Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01383928
• Collaborator: (none)
• Enrollment: 64
• Locations: 20
• Arms: 2
• Actual Duration (Months): 72.9
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) in phase 1 and to determine the combined response rate of clinical response CR and very good partial response (VGPR) in phase 2 of oral (PO) ixazomib administered twice-weekly in combination with lenalidomide and low-dose dexamethasone in a 21-day cycle in participants with newly diagnosed multiple myeloma (NDDM).

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone	Phase 1/Phase 2

Detailed Description

The drug being tested in this study is called ixazomib. Ixazomib was tested to slow disease progression and improve overall survival in participants who have newly diagnosed multiple myeloma (NDMM). This study looked at the safety, tolerability and response in participants when administered in combination with lenalidomide and low-dose dexamethasone.

The study enrolled 64 patients. Participants were assigned to one of the 3 treatment groups:

• Phase 1 Ixazomib 3 mg

• Phase 1 Ixazomib 3.7 mg

• Phase 2 Ixazomib 3 mg

All participants were administered with Ixazomib capsules, orally, twice-weekly on Days 1, 4, 8, and 11 along with lenalidomide capsules, orally, once daily on Days 1-14 and dexamethasone, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib capsules, orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.

This multi-center trial conducted in the United States. The overall time to participate in this study was 2037 days. Participants will make multiple visits to the clinic, and a final visit after 30 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Formulation of IXAZOMIB (MLN9708), Administered Twice-weekly in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment
• Actual Study Start Date: Oct 31, 2011
• Actual Primary Completion Date: Oct 13, 2014
• Actual Study Completion Date: Nov 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1: Ixazomib 3 mg or 3.7 mg Ixazomib (MLN9708), orally, twice-weekly in combination with lenalidomide orally and dexamethasone orally as prescribed, in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.	Drug: Ixazomib; Ixazomib capsules; Drug: Lenalidomide; Lenalidomide capsules; Drug: Dexamethasone; Dexamethasone Tablets
Experimental: Phase 2: Ixazomib 3 mg Ixazomib (MLN9708), orally, twice-weekly in combination with lenalidomide orally and dexamethasone orally as prescribed, in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.	Drug: Ixazomib; Ixazomib capsules; Drug: Lenalidomide; Lenalidomide capsules; Drug: Dexamethasone; Dexamethasone Tablets

Outcome Measures

Primary Outcome Measures

1. Phase 1: Maximum Tolerated Dose (MTD) [Cycle 1 (21 days)]

   MTD was highest dose of ixazomib given with combination drugs, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cell per cubic millimeter [cells/mm^3]) for >7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for >7 days; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count <10,000/mm^3; Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or <1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by >14 days; <=80% lenalidomide doses administered due to other >=Grade 2 combination study drug-related nonhematologic toxicities requiring therapy discontinuation.

2. Phase 1: Recommended Phase 2 Dose (RP2D) [Cycle 1 (21 days)]

   The RP2D of ixazomib was determined after the evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to analyses of efficacy results, toxicity characterization, all grades peripheral neuropathy, and treatment discontinuation. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).

3. Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) [Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

4. Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) [Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)]

   Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

5. Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity [Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)]

   TEAE related to neurotoxicity grading based on common terminology criteria for adverse events (CTACE) version 4.03 are reported. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening consequences; urgent intervention indicated; Grade 5= death. Only TEAEs related to neurotoxicity with values are reported.

6. Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs [Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)]

   Vital signs included body temperature, blood pressure and heart rate.

7. Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

   CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal.

8. Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events [Baseline up to 30 days after the last dose of study drug (approximately 1905 days)]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. As per Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.

9. Phase 2: Percentage of Participants Experiencing Serious Adverse Events [Baseline up to 30 days after the last dose of study drug (approximately 1905 days)]

   A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

10. Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation [Baseline up to 30 days after the last dose of study drug (approximately 1905 days)]

    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

Secondary Outcome Measures

1. Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib [Cycle 1, Days 1 and 11]

   Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve.

2. Phase 1: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib [Cycle 1, Days 1 and 11]

   AUC(0-72) is a measure of the area under the plasma concentration time-curve from time zero to 72 hours post-dose for ixazomib.

3. Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib [Cycle 1, Days 1 and 11]

   Tmax: Time to reach the first maximum plasma concentration (Cmax), equal to time (hours) to Cmax of ixazomib after administration, obtained directly from the plasma concentration-time curve.

4. Phase 1: Rac: Accumulation Ratio of Ixazomib [Cycle 1, Days 1 and 11]

   The accumulation ratio (Rac) was estimated as the ratio of AUC (0-72) on Day 11 to the AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time zero to 72 hours post-dose for ixazomib.

5. Phase 1: Percentage of Participants With Best Overall Response [Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)]

   CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Partial response(PR):>=50% reduction of serum M-protein,urinary M-protein by >=90%/to <200 mg/24 hr reduction.Near CR(nCR):positive immunofixation of serum/urine;soft tissue plasmacytomas disappearance;<=5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal.

6. Phase 2: Percentage of Participants With Overall Response (CR+VGPR+PR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

   Overall response is defined as CR, VGPR or PR based on IMWG Response Criteria for malignant lymphoma. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein+urine M-protein level <100 mg/24h. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes.

7. Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) After Cycles 4, 8, and 16 [Cycles 4, 8, and 16]

   CR as per IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. VGPR were applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein; Urine M-protein; Serum FLC assay.

8. Phase 2: Percentage of Participants With Complete Response (CR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

   CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow.

