0.9%)		0/540 (0%)		4/541 (0.7%)
PERFORMANCE STATUS DECREASED	1/532 (0.2%)		1/540 (0.2%)		1/541 (0.2%)
PYREXIA	22/532 (4.1%)		11/540 (2%)		8/541 (1.5%)
SPINAL PAIN	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
SUDDEN DEATH	5/532 (0.9%)		2/540 (0.4%)		2/541 (0.4%)
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ULCER HAEMORRHAGE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
Hepatobiliary disorders
BILE DUCT OBSTRUCTION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
BILE DUCT STONE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
CHOLANGITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
CHOLECYSTITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
CHOLECYSTITIS ACUTE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
CHOLELITHIASIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
DRUG-INDUCED LIVER INJURY	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HEPATIC FAILURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HEPATITIS ACUTE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPERBILIRUBINAEMIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPERTRANSAMINASAEMIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
LIVER DISORDER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
Immune system disorders
AMYLOIDOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ANAPHYLACTIC SHOCK	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DRUG HYPERSENSITIVITY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPERSENSITIVITY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
Infections and infestations
ABDOMINAL ABSCESS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ABDOMINAL WALL ABSCESS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ABSCESS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ABSCESS LIMB	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ANORECTAL INFECTION BACTERIAL	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
APPENDICITIS	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
ARTHRITIS BACTERIAL	5/532 (0.9%)		0/540 (0%)		0/541 (0%)
ARTHRITIS INFECTIVE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
ATYPICAL PNEUMONIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
BACTERAEMIA	3/532 (0.6%)		2/540 (0.4%)		2/541 (0.4%)
BACTERIAL SEPSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
BRONCHITIS	13/532 (2.4%)		6/540 (1.1%)		2/541 (0.4%)
BRONCHOPNEUMONIA	2/532 (0.4%)		5/540 (0.9%)		2/541 (0.4%)
BRONCHOPULMONARY ASPERGILLOSIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
BURSITIS INFECTIVE STAPHYLOCOCCAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CAMPYLOBACTER INFECTION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
CELLULITIS	8/532 (1.5%)		3/540 (0.6%)		2/541 (0.4%)
CHOLECYSTITIS INFECTIVE	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
CLOSTRIDIAL INFECTION	2/532 (0.4%)		0/540 (0%)		2/541 (0.4%)
CLOSTRIDIUM DIFFICILE COLITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
CYSTITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
DEVICE RELATED INFECTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DIARRHOEA INFECTIOUS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DIVERTICULITIS	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
DOUGLAS' ABSCESS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
EMBOLIC PNEUMONIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ENDOCARDITIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ENDOCARDITIS BACTERIAL	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ENDOCARDITIS STAPHYLOCOCCAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ENDOPHTHALMITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ENTEROCOCCAL SEPSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ENTEROCOLITIS INFECTIOUS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
EPIGLOTTITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ERYSIPELAS	3/532 (0.6%)		1/540 (0.2%)		1/541 (0.2%)
ESCHERICHIA SEPSIS	0/532 (0%)		3/540 (0.6%)		0/541 (0%)
ESCHERICHIA URINARY TRACT INFECTION	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
FUNGAL INFECTION	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
FURUNCLE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
GASTROENTERITIS	0/532 (0%)		3/540 (0.6%)		2/541 (0.4%)
GASTROENTERITIS SALMONELLA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GASTROENTERITIS VIRAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GASTROINTESTINAL INFECTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HEPATITIS B	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
HERPES ZOSTER	3/532 (0.6%)		1/540 (0.2%)		1/541 (0.2%)
INFECTION	4/532 (0.8%)		1/540 (0.2%)		4/541 (0.7%)