9. Phase 2: Percentage of Participants With Stringent Complete Response (sCR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

   sCR as per IMWG criteria is CR plus normal FLC ratio and absence of clonal cells in bone marrow. CR is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow.

10. Phase 2: Percentage of Participants With Very Good Partial Response (VGPR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

    VGPR as per IMWG criteria is serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours.

11. Phase 2: Percentage of Participants With Near Complete Response (nCR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

    nCR as per IMWG criteria is positive immunofixation analysis of serum or urine as the only evidence of disease; appearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow.

12. Phase 2: Percentage of Participants With Partial Response (PR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

    PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by 90% or to <200 mg per 24 hours.

13. Phase 2: Percentage of Participants With Minimal Response (MR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

    MR as per IMWG criteria is 25%-49% reduction in serum paraprotein and 50%-89% reduction in urine light chain excretion for 6 weeks.

14. Phase 2: Time to Response [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

    Time to first response is defined as the time from the date of first dose of study treatment to the date of the first documentation of a confirmed response (PR or better) in a participant who responded + 1 day. PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg per 24 hours.

15. Phase 2: Duration of Response (DOR) [Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)]

    DOR was measured as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as >=25% increase from lowest value in: serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; development of new bone lesions or soft tissue plasmacytomas development or increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcaemia development.

16. Time to Disease Progression (TTP) [Baseline up to a follow-up of 62.1 months]

    Time to progression was defined as the time from the date of first dose of study treatment to the date of first documentation of PD + 1 day. Participants that did not experience PD will be censored at the last response assessment that is SD or better. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants that received Autologous Stem Cell Transplantation (ASCT) or an alternate cancer therapy were also be censored at the last response assessment that is, SD or better prior to initiation of therapy. Participants without response assessment will be censored at the date of first dose. TTP was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

17. Progression Free Survival (PFS) [Baseline up to a follow-up of 62.1 months]

    PFS was defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease or to death due to any cause, whichever occurred first plus 1. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved,uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants who received ASCT or an alternate anticancer therapy were censored at the last response assessment that was SD or better before initiation of therapy. Participants without a response assessment were censored at the date of first dose. PFS was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

18. Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Year 1 [1 year after the first dose of study treatment]

    The Kaplan-Meier estimate reports the percentage of participants surviving at Year 1.

19. Overall Survival [Baseline up to a follow-up of 62.1 months]

    Overall survival was measured as the time from the date of first dose of study treatment to the time of death plus 1 day. For participants who did not die, survival was censored at the date of last contact. Overall Survival was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female patients 18 years or older

• Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria

• Measurable disease as specified in study protocol

• Hematologic, liver, and renal function as specified in the study protocol.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program

• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse AND must adhere to the guidelines of the lenalidomide pregnancy prevention program

• Must be able to take concurrent aspirin 325 mg daily

• Voluntary written consent

Exclusion Criteria

• Peripheral neuropathy that is greater or equal to Grade 2

• Female patients who are lactating or pregnant

• Major surgery or radiotherapy within 14 days before the first dose of study drug

• Uncontrolled infection requiring systematic antibiotics within 14 days before the first dose of study drug

• Diarrhea (> Grade 1)

• Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient)

• Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment

• Central nervous system involvement

• Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome

• Evidence of current uncontrolled cardiovascular conditions

• Prior or concurrent deep vein thrombosis or pulmonary embolism

• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

• Known allergy to any of the study medications

• Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption, or tolerance of IXAZOMIB

• Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Medical Center	Berkeley	California	United States	94704
2	City of Hope National Medical Center	Duarte	California	United States	91010
3	Stanford University	Stanford	California	United States	94305
4	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
5	University of Chicago Medical Center	Chicago	Illinois	United States	60637
6	Associates of Oncology/Hematology PC	Rockville	Maryland	United States	20850
7	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
8	University of Michigan	Ann Arbor	Michigan	United States	48109
9	Michigan State University	Lansing	Michigan	United States	48910
10	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
11	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
12	Mount Sinai Hospital	New York	New York	United States	31406
13	Duke University Medical Center	Durham	North Carolina	United States	27705
14	Ohio State University	Columbus	Ohio	United States	43210
15	Mercy St Anne Hospital	Toledo	Ohio	United States	43623
16	Oregon Health and Science University	Portland	Oregon	United States	97239
17	SCRI Tennessee Oncology Nashville	Nashville	Tennessee	United States	37203
18	Baylor Sammons Cancer Center	Dallas	Texas	United States	75246
19	Virginia Cancer Care Specialist	Fairfax	Virginia	United States	22031
20	Virginia Cancer Specialists PC	Fairfax	Virginia	United States	22031

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01383928
• Other Study ID Numbers: C16008; U1111-1168-1172
• First Posted: Jun 28, 2011
• Last Update Posted: Mar 21, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Lenalidomide; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 15 investigative sites in the United States from 31 October 2011 to 27 November 2017 when the sponsor closed the study.
Pre-assignment Detail	Participants with newly diagnosed multiple myeloma were enrolled in 1 of the 2 dose escalation treatment arms in Phase 1: ixazomib 3 mg and 3.7 mg induction followed by maintenance. Phase 2 consisted of ixazomib 3 mg during induction followed by maintenance.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Period Title: Overall Study
STARTED	7	7	50
COMPLETED	2	0	10
NOT COMPLETED	5	7	40

Baseline Characteristics

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg	Phase 2: Ixazomib 3 mg	Total
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).	Total of all reporting groups
Overall Participants	7	7	50	64
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.3 (12.04)	61.1 (6.20)	61.5 (10.03)	61.8 (9.82)
Sex: Female, Male (Count of Participants)
Female	2 28.6%	3 42.9%	19 38%	24 37.5%
Male	5 71.4%	4 57.1%	31 62%	40 62.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 2%	1 1.6%
Not Hispanic or Latino	7 100%	7 100%	48 96%	62 96.9%
Not Reported	0 0%	0 0%	1 2%	1 1.6%
Race/Ethnicity, Customized (Count of Participants)
White	5 71.4%	7 100%	42 84%	54 84.4%
Black or African American	1 14.3%	0 0%	7 14%	8 12.5%
Other	1 14.3%	0 0%	0 0%	1 1.6%
Not Reported	0 0%	0 0%	1 2%	1 1.6%
Region of Enrollment (Count of Participants)
United States	7 100%	7 100%	50 100%	64 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.1 (13.09)	170.9 (7.10)	171.2 (9.30)	171.1 (9.43)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	94.29 (17.083)	82.56 (19.295)	81.22 (16.701)	82.80 (17.228)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	2.109 (0.2192)	1.960 (0.2657)	1.958 (0.2373)	1.975 (0.2390)
Type of Myeloma (Count of Participants)
IgG Kappa	2 28.6%	3 42.9%	24 48%	29 45.3%
IgG Lambda	1 14.3%	1 14.3%	7 14%	9 14.1%
IgA Kappa	1 14.3%	1 14.3%	10 20%	12 18.8%
IgA Lambda	1 14.3%	0 0%	3 6%	4 6.3%
Biclonal	0 0%	1 14.3%	1 2%	2 3.1%
Lambda Free Light Chains	1 14.3%	0 0%	3 6%	4 6.3%
Kappa Free Light Chains	1 14.3%	1 14.3%	1 2%	3 4.7%
Unknown	0 0%	0 0%	1 2%	1 1.6%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0	3 42.9%	5 71.4%	27 54%	35 54.7%
1	4 57.1%	1 14.3%	21 42%	26 40.6%
2	0 0%	1 14.3%	2 4%	3 4.7%
Serum Creatinine Category (Count of Participants)
Less than or equal to (<=) 2 mg/dL	7 100%	7 100%	50 100%	64 100%
Greater than (>) 2 mg/dL	0 0%	0 0%	0 0%	0 0%
Creatinine Clearance Category (Count of Participants)
30 - 60 mL/min	2 28.6%	2 28.6%	8 16%	12 18.8%
>60 mL/min	5 71.4%	5 71.4%	42 84%	52 81.3%
Corrected Calcium (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	9.83 (0.275)	9.79 (0.561)	10.01 (0.617)	9.96 (0.583)
Hemoglobin (gram per liter (g/L)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [gram per liter (g/L)]	103.4 (21.59)	112.0 (16.42)	108.9 (14.36)	108.6 (15.32)
Participants with Lytic Bone Lesions Present (Count of Participants)
Present	5 71.4%	3 42.9%	37 74%	45 70.3%
Not Present	1 14.3%	2 28.6%	7 14%	10 15.6%
Indeterminate	0 0%	0 0%	1 2%	1 1.6%
Missing	1 14.3%	2 28.6%	5 10%	8 12.5%
Participants with Extramedullary Plasmacytomas (Count of Participants)
Plasmacytomas Present	1 14.3%	1 14.3%	18 36%	20 31.3%
Plasmacytomas Not Present	2 28.6%	2 28.6%	4 8%	8 12.5%
Not Reported	4 57.1%	4 57.1%	28 56%	36 56.3%

Outcome Measures

1. Primary Outcome

Title	Phase 1: Maximum Tolerated Dose (MTD)
Description	MTD was highest dose of ixazomib given with combination drugs, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cell per cubic millimeter [cells/mm^3]) for >7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for >7 days; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count <10,000/mm^3; Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or <1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by >14 days; <=80% lenalidomide doses administered due to other >=Grade 2 combination study drug-related nonhematologic toxicities requiring therapy discontinuation.
Time Frame	Cycle 1 (21 days)

Outcome Measure Data

Analysis Population Description

DLT-evaluable population included all participants who received all Cycle 1 doses of MLN9708 and completed Cycle 1 procedures, or experienced a DLT in Cycle 1 in Phase 1.

Arm/Group Title	Phase 1: All Participants
Arm/Group Description	Ixazomib 3 mg or 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Measure Participants	14
Number [mg]	3.7

2. Primary Outcome

Title	Phase 1: Recommended Phase 2 Dose (RP2D)
Description	The RP2D of ixazomib was determined after the evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to analyses of efficacy results, toxicity characterization, all grades peripheral neuropathy, and treatment discontinuation. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Time Frame	Cycle 1 (21 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug.

Arm/Group Title	Phase 1: All Participants
Arm/Group Description	Ixazomib 3 mg or 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Measure Participants	14
Number [mg]	3

3. Primary Outcome

Title	Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Adverse Event	100 1428.6%	100 1428.6%
Serious Adverse Event	71 1014.3%	29 414.3%

4. Primary Outcome

Title	Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
Description	Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug and reported baseline and at least 1 post-baseline value.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Alanine aminotransferase increased	0 0%	3 42.9%
Aspartate aminotransferase increased	0 0%	2 28.6%
Blood creatinine increased	2 28.6%	0 0%
Shift to the left	0 0%	1 14.3%
Platelet count decreased	1 14.3%	0 0%
Blood bicarbonate decreased	1 14.3%	0 0%
Anaemia	1 14.3%	0 0%
Neutropenia	1 14.3%	0 0%
Thrombocytopenia	1 14.3%	1 14.3%
Eosinophilia	0 0%	1 14.3%
Hypokalaemia	1 14.3%	0 0%
Hyperkalaemia	1 14.3%	0 0%
Hyperglycaemia	4 57.1%	0 0%
Hyponatraemia	0 0%	1 14.3%
Hypomagnesaemia	0 0%	2 28.6%
Hyperchloraemia	1 14.3%	0 0%
Iron deficiency anaemia	1 14.3%	0 0%