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE	4/532 (0.8%)		0/540 (0%)		0/541 (0%)
INFECTIVE TENOSYNOVITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
INFLUENZA	7/532 (1.3%)		3/540 (0.6%)		1/541 (0.2%)
INTERVERTEBRAL DISCITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
KLEBSIELLA BACTERAEMIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
KLEBSIELLA INFECTION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
KLEBSIELLA SEPSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
LOBAR PNEUMONIA	8/532 (1.5%)		7/540 (1.3%)		3/541 (0.6%)
LOCALISED INFECTION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LOWER RESPIRATORY TRACT INFECTION	8/532 (1.5%)		3/540 (0.6%)		4/541 (0.7%)
LUNG INFECTION	3/532 (0.6%)		8/540 (1.5%)		5/541 (0.9%)
LUNG INFECTION PSEUDOMONAL	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
MENINGITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
MENINGITIS CRYPTOCOCCAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MENINGOCOCCAL SEPSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
NEUTROPENIC SEPSIS	2/532 (0.4%)		1/540 (0.2%)		2/541 (0.4%)
OESOPHAGEAL CANDIDIASIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
ORCHITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
OROPHARYNGEAL CANDIDIASIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
OSTEOMYELITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PERIODONTITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PERIORBITAL ABSCESS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PERIORBITAL CELLULITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PERITONITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
PNEUMOCOCCAL BACTERAEMIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PNEUMOCOCCAL SEPSIS	3/532 (0.6%)		0/540 (0%)		0/541 (0%)
PNEUMOCYSTIS JIROVECI PNEUMONIA	3/532 (0.6%)		0/540 (0%)		1/541 (0.2%)
PNEUMONIA	60/532 (11.3%)		48/540 (8.9%)		35/541 (6.5%)
PNEUMONIA BACTERIAL	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
PNEUMONIA ESCHERICHIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PNEUMONIA KLEBSIELLA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PNEUMONIA LEGIONELLA	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
PNEUMONIA PNEUMOCOCCAL	4/532 (0.8%)		2/540 (0.4%)		1/541 (0.2%)
PNEUMONIA STAPHYLOCOCCAL	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
PNEUMONIA STREPTOCOCCAL	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PNEUMONIA VIRAL	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
POST PROCEDURAL SEPSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
POSTOPERATIVE ABSCESS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PROSTATIC ABSCESS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PSEUDOMEMBRANOUS COLITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PSEUDOMONAL SEPSIS	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
PULMONARY TUBERCULOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PYELONEPHRITIS	4/532 (0.8%)		1/540 (0.2%)		0/541 (0%)
PYELONEPHRITIS ACUTE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
RESPIRATORY SYNCYTIAL VIRUS INFECTION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
RESPIRATORY TRACT INFECTION	9/532 (1.7%)		5/540 (0.9%)		4/541 (0.7%)
SEPSIS	17/532 (3.2%)		10/540 (1.9%)		8/541 (1.5%)
SEPTIC SHOCK	5/532 (0.9%)		7/540 (1.3%)		3/541 (0.6%)
SINUSITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SOFT TISSUE INFECTION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
STAPHYLOCOCCAL BACTERAEMIA	4/532 (0.8%)		0/540 (0%)		0/541 (0%)
STAPHYLOCOCCAL IMPETIGO	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
STAPHYLOCOCCAL INFECTION	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
STAPHYLOCOCCAL SEPSIS	2/532 (0.4%)		3/540 (0.6%)		0/541 (0%)
STRONGYLOIDIASIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SUBCUTANEOUS ABSCESS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
TOOTH ABSCESS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
TRACHEOBRONCHITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
TUBERCULOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
TUBERCULOUS PLEURISY	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
UPPER RESPIRATORY TRACT INFECTION	8/532 (1.5%)		9/540 (1.7%)		2/541 (0.4%)
URINARY TRACT INFECTION	9/532 (1.7%)		5/540 (0.9%)		3/541 (0.6%)
URINARY TRACT INFECTION BACTERIAL	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
UROSEPSIS	3/532 (0.6%)		1/540 (0.2%)		0/541 (0%)
WHIPPLE'S DISEASE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE	1/532 (0.2%)		1/540 (0.2%)		2/541 (0.4%)
ACETABULUM FRACTURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ALCOHOL POISONING	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ANKLE FRACTURE	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