5. Primary Outcome

Title	Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity
Description	TEAE related to neurotoxicity grading based on common terminology criteria for adverse events (CTACE) version 4.03 are reported. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening consequences; urgent intervention indicated; Grade 5= death. Only TEAEs related to neurotoxicity with values are reported.
Time Frame	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug and reported baseline and at least 1 post-baseline value.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Neuropathy Peripheral (Grade 1)	0 0%	1 14.3%
Neuropathy Peripheral (Grade 2)	2 28.6%	1 14.3%
Neuropathy Peripheral (Grade 3)	0 0%	1 14.3%
Peripheral Sensory Neuropathy (Grade 1)	2 28.6%	1 14.3%
Peripheral Sensory Neuropathy (Grade 2)	0 0%	1 14.3%
Peripheral Sensory Neuropathy (Grade 3)	1 14.3%	0 0%
Peripheral Motor Neuropathy (Grade 1)	1 14.3%	0 0%

6. Primary Outcome

Title	Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Description	Vital signs included body temperature, blood pressure and heart rate.
Time Frame	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Pyrexia	1 14.3%	3 42.9%
Bradycardia	1 14.3%	0 0%
Orthostatic hypotension	0 0%	1 14.3%
Hypotension	1 14.3%	1 14.3%

7. Primary Outcome

Title	Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR)
Description	CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	65 928.6%

8. Primary Outcome

Title	Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. As per Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.
Time Frame	Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	50
Number [percentage of participants]	74 1057.1%

9. Primary Outcome

Title	Phase 2: Percentage of Participants Experiencing Serious Adverse Events
Description	A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Time Frame	Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of any study drug.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	50
Number [percentage of participants]	46 657.1%

10. Primary Outcome

Title	Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	Baseline up to 30 days after the last dose of study drug (approximately 1905 days)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of any study drug.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	50
Number [percentage of participants]	14 200%

11. Secondary Outcome

Title	Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib
Description	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve.
Time Frame	Cycle 1, Days 1 and 11

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Day 1	33.515 (22.9634)	46.946 (26.6436)
Day 11	58.674 (19.9559)	51.832 (23.5112)

12. Secondary Outcome

Title	Phase 1: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib
Description	AUC(0-72) is a measure of the area under the plasma concentration time-curve from time zero to 72 hours post-dose for ixazomib.
Time Frame	Cycle 1, Days 1 and 11

Outcome Measure Data

Analysis Population Description

PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Day 1	315.450 (75.0886)	284.576 (47.8233)
Day 11	1105.44 (457.5939)	1023.52 (284.3709)

13. Secondary Outcome

Title	Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Description	Tmax: Time to reach the first maximum plasma concentration (Cmax), equal to time (hours) to Cmax of ixazomib after administration, obtained directly from the plasma concentration-time curve.
Time Frame	Cycle 1, Days 1 and 11

Outcome Measure Data

Analysis Population Description

PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	7	7
Day 1	1.035	1.000
Day 11	1.030	0.984

14. Secondary Outcome

Title	Phase 1: Rac: Accumulation Ratio of Ixazomib
Description	The accumulation ratio (Rac) was estimated as the ratio of AUC (0-72) on Day 11 to the AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time zero to 72 hours post-dose for ixazomib.
Time Frame	Cycle 1, Days 1 and 11

Outcome Measure Data

Analysis Population Description

PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.

Arm/Group Title	Phase 1: Ixazomib 3 mg	Phase 1: Ixazomib 3.7 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).	Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Measure Participants	5	5
Geometric Mean (Standard Deviation) [ratio]	3.785 (1.4653)	3.967 (0.7546)

15. Secondary Outcome

Title	Phase 1: Percentage of Participants With Best Overall Response
Description	CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Partial response(PR):>=50% reduction of serum M-protein,urinary M-protein by >=90%/to <200 mg/24 hr reduction.Near CR(nCR):positive immunofixation of serum/urine;soft tissue plasmacytomas disappearance;<=5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal.
Time Frame	Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment. Results were summarized together for all Phase 1 participants, as per planned analysis.

Arm/Group Title	Phase 1: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Measure Participants	13
Number (95% Confidence Interval) [percentage of participants]	92 1314.3%

16. Secondary Outcome

Title	Phase 2: Percentage of Participants With Overall Response (CR+VGPR+PR)
Description	Overall response is defined as CR, VGPR or PR based on IMWG Response Criteria for malignant lymphoma. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein+urine M-protein level <100 mg/24h. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	94 1342.9%

17. Secondary Outcome

Title	Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) After Cycles 4, 8, and 16
Description	CR as per IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. VGPR were applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein; Urine M-protein; Serum FLC assay.
Time Frame	Cycles 4, 8, and 16

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least one 1 dose of ixazomib, had measurable disease at baseline, and at least one 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
After 4 cycles	49 700%
After 8 cycles	64 914.3%
After 16 cycles	92 1314.3%

18. Secondary Outcome

Title	Phase 2: Percentage of Participants With Complete Response (CR)
Description	CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	29 414.3%

19. Secondary Outcome

Title	Phase 2: Percentage of Participants With Stringent Complete Response (sCR)
Description	sCR as per IMWG criteria is CR plus normal FLC ratio and absence of clonal cells in bone marrow. CR is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least one 1 dose of ixazomib, had measurable disease at baseline, and at least one 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	22 314.3%

20. Secondary Outcome

Title	Phase 2: Percentage of Participants With Very Good Partial Response (VGPR)
Description	VGPR as per IMWG criteria is serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	37 528.6%

21. Secondary Outcome

Title	Phase 2: Percentage of Participants With Near Complete Response (nCR)
Description	nCR as per IMWG criteria is positive immunofixation analysis of serum or urine as the only evidence of disease; appearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	10 142.9%

22. Secondary Outcome

Title	Phase 2: Percentage of Participants With Partial Response (PR)
Description	PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by 90% or to <200 mg per 24 hours.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	65 928.6%

23. Secondary Outcome

Title	Phase 2: Percentage of Participants With Minimal Response (MR)
Description	MR as per IMWG criteria is 25%-49% reduction in serum paraprotein and 50%-89% reduction in urine light chain excretion for 6 weeks.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	6 85.7%

24. Secondary Outcome

Title	Phase 2: Time to Response
Description	Time to first response is defined as the time from the date of first dose of study treatment to the date of the first documentation of a confirmed response (PR or better) in a participant who responded + 1 day. PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg per 24 hours.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Response-evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	46
Median (Full Range) [months]	0.72

25. Secondary Outcome

Title	Phase 2: Duration of Response (DOR)
Description	DOR was measured as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as >=25% increase from lowest value in: serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; development of new bone lesions or soft tissue plasmacytomas development or increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcaemia development.
Time Frame	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)

Outcome Measure Data

Analysis Population Description

Included a subset of response-evaluable population who achieved response.

Arm/Group Title	Phase 2: Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Measure Participants	49
Median (95% Confidence Interval) [months]	29.0

26. Secondary Outcome

Title	Time to Disease Progression (TTP)
Description	Time to progression was defined as the time from the date of first dose of study treatment to the date of first documentation of PD + 1 day. Participants that did not experience PD will be censored at the last response assessment that is SD or better. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants that received Autologous Stem Cell Transplantation (ASCT) or an alternate cancer therapy were also be censored at the last response assessment that is, SD or better prior to initiation of therapy. Participants without response assessment will be censored at the date of first dose. TTP was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Time Frame	Baseline up to a follow-up of 62.1 months

Outcome Measure Data

Analysis Population Description

modified-intent-to-treat (mITT) population included all participants who received at least one dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

Arm/Group Title	Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Measure Participants	57
Median (95% Confidence Interval) [months]	29.7

27. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease or to death due to any cause, whichever occurred first plus 1. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved,uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants who received ASCT or an alternate anticancer therapy were censored at the last response assessment that was SD or better before initiation of therapy. Participants without a response assessment were censored at the date of first dose. PFS was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Time Frame	Baseline up to a follow-up of 62.1 months

Outcome Measure Data

Analysis Population Description

mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

Arm/Group Title	Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Measure Participants	57
Median (95% Confidence Interval) [months]	29.7

28. Secondary Outcome

Title	Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Year 1
Description	The Kaplan-Meier estimate reports the percentage of participants surviving at Year 1.
Time Frame	1 year after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

Arm/Group Title	Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Measure Participants	57
Number (95% Confidence Interval) [percentage of participants]	94 1342.9%

29. Secondary Outcome

Title	Overall Survival
Description	Overall survival was measured as the time from the date of first dose of study treatment to the time of death plus 1 day. For participants who did not die, survival was censored at the date of last contact. Overall Survival was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Time Frame	Baseline up to a follow-up of 62.1 months

Outcome Measure Data

Analysis Population Description

mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.

Arm/Group Title	Ixazomib 3 mg
Arm/Group Description	Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Measure Participants	57
Median (95% Confidence Interval) [months]	NA