BLADDER INJURY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
CERVICAL VERTEBRAL FRACTURE	1/532 (0.2%)		0/540 (0%)		2/541 (0.4%)
CLAVICLE FRACTURE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
CONTUSION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CRANIOCEREBRAL INJURY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
FACE INJURY	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
FALL	5/532 (0.9%)		3/540 (0.6%)		4/541 (0.7%)
FEMORAL NECK FRACTURE	3/532 (0.6%)		2/540 (0.4%)		1/541 (0.2%)
FEMUR FRACTURE	6/532 (1.1%)		1/540 (0.2%)		0/541 (0%)
FOOT FRACTURE	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
FRACTURED SACRUM	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HEAD INJURY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HEART INJURY	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
HIP FRACTURE	4/532 (0.8%)		2/540 (0.4%)		1/541 (0.2%)
HUMERUS FRACTURE	6/532 (1.1%)		1/540 (0.2%)		1/541 (0.2%)
INCISIONAL HERNIA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
INFUSION RELATED REACTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
JAW FRACTURE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
JOINT DISLOCATION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LACERATION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
LUMBAR VERTEBRAL FRACTURE	0/532 (0%)		1/540 (0.2%)		2/541 (0.4%)
MEDICATION ERROR	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
MENISCUS LESION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OVERDOSE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PELVIC FRACTURE	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
POST PROCEDURAL HAEMATOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PUBIS FRACTURE	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
RADIUS FRACTURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
RESPIRATORY FUME INHALATION DISORDER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
RIB FRACTURE	2/532 (0.4%)		3/540 (0.6%)		1/541 (0.2%)
SPINAL COMPRESSION FRACTURE	6/532 (1.1%)		3/540 (0.6%)		5/541 (0.9%)
SPINAL FRACTURE	1/532 (0.2%)		0/540 (0%)		2/541 (0.4%)
STERNAL FRACTURE	0/532 (0%)		1/540 (0.2%)		2/541 (0.4%)
SUBDURAL HAEMATOMA	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
SUBDURAL HAEMORRHAGE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
TENDON RUPTURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
THORACIC VERTEBRAL FRACTURE	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
TRANSFUSION-RELATED ACUTE LUNG INJURY	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
TRAUMATIC FRACTURE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ULNA FRACTURE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
UPPER LIMB FRACTURE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
WRIST FRACTURE	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
Investigations
ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ALANINE AMINOTRANSFERASE INCREASED	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
BIOPSY BONE MARROW ABNORMAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
BLOOD BILIRUBIN INCREASED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
BLOOD CREATININE INCREASED	2/532 (0.4%)		2/540 (0.4%)		0/541 (0%)
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS WORSENED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
EJECTION FRACTION DECREASED	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
HAEMOGLOBIN ABNORMAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HEART RATE INCREASED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HEPATIC ENZYME INCREASED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INTERNATIONAL NORMALISED RATIO INCREASED	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LIVER FUNCTION TEST ABNORMAL	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PROTEIN URINE PRESENT	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PROTHROMBIN TIME RATIO INCREASED	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
TROPONIN INCREASED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
TROPONIN T INCREASED	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
WEIGHT DECREASED	3/532 (0.6%)		1/540 (0.2%)		1/541 (0.2%)
Metabolism and nutrition disorders
CACHEXIA	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
DECREASED APPETITE	6/532 (1.1%)		1/540 (0.2%)		1/541 (0.2%)
DEHYDRATION	7/532 (1.3%)		9/540 (1.7%)		7/541 (1.3%)
DIABETES MELLITUS	3/532 (0.6%)		2/540 (0.4%)		1/541 (0.2%)
DIABETES MELLITUS INADEQUATE CONTROL	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
FAILURE TO THRIVE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