Adverse Events

Time Frame	From first study drug administration up to 30 days after the last dose (Up to approximately 2067 days)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Phase 1: Ixazomib 3 mg		Phase 1: Ixazomib 3.7 mg		Phase 2: Ixazomib 3.0 mg
Arm/Group Description	Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).		Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).		Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
All Cause Mortality
	Phase 1: Ixazomib 3 mg		Phase 1: Ixazomib 3.7 mg		Phase 2: Ixazomib 3.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		1/50 (2%)
Serious Adverse Events
	Phase 1: Ixazomib 3 mg		Phase 1: Ixazomib 3.7 mg		Phase 2: Ixazomib 3.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/7 (71.4%)		2/7 (28.6%)		23/50 (46%)
Blood and lymphatic system disorders
Anaemia	0/7 (0%)		0/7 (0%)		1/50 (2%)
Cardiac disorders
Atrial fibrillation	0/7 (0%)		0/7 (0%)		2/50 (4%)
Atrial flutter	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Cardiac failure	0/7 (0%)		0/7 (0%)		1/50 (2%)
Cardio-respiratory arrest	0/7 (0%)		0/7 (0%)		1/50 (2%)
Gastrointestinal disorders
Dyspepsia	0/7 (0%)		0/7 (0%)		1/50 (2%)
Abdominal pain	0/7 (0%)		0/7 (0%)		1/50 (2%)
Intestinal perforation	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Vomiting	0/7 (0%)		0/7 (0%)		1/50 (2%)
Impaired gastric emptying	0/7 (0%)		0/7 (0%)		1/50 (2%)
General disorders
Pyrexia	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Non-cardiac chest pain	0/7 (0%)		0/7 (0%)		1/50 (2%)
Infections and infestations
Pneumonia	1/7 (14.3%)		0/7 (0%)		3/50 (6%)
Lung infection	0/7 (0%)		0/7 (0%)		2/50 (4%)
Cellulitis	0/7 (0%)		0/7 (0%)		2/50 (4%)
Skin infection	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Subcutaneous abscess	0/7 (0%)		0/7 (0%)		1/50 (2%)
Influenza	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Scrotal infection	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Infective myositis	0/7 (0%)		0/7 (0%)		1/50 (2%)
Sepsis	0/7 (0%)		0/7 (0%)		1/50 (2%)
Urinary tract infection	0/7 (0%)		0/7 (0%)		1/50 (2%)
Gastroenteritis viral	0/7 (0%)		0/7 (0%)		1/50 (2%)
Injury, poisoning and procedural complications
Femur fracture	0/7 (0%)		0/7 (0%)		1/50 (2%)
Overdose	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Thoracic vertebral fracture	0/7 (0%)		0/7 (0%)		1/50 (2%)
Investigations
Alanine aminotransferase increased	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Transaminases increased	0/7 (0%)		0/7 (0%)		1/50 (2%)
Metabolism and nutrition disorders
Hyponatraemia	0/7 (0%)		0/7 (0%)		1/50 (2%)
Musculoskeletal and connective tissue disorders
Back pain	0/7 (0%)		0/7 (0%)		1/50 (2%)
Pain in extremity	0/7 (0%)		0/7 (0%)		1/50 (2%)
Muscular weakness	0/7 (0%)		0/7 (0%)		1/50 (2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/7 (0%)		0/7 (0%)		1/50 (2%)
Nervous system disorders
Guillain-Barre syndrome	0/7 (0%)		0/7 (0%)		1/50 (2%)
Syncope	0/7 (0%)		0/7 (0%)		1/50 (2%)
Headache	0/7 (0%)		0/7 (0%)		1/50 (2%)
Amnesia	0/7 (0%)		0/7 (0%)		1/50 (2%)
Cognitive disorder	0/7 (0%)		0/7 (0%)		1/50 (2%)
Neuropathy peripheral	0/7 (0%)		0/7 (0%)		1/50 (2%)
Generalised tonic-clonic seizure	0/7 (0%)		0/7 (0%)		1/50 (2%)
Myelitis transverse	0/7 (0%)		0/7 (0%)		1/50 (2%)
Renal and urinary disorders
Tubulointerstitial nephritis	0/7 (0%)		0/7 (0%)		1/50 (2%)
Renal failure	0/7 (0%)		0/7 (0%)		1/50 (2%)
Renal tubular necrosis	0/7 (0%)		0/7 (0%)		1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Pleuritic pain	0/7 (0%)		0/7 (0%)		1/50 (2%)
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Rash macular	0/7 (0%)		0/7 (0%)		1/50 (2%)
Vascular disorders
Deep vein thrombosis	0/7 (0%)		0/7 (0%)		1/50 (2%)
Thrombophlebitis superficial	0/7 (0%)		0/7 (0%)		1/50 (2%)
Hypotension	0/7 (0%)		0/7 (0%)		1/50 (2%)
Other (Not Including Serious) Adverse Events
	Phase 1: Ixazomib 3 mg		Phase 1: Ixazomib 3.7 mg		Phase 2: Ixazomib 3.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		7/7 (100%)		50/50 (100%)
Blood and lymphatic system disorders
Neutropenia	1/7 (14.3%)		0/7 (0%)		4/50 (8%)
Thrombocytopenia	1/7 (14.3%)		1/7 (14.3%)		4/50 (8%)
Lymphopenia	0/7 (0%)		0/7 (0%)		3/50 (6%)
Eosinophilia	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Lymphadenopathy	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Iron deficiency anaemia	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Anaemia	1/7 (14.3%)		0/7 (0%)		6/50 (12%)
Cardiac disorders
Palpitations	0/7 (0%)		0/7 (0%)		3/50 (6%)
Tachycardia	0/7 (0%)		0/7 (0%)		4/50 (8%)