FOOD INTOLERANCE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
GOUT	3/532 (0.6%)		1/540 (0.2%)		1/541 (0.2%)
HYPERCALCAEMIA	5/532 (0.9%)		10/540 (1.9%)		7/541 (1.3%)
HYPERGLYCAEMIA	4/532 (0.8%)		3/540 (0.6%)		0/541 (0%)
HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HYPERKALAEMIA	0/532 (0%)		1/540 (0.2%)		2/541 (0.4%)
HYPERURICAEMIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
HYPOALBUMINAEMIA	1/532 (0.2%)		2/540 (0.4%)		0/541 (0%)
HYPOCALCAEMIA	5/532 (0.9%)		4/540 (0.7%)		1/541 (0.2%)
HYPOGLYCAEMIA	4/532 (0.8%)		2/540 (0.4%)		1/541 (0.2%)
HYPOKALAEMIA	6/532 (1.1%)		1/540 (0.2%)		1/541 (0.2%)
HYPOMAGNESAEMIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HYPONATRAEMIA	6/532 (1.1%)		6/540 (1.1%)		1/541 (0.2%)
HYPOPROTEINAEMIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
IRON DEFICIENCY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MALNUTRITION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MARASMUS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
METABOLIC ACIDOSIS	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
METABOLIC ALKALOSIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
SHOCK HYPOGLYCAEMIC	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
TETANY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
TYPE 2 DIABETES MELLITUS	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/532 (0.2%)		2/540 (0.4%)		0/541 (0%)
ARTHRITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
BACK PAIN	22/532 (4.1%)		19/540 (3.5%)		10/541 (1.8%)
BONE LESION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
BONE PAIN	10/532 (1.9%)		6/540 (1.1%)		6/541 (1.1%)
CHONDROCALCINOSIS PYROPHOSPHATE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
DUPUYTREN'S CONTRACTURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
FIBROMYALGIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
FLANK PAIN	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GOUTY ARTHRITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GOUTY TOPHUS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INTERVERTEBRAL DISC DEGENERATION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
INTERVERTEBRAL DISC DISORDER	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
INTERVERTEBRAL DISC PROTRUSION	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
LUMBAR SPINAL STENOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MONARTHRITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MUSCLE HAEMORRHAGE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MUSCULAR WEAKNESS	1/532 (0.2%)		1/540 (0.2%)		1/541 (0.2%)
MUSCULOSKELETAL CHEST PAIN	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
MUSCULOSKELETAL PAIN	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
MYALGIA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
MYOPATHY	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
NECK PAIN	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
OSTEOARTHRITIS	2/532 (0.4%)		2/540 (0.4%)		1/541 (0.2%)
OSTEOCHONDROSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OSTEOLYSIS	1/532 (0.2%)		1/540 (0.2%)		2/541 (0.4%)
OSTEONECROSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OSTEONECROSIS OF JAW	3/532 (0.6%)		1/540 (0.2%)		0/541 (0%)
OSTEOPOROSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
OSTEOPOROTIC FRACTURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PAIN IN EXTREMITY	0/532 (0%)		2/540 (0.4%)		4/541 (0.7%)
PATHOLOGICAL FRACTURE	0/532 (0%)		4/540 (0.7%)		3/541 (0.6%)
POLYARTHRITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SOFT TISSUE MASS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SPINAL COLUMN STENOSIS	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
SPINAL DISORDER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SYNOVIAL CYST	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
VERTEBRAL WEDGING	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE LYMPHOCYTIC LEUKAEMIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ACUTE MYELOID LEUKAEMIA	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
BASAL CELL CARCINOMA	11/532 (2.1%)		4/540 (0.7%)		1/541 (0.2%)
BLADDER CANCER	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
BLADDER TRANSITIONAL CELL CARCINOMA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
BOWEN'S DISEASE	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
BREAST CANCER	1/532 (0.2%)		2/540 (0.4%)		0/541 (0%)
BREAST CANCER IN SITU	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
CANCER PAIN	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CARCINOID TUMOUR OF THE APPENDIX	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
CARDIAC MYXOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
COLON ADENOMA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
COLON CANCER METASTATIC	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
COLON CANCER STAGE IV	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ENDOMETRIAL CANCER METASTATIC	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ENDOMETRIAL CANCER STAGE III	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GASTRIC CANCER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
GASTROINTESTINAL NEOPLASM	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HEPATIC NEOPLASM MALIGNANT	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LENTIGO MALIGNA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
LEUKAEMIA PLASMACYTIC	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
LUNG ADENOCARCINOMA METASTATIC	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
LUNG ADENOCARCINOMA STAGE IV	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
LUNG CANCER METASTATIC	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
LUNG NEOPLASM	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
LUNG NEOPLASM MALIGNANT	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
LUNG SQUAMOUS CELL CARCINOMA STAGE I	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
MALIGNANT MELANOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MENINGIOMA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
METASTASES TO CENTRAL NERVOUS SYSTEM	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
METASTATIC MALIGNANT MELANOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
MULTIPLE MYELOMA	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
MYELODYSPLASTIC SYNDROME	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
NEOPLASM SWELLING	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
OESOPHAGEAL ADENOCARCINOMA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ORAL NEOPLASM BENIGN	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PLASMACYTOMA	1/532 (0.2%)		0/540 (0%)		3/541 (0.6%)
PROSTATE CANCER	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
PROSTATE CANCER RECURRENT	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PROSTATIC ADENOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
RECTAL CANCER	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
SALIVARY GLAND CANCER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SMALL INTESTINE CARCINOMA METASTATIC	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SQUAMOUS CELL CARCINOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SQUAMOUS CELL CARCINOMA OF SKIN	16/532 (3%)		5/540 (0.9%)		1/541 (0.2%)
TRANSITIONAL CELL CANCER OF THE RENAL PELVIS AND URETER	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
TUMOUR FLARE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
Nervous system disorders
ALTERED STATE OF CONSCIOUSNESS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
APHASIA	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
BRAIN STEM INFARCTION	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
CAROTID ARTERY STENOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CAUDA EQUINA SYNDROME	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CEREBRAL HAEMORRHAGE	1/532 (0.2%)		1/540 (0.2%)		1/541 (0.2%)
CEREBRAL INFARCTION	4/532 (0.8%)		1/540 (0.2%)		1/541 (0.2%)
CEREBRAL ISCHAEMIA	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
CEREBROVASCULAR ACCIDENT	8/532 (1.5%)		3/540 (0.6%)		3/541 (0.6%)
COMA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
CONVULSION	3/532 (0.6%)		0/540 (0%)		0/541 (0%)
COORDINATION ABNORMAL	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
DEMENTIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DIZZINESS	5/532 (0.9%)		0/540 (0%)		3/541 (0.6%)
DYSTONIA	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
EPIDURITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
EPILEPSY	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
GRAND MAL CONVULSION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
GUILLAIN-BARRE SYNDROME	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HAEMORRHAGIC STROKE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HEADACHE	1/532 (0.2%)		1/540 (0.2%)		1/541 (0.2%)
HEMIPARESIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPOAESTHESIA	0/532 (0%)		1/540 (0.2%)		1/541 (0.2%)
ISCHAEMIC CEREBRAL INFARCTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ISCHAEMIC STROKE	4/532 (0.8%)		0/540 (0%)		0/541 (0%)
LACUNAR INFARCTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
LETHARGY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
LOSS OF CONSCIOUSNESS	1/532 (0.2%)		2/540 (0.4%)		1/541 (0.2%)