Bradycardia	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Supraventricular extrasystoles	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Ventricular extrasystoles	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Ear and labyrinth disorders
Tinnitus	1/7 (14.3%)		1/7 (14.3%)		4/50 (8%)
Hypoacusis	1/7 (14.3%)		0/7 (0%)		3/50 (6%)
Endocrine disorders
Cushingoid	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Eye disorders
Vision blurred	1/7 (14.3%)		1/7 (14.3%)		15/50 (30%)
Cataract	0/7 (0%)		0/7 (0%)		5/50 (10%)
Gastrointestinal disorders
Diarrhoea	4/7 (57.1%)		3/7 (42.9%)		23/50 (46%)
Nausea	4/7 (57.1%)		4/7 (57.1%)		20/50 (40%)
Constipation	2/7 (28.6%)		3/7 (42.9%)		20/50 (40%)
Dry mouth	1/7 (14.3%)		0/7 (0%)		8/50 (16%)
Gastrooesophageal reflux disease	1/7 (14.3%)		3/7 (42.9%)		3/50 (6%)
Abdominal distension	1/7 (14.3%)		1/7 (14.3%)		6/50 (12%)
Abdominal pain upper	0/7 (0%)		0/7 (0%)		5/50 (10%)
Abdominal pain	5/7 (71.4%)		0/7 (0%)		3/50 (6%)
Stomatitis	1/7 (14.3%)		1/7 (14.3%)		2/50 (4%)
Epigastric discomfort	1/7 (14.3%)		0/7 (0%)		1/50 (2%)
Flatulence	1/7 (14.3%)		0/7 (0%)		1/50 (2%)
Rectal haemorrhage	2/7 (28.6%)		0/7 (0%)		1/50 (2%)
Anal fissure	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Gingival pain	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Lip pain	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Oral dysaesthesia	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Palatal oedema	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Tongue erythema	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Vomiting	3/7 (42.9%)		0/7 (0%)		13/50 (26%)
Dyspepsia	0/7 (0%)		0/7 (0%)		4/50 (8%)
Enlarged uvula	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
General disorders
Oedema peripheral	4/7 (57.1%)		4/7 (57.1%)		22/50 (44%)
Fatigue	5/7 (71.4%)		6/7 (85.7%)		24/50 (48%)
Asthenia	2/7 (28.6%)		0/7 (0%)		9/50 (18%)
Chills	1/7 (14.3%)		1/7 (14.3%)		4/50 (8%)
Pain	1/7 (14.3%)		0/7 (0%)		5/50 (10%)
Gait disturbance	0/7 (0%)		0/7 (0%)		3/50 (6%)
Localised oedema	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Pyrexia	4/7 (57.1%)		0/7 (0%)		8/50 (16%)
Peripheral swelling	1/7 (14.3%)		0/7 (0%)		9/50 (18%)
Non-cardiac chest pain	1/7 (14.3%)		0/7 (0%)		4/50 (8%)
Infections and infestations
Upper respiratory tract infection	1/7 (14.3%)		2/7 (28.6%)		19/50 (38%)
Sinusitis	1/7 (14.3%)		1/7 (14.3%)		8/50 (16%)
Viral upper respiratory tract infection	2/7 (28.6%)		0/7 (0%)		7/50 (14%)
Oral candidiasis	0/7 (0%)		0/7 (0%)		6/50 (12%)
Oral herpes	0/7 (0%)		0/7 (0%)		4/50 (8%)
Herpes zoster	0/7 (0%)		1/7 (14.3%)		2/50 (4%)
Folliculitis	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Tinea cruris	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Tooth infection	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Urinary tract infection	0/7 (0%)		0/7 (0%)		4/50 (8%)
Conjunctivitis	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Skin infection	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Injury, poisoning and procedural complications
Fall	1/7 (14.3%)		0/7 (0%)		6/50 (12%)
Contusion	1/7 (14.3%)		0/7 (0%)		4/50 (8%)
Procedural pain	0/7 (0%)		0/7 (0%)		3/50 (6%)
Spinal compression fracture	1/7 (14.3%)		1/7 (14.3%)		0/50 (0%)
Foot fracture	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Investigations
Blood creatinine increased	2/7 (28.6%)		0/7 (0%)		5/50 (10%)
Weight decreased	1/7 (14.3%)		1/7 (14.3%)		4/50 (8%)
Aspartate aminotransferase increased	0/7 (0%)		2/7 (28.6%)		3/50 (6%)
Lymphocyte count decreased	0/7 (0%)		0/7 (0%)		3/50 (6%)
Neutrophil count decreased	0/7 (0%)		0/7 (0%)		3/50 (6%)
Weight increased	0/7 (0%)		0/7 (0%)		4/50 (8%)
Blood bicarbonate decreased	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Electrocardiogram QT prolonged	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Shift to the left	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Alanine aminotransferase increased	2/7 (28.6%)		0/7 (0%)		4/50 (8%)
Platelet count decreased	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Metabolism and nutrition disorders
Hypokalaemia	1/7 (14.3%)		0/7 (0%)		16/50 (32%)
Hyperglycaemia	4/7 (57.1%)		0/7 (0%)		6/50 (12%)
Dehydration	2/7 (28.6%)		3/7 (42.9%)		5/50 (10%)
Decreased appetite	1/7 (14.3%)		0/7 (0%)		7/50 (14%)
Hypophosphataemia	0/7 (0%)		0/7 (0%)		9/50 (18%)
Hypocalcaemia	0/7 (0%)		0/7 (0%)		5/50 (10%)
Hypomagnesaemia	0/7 (0%)		2/7 (28.6%)		4/50 (8%)
Hyperchloraemia	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Increased appetite	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Hyperkalaemia	1/7 (14.3%)		0/7 (0%)		1/50 (2%)