MOTOR NEURONE DISEASE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PARAESTHESIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PARALYSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PARAPARESIS	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
PARAPLEGIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PARKINSON'S DISEASE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PARKINSONISM	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PERIPHERAL MOTOR NEUROPATHY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PERIPHERAL SENSORIMOTOR NEUROPATHY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PERIPHERAL SENSORY NEUROPATHY	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
POLYNEUROPATHY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
POST HERPETIC NEURALGIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PRESYNCOPE	6/532 (1.1%)		1/540 (0.2%)		2/541 (0.4%)
PYRAMIDAL TRACT SYNDROME	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
RADICULITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
REPETITIVE SPEECH	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SCIATICA	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
SOMNOLENCE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SPEECH DISORDER	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SPINAL CORD COMPRESSION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
SUBARACHNOID HAEMORRHAGE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
SYNCOPE	9/532 (1.7%)		3/540 (0.6%)		8/541 (1.5%)
TRANSIENT GLOBAL AMNESIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
TRANSIENT ISCHAEMIC ATTACK	2/532 (0.4%)		2/540 (0.4%)		2/541 (0.4%)
TRIGEMINAL NEURALGIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
VASCULAR ENCEPHALOPATHY	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
Psychiatric disorders
AGITATED DEPRESSION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
ANXIETY	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
COMPLETED SUICIDE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CONFUSIONAL STATE	7/532 (1.3%)		6/540 (1.1%)		2/541 (0.4%)
DELIRIUM	4/532 (0.8%)		2/540 (0.4%)		1/541 (0.2%)
DEPRESSED MOOD	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
DEPRESSION	4/532 (0.8%)		2/540 (0.4%)		0/541 (0%)
DISORIENTATION	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
EUPHORIC MOOD	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HALLUCINATION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
IMPAIRED SELF-CARE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
MAJOR DEPRESSION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
MENTAL STATUS CHANGES	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
SUICIDE ATTEMPT	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
Renal and urinary disorders
ACUTE PRERENAL FAILURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
AZOTAEMIA	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
BLADDER PROLAPSE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DYSURIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HAEMATURIA	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
OLIGURIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PROTEINURIA	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
RENAL ARTERY STENOSIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
RENAL COLIC	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
RENAL FAILURE	8/532 (1.5%)		18/540 (3.3%)		14/541 (2.6%)
RENAL FAILURE ACUTE	21/532 (3.9%)		16/540 (3%)		10/541 (1.8%)
RENAL FAILURE CHRONIC	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
RENAL IMPAIRMENT	5/532 (0.9%)		2/540 (0.4%)		4/541 (0.7%)
URINARY BLADDER HAEMORRHAGE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
URINARY RETENTION	2/532 (0.4%)		4/540 (0.7%)		2/541 (0.4%)
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
EPIDIDYMITIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
GENITAL PROLAPSE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PROSTATITIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA	2/532 (0.4%)		1/540 (0.2%)		1/541 (0.2%)
ACUTE RESPIRATORY DISTRESS SYNDROME	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
ACUTE RESPIRATORY FAILURE	3/532 (0.6%)		1/540 (0.2%)		2/541 (0.4%)
ASTHMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
BRONCHIECTASIS	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
BRONCHOPNEUMOPATHY	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
BRONCHOSPASM	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	12/532 (2.3%)		5/540 (0.9%)		2/541 (0.4%)
COUGH	1/532 (0.2%)		1/540 (0.2%)		1/541 (0.2%)
DYSPNOEA	14/532 (2.6%)		7/540 (1.3%)		8/541 (1.5%)
DYSPNOEA EXERTIONAL	3/532 (0.6%)		1/540 (0.2%)		0/541 (0%)
EPISTAXIS	2/532 (0.4%)		1/540 (0.2%)		0/541 (0%)
HAEMOPTYSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HAEMOTHORAX	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
HYPOXIA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
INTERSTITIAL LUNG DISEASE	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
LUNG DISORDER	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PLEURAL EFFUSION	1/532 (0.2%)		3/540 (0.6%)		3/541 (0.6%)
PNEUMONIA ASPIRATION	2/532 (0.4%)		0/540 (0%)		2/541 (0.4%)
PULMONARY ALVEOLAR HAEMORRHAGE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PULMONARY ARTERIAL HYPERTENSION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PULMONARY EMBOLISM	20/532 (3.8%)		15/540 (2.8%)		20/541 (3.7%)
PULMONARY HAEMORRHAGE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PULMONARY HYPERTENSION	3/532 (0.6%)		0/540 (0%)		0/541 (0%)
PULMONARY INFARCTION	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PULMONARY OEDEMA	6/532 (1.1%)		1/540 (0.2%)		2/541 (0.4%)
PULMONARY THROMBOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
RESPIRATORY ALKALOSIS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
RESPIRATORY DISTRESS	3/532 (0.6%)		1/540 (0.2%)		1/541 (0.2%)
RESPIRATORY FAILURE	8/532 (1.5%)		5/540 (0.9%)		4/541 (0.7%)
SLEEP APNOEA SYNDROME	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
ACUTE FEBRILE NEUTROPHILIC DERMATOSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
CUTANEOUS VASCULITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DECUBITUS ULCER	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
DERMATITIS ALLERGIC	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
DERMATITIS EXFOLIATIVE	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
DRUG ERUPTION	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
EXFOLIATIVE RASH	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
HYPERHIDROSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PRURITUS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
RASH	5/532 (0.9%)		5/540 (0.9%)		3/541 (0.6%)
RASH ERYTHEMATOUS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
RASH MACULAR	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
RASH MACULO-PAPULAR	0/532 (0%)		2/540 (0.4%)		0/541 (0%)
RASH PRURITIC	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
SKIN ULCER	2/532 (0.4%)		0/540 (0%)		0/541 (0%)
TOXIC EPIDERMAL NECROLYSIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
Vascular disorders
AORTIC ANEURYSM	1/532 (0.2%)		1/540 (0.2%)		0/541 (0%)
AORTIC ANEURYSM RUPTURE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
AORTIC DISSECTION	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
ARTERIAL HAEMORRHAGE	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
DEEP VEIN THROMBOSIS	19/532 (3.6%)		11/540 (2%)		8/541 (1.5%)
HAEMATOMA	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
HYPERTENSION	0/532 (0%)		0/540 (0%)		2/541 (0.4%)
HYPERTENSIVE CRISIS	1/532 (0.2%)		0/540 (0%)		1/541 (0.2%)
HYPOTENSION	8/532 (1.5%)		7/540 (1.3%)		1/541 (0.2%)
HYPOVOLAEMIC SHOCK	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
ORTHOSTATIC HYPOTENSION	3/532 (0.6%)		0/540 (0%)		1/541 (0.2%)
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
PERIPHERAL ARTERY ANEURYSM	0/532 (0%)		1/540 (0.2%)		0/541 (0%)
PERIPHERAL ARTERY THROMBOSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
PHLEBITIS	2/532 (0.4%)		0/540 (0%)		5/541 (0.9%)
SHOCK	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
THROMBOPHLEBITIS	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
THROMBOPHLEBITIS SUPERFICIAL	1/532 (0.2%)		0/540 (0%)		0/541 (0%)
THROMBOSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
VENOUS THROMBOSIS	0/532 (0%)		0/540 (0%)		1/541 (0.2%)
Other (Not Including Serious) Adverse Events
	Lenalidomide and Low-Dose Dexamethasone (Rd)		Lenalidomide and Dexamethasone (Rd18)		Melphalan + Prednisone + Thalidomide (MPT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	523/532 (98.3%)		532/540 (98.5%)		532/541 (98.3%)
Blood and lymphatic system disorders
ANAEMIA	237/532 (44.5%)		191/540 (35.4%)		219/541 (40.5%)
LEUKOPENIA	66/532 (12.4%)		59/540 (10.9%)		92/541 (17%)
LYMPHOPENIA	60/532 (11.3%)		43/540 (8%)		71/541 (13.1%)
NEUTROPENIA	194/532 (36.5%)		177/540 (32.8%)		325/541 (60.1%)
THROMBOCYTOPENIA	111/532 (20.9%)		99/540 (18.3%)		132/541 (24.4%)
Cardiac disorders
ATRIAL FIBRILLATION	30/532 (5.6%)		0/540 (0%)		0/541 (0%)
Ear and labyrinth disorders
VERTIGO	27/532 (5.1%)		0/540 (0%)		35/541 (6.5%)
Eye disorders
CATARACT	84/532 (15.8%)		31/540 (5.7%)		0/541 (0%)
VISION BLURRED	30/532 (5.6%)		0/540 (0%)		0/541 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	68/532 (12.8%)		40/540 (7.4%)		28/541 (5.2%)
ABDOMINAL PAIN UPPER	50/532 (9.4%)		34/540 (6.3%)		29/541 (5.4%)
CONSTIPATION	233/532 (43.8%)		210/540 (38.9%)		282/541 (52.1%)