Hyponatraemia	1/7 (14.3%)		0/7 (0%)		5/50 (10%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/7 (57.1%)		0/7 (0%)		15/50 (30%)
Muscle spasms	2/7 (28.6%)		2/7 (28.6%)		12/50 (24%)
Musculoskeletal chest pain	1/7 (14.3%)		1/7 (14.3%)		5/50 (10%)
Myalgia	0/7 (0%)		2/7 (28.6%)		6/50 (12%)
Bone pain	1/7 (14.3%)		0/7 (0%)		5/50 (10%)
Musculoskeletal pain	0/7 (0%)		0/7 (0%)		7/50 (14%)
Joint swelling	0/7 (0%)		1/7 (14.3%)		4/50 (8%)
Musculoskeletal discomfort	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Osteonecrosis of jaw	1/7 (14.3%)		0/7 (0%)		1/50 (2%)
Spinal column stenosis	1/7 (14.3%)		0/7 (0%)		1/50 (2%)
Limb discomfort	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Muscle tightness	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Osteoarthritis	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Back pain	5/7 (71.4%)		0/7 (0%)		14/50 (28%)
Pain in extremity	2/7 (28.6%)		0/7 (0%)		17/50 (34%)
Muscular weakness	3/7 (42.9%)		0/7 (0%)		9/50 (18%)
Flank pain	0/7 (0%)		0/7 (0%)		3/50 (6%)
Osteopenia	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Nervous system disorders
Dysgeusia	2/7 (28.6%)		2/7 (28.6%)		20/50 (40%)
Dizziness	3/7 (42.9%)		1/7 (14.3%)		15/50 (30%)
Tremor	5/7 (71.4%)		0/7 (0%)		7/50 (14%)
Hypoaesthesia	2/7 (28.6%)		2/7 (28.6%)		7/50 (14%)
Paraesthesia	1/7 (14.3%)		1/7 (14.3%)		5/50 (10%)
Ageusia	1/7 (14.3%)		1/7 (14.3%)		1/50 (2%)
Dysaesthesia	0/7 (0%)		2/7 (28.6%)		1/50 (2%)
Lethargy	1/7 (14.3%)		1/7 (14.3%)		1/50 (2%)
Memory impairment	0/7 (0%)		0/7 (0%)		3/50 (6%)
Presyncope	0/7 (0%)		1/7 (14.3%)		1/50 (2%)
Peripheral motor neuropathy	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Sedation	1/7 (14.3%)		1/7 (14.3%)		0/50 (0%)
Tension headache	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Neuropathy peripheral	5/7 (71.4%)		0/7 (0%)		18/50 (36%)
Headache	6/7 (85.7%)		0/7 (0%)		12/50 (24%)
Peripheral sensory neuropathy	3/7 (42.9%)		2/7 (28.6%)		12/50 (24%)
Balance disorder	0/7 (0%)		0/7 (0%)		3/50 (6%)
Syncope	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Psychiatric disorders
Insomnia	2/7 (28.6%)		6/7 (85.7%)		17/50 (34%)
Anxiety	2/7 (28.6%)		1/7 (14.3%)		13/50 (26%)
Depression	0/7 (0%)		1/7 (14.3%)		4/50 (8%)
Mood altered	0/7 (0%)		0/7 (0%)		4/50 (8%)
Agitation	0/7 (0%)		2/7 (28.6%)		0/50 (0%)
Mood swings	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Irritability	1/7 (14.3%)		0/7 (0%)		6/50 (12%)
Renal and urinary disorders
Pollakiuria	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Renal failure	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Reproductive system and breast disorders
Breast cyst	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Testicular pain	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/7 (71.4%)		1/7 (14.3%)		12/50 (24%)
Cough	2/7 (28.6%)		2/7 (28.6%)		10/50 (20%)
Oropharyngeal pain	1/7 (14.3%)		2/7 (28.6%)		7/50 (14%)
Nasal congestion	3/7 (42.9%)		2/7 (28.6%)		5/50 (10%)
Hiccups	0/7 (0%)		2/7 (28.6%)		3/50 (6%)
Productive cough	0/7 (0%)		0/7 (0%)		5/50 (10%)
Rhinitis allergic	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Upper-airway cough syndrome	1/7 (14.3%)		0/7 (0%)		1/50 (2%)
Dysphonia	0/7 (0%)		0/7 (0%)		3/50 (6%)
Dyspnoea exertional	0/7 (0%)		0/7 (0%)		3/50 (6%)
Oropharyngeal discomfort	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/7 (28.6%)		3/7 (42.9%)		16/50 (32%)
Dry skin	1/7 (14.3%)		1/7 (14.3%)		5/50 (10%)
Rash	0/7 (0%)		2/7 (28.6%)		6/50 (12%)
Night sweats	1/7 (14.3%)		1/7 (14.3%)		6/50 (12%)
Alopecia	0/7 (0%)		0/7 (0%)		7/50 (14%)
Rash papular	0/7 (0%)		2/7 (28.6%)		4/50 (8%)
Rash pruritic	0/7 (0%)		2/7 (28.6%)		4/50 (8%)
Pruritus	2/7 (28.6%)		1/7 (14.3%)		3/50 (6%)
Dermatitis acneiform	1/7 (14.3%)		1/7 (14.3%)		2/50 (4%)
Hyperhidrosis	1/7 (14.3%)		0/7 (0%)		4/50 (8%)
Urticaria	0/7 (0%)		1/7 (14.3%)		3/50 (6%)
Dermatitis exfoliative	0/7 (0%)		2/7 (28.6%)		0/50 (0%)
Rash erythematous	0/7 (0%)		1/7 (14.3%)		1/50 (2%)
Acne	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Actinic keratosis	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Dermatitis contact	1/7 (14.3%)		0/7 (0%)		0/50 (0%)
Pain of skin	0/7 (0%)		1/7 (14.3%)		0/50 (0%)
Rash macular	4/7 (57.1%)		0/7 (0%)		4/50 (8%)
Erythema	0/7 (0%)		0/7 (0%)		3/50 (6%)
Skin exfoliation	0/7 (0%)		0/7 (0%)		3/50 (6%)
Vascular disorders
Flushing	2/7 (28.6%)		2/7 (28.6%)		3/50 (6%)
Hot flush	1/7 (14.3%)		0/7 (0%)		2/50 (4%)
Hypertension	0/7 (0%)		0/7 (0%)		4/50 (8%)
Orthostatic hypotension	0/7 (0%)		1/7 (14.3%)		2/50 (4%)
Hypotension	2/7 (28.6%)		0/7 (0%)		2/50 (4%)
Deep vein thrombosis	0/7 (0%)		0/7 (0%)		3/50 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.