DIARRHOEA	248/532 (46.6%)		205/540 (38%)		86/541 (15.9%)
DRY MOUTH	38/532 (7.1%)		38/540 (7%)		62/541 (11.5%)
DYSPEPSIA	59/532 (11.1%)		28/540 (5.2%)		36/541 (6.7%)
NAUSEA	156/532 (29.3%)		127/540 (23.5%)		163/541 (30.1%)
TOOTHACHE	28/532 (5.3%)		0/540 (0%)		0/541 (0%)
VOMITING	97/532 (18.2%)		66/540 (12.2%)		104/541 (19.2%)
General disorders
ASTHENIA	148/532 (27.8%)		122/540 (22.6%)		123/541 (22.7%)
FATIGUE	178/532 (33.5%)		176/540 (32.6%)		153/541 (28.3%)
NON-CARDIAC CHEST PAIN	31/532 (5.8%)		27/540 (5%)		0/541 (0%)
OEDEMA	38/532 (7.1%)		28/540 (5.2%)		32/541 (5.9%)
OEDEMA PERIPHERAL	220/532 (41.4%)		168/540 (31.1%)		213/541 (39.4%)
PYREXIA	111/532 (20.9%)		94/540 (17.4%)		69/541 (12.8%)
Infections and infestations
BRONCHITIS	90/532 (16.9%)		57/540 (10.6%)		42/541 (7.8%)
GASTROENTERITIS	35/532 (6.6%)		0/540 (0%)		0/541 (0%)
INFLUENZA	33/532 (6.2%)		0/540 (0%)		0/541 (0%)
LOWER RESPIRATORY TRACT INFECTION	29/532 (5.5%)		0/540 (0%)		0/541 (0%)
NASOPHARYNGITIS	90/532 (16.9%)		54/540 (10%)		33/541 (6.1%)
PNEUMONIA	29/532 (5.5%)		34/540 (6.3%)		0/541 (0%)
RESPIRATORY TRACT INFECTION	35/532 (6.6%)		0/540 (0%)		0/541 (0%)
RHINITIS	31/532 (5.8%)		0/540 (0%)		0/541 (0%)
UPPER RESPIRATORY TRACT INFECTION	71/532 (13.3%)		48/540 (8.9%)		31/541 (5.7%)
URINARY TRACT INFECTION	77/532 (14.5%)		59/540 (10.9%)		38/541 (7%)
Injury, poisoning and procedural complications
CONTUSION	39/532 (7.3%)		0/540 (0%)		0/541 (0%)
FALL	46/532 (8.6%)		0/540 (0%)		0/541 (0%)
Investigations
BLOOD CREATININE INCREASED	39/532 (7.3%)		0/540 (0%)		0/541 (0%)
WEIGHT DECREASED	73/532 (13.7%)		78/540 (14.4%)		47/541 (8.7%)
Metabolism and nutrition disorders
DECREASED APPETITE	128/532 (24.1%)		115/540 (21.3%)		72/541 (13.3%)
HYPERGLYCAEMIA	61/532 (11.5%)		50/540 (9.3%)		0/541 (0%)
HYPOCALCAEMIA	60/532 (11.3%)		54/540 (10%)		30/541 (5.5%)
HYPOKALAEMIA	104/532 (19.5%)		62/540 (11.5%)		38/541 (7%)
HYPOMAGNESAEMIA	27/532 (5.1%)		0/540 (0%)		0/541 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	110/532 (20.7%)		71/540 (13.1%)		67/541 (12.4%)
BACK PAIN	175/532 (32.9%)		137/540 (25.4%)		115/541 (21.3%)
BONE PAIN	83/532 (15.6%)		72/540 (13.3%)		58/541 (10.7%)
JOINT SWELLING	29/532 (5.5%)		0/540 (0%)		0/541 (0%)
MUSCLE SPASMS	115/532 (21.6%)		102/540 (18.9%)		61/541 (11.3%)
MUSCULAR WEAKNESS	46/532 (8.6%)		34/540 (6.3%)		28/541 (5.2%)
MUSCULOSKELETAL CHEST PAIN	63/532 (11.8%)		51/540 (9.4%)		39/541 (7.2%)
MUSCULOSKELETAL PAIN	72/532 (13.5%)		58/540 (10.7%)		36/541 (6.7%)
MYALGIA	31/532 (5.8%)		0/540 (0%)		0/541 (0%)
NECK PAIN	43/532 (8.1%)		0/540 (0%)		0/541 (0%)
PAIN IN EXTREMITY	91/532 (17.1%)		65/540 (12%)		60/541 (11.1%)
Nervous system disorders
DIZZINESS	87/532 (16.4%)		70/540 (13%)		114/541 (21.1%)
DYSGEUSIA	41/532 (7.7%)		45/540 (8.3%)		0/541 (0%)
HEADACHE	80/532 (15%)		52/540 (9.6%)		55/541 (10.2%)
HYPOAESTHESIA	46/532 (8.6%)		0/540 (0%)		40/541 (7.4%)
NEUROPATHY PERIPHERAL	35/532 (6.6%)		0/540 (0%)		62/541 (11.5%)
PARAESTHESIA	88/532 (16.5%)		74/540 (13.7%)		102/541 (18.9%)
PERIPHERAL MOTOR NEUROPATHY	28/532 (5.3%)		0/540 (0%)		0/541 (0%)
PERIPHERAL SENSORY NEUROPATHY	113/532 (21.2%)		93/540 (17.2%)		191/541 (35.3%)
SOMNOLENCE	31/532 (5.8%)		0/540 (0%)		51/541 (9.4%)
TREMOR	77/532 (14.5%)		73/540 (13.5%)		100/541 (18.5%)
Psychiatric disorders
ANXIETY	45/532 (8.5%)		36/540 (6.7%)		41/541 (7.6%)
CONFUSIONAL STATE	35/532 (6.6%)		0/540 (0%)		0/541 (0%)
DEPRESSION	66/532 (12.4%)		45/540 (8.3%)		30/541 (5.5%)
INSOMNIA	150/532 (28.2%)		127/540 (23.5%)		53/541 (9.8%)
Renal and urinary disorders
RENAL FAILURE	27/532 (5.1%)		0/540 (0%)		0/541 (0%)
Respiratory, thoracic and mediastinal disorders
COUGH	129/532 (24.2%)		94/540 (17.4%)		67/541 (12.4%)
DYSPHONIA	31/532 (5.8%)		0/540 (0%)		0/541 (0%)
DYSPNOEA	112/532 (21.1%)		85/540 (15.7%)		110/541 (20.3%)
DYSPNOEA EXERTIONAL	30/532 (5.6%)		28/540 (5.2%)		0/541 (0%)
EPISTAXIS	32/532 (6%)		31/540 (5.7%)		0/541 (0%)
OROPHARYNGEAL PAIN	32/532 (6%)		0/540 (0%)		0/541 (0%)
PRODUCTIVE COUGH	35/532 (6.6%)		0/540 (0%)		0/541 (0%)
Skin and subcutaneous tissue disorders
DRY SKIN	32/532 (6%)		30/540 (5.6%)		36/541 (6.7%)
ERYTHEMA	35/532 (6.6%)		27/540 (5%)		0/541 (0%)
PRURITUS	49/532 (9.2%)		49/540 (9.1%)		0/541 (0%)
RASH	117/532 (22%)		129/540 (23.9%)		91/541 (16.8%)
Vascular disorders
DEEP VEIN THROMBOSIS	40/532 (7.5%)		0/540 (0%)		0/541 (0%)
HYPERTENSION	43/532 (8.1%)		27/540 (5%)		35/541 (6.5%)
HYPOTENSION	52/532 (9.8%)		28/540 (5.2%)		35/541 (6.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than one year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to ninety days; Investigator must delete confidential information before submission or defer publication to permit patent applications