Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01335685
• Collaborator: (none)
• Enrollment: 61
• Locations: 20
• Arms: 8
• Actual Duration (Months): 66.1
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this phase 1/2, open-label study was to evaluate the effect of oral formulation of Ixazomib when added to standard melphalan and prednisone (MP) treatment. Both phases of the study included participants who had newly diagnosed multiple myeloma and were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years of age) or coexisting conditions and for whom standard MP treatment was indicated.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Ixazomib; Drug: Melphalan; Drug: Prednisone	Phase 1/Phase 2

Detailed Description

The drug tested in this study was called ixazomib (MLN9708). Ixazomib was tested to treat the people with newly diagnosed multiple myeloma requiring systemic treatment who were not eligible for stem cell transplantation. This study determined the safety, tolerability, efficacy, quality of life (QOL), and pharmacokinetics (PK)/pharmacodynamics (PD) of ixazomib.

The study enrolled 61 patients. The study was conducted in 2 parts: 1) phase 1 dose escalation and 2) phase 2 expansion at maximum tolerated dose. Participants were enrolled to receive:

• Ixazomib 3.0 mg, 3.7 mg, 4.0 mg, or 5.5. mg depending on the treatment assignment

This multicenter trial was conducted in the Unites states, Canada, United Kingdom, Spain and Czech Republic. The overall time to participate in this study is 5.5 years. Participants made multiple visits to the clinic and were followed up every 16 weeks after end of treatment until disease progression if stopped treatment before disease progression and then every 16 weeks up to start of next therapy or death whichever occurs first.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Next-Generation Proteasome Inhibitor, Administered in Combination With a Standard Care Regimen of Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment
• Actual Study Start Date: Jun 27, 2011
• Actual Primary Completion Date: Dec 29, 2016
• Actual Study Completion Date: Dec 29, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Ixazomib 3.0 mg Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm A: Ixazomib 3.7 mg Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm B: Ixazomib 3.0 mg Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm B: Ixazomib 4.0 mg Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm B: Ixazomib 5.5 mg Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm C: Ixazomib 3.0 mg Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm C: Ixazomib 4.0 mg Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets
Experimental: Arm D: Ixazomib 4.0 mg Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).	Drug: Ixazomib; Ixazomib capsules; Drug: Melphalan; Melphalan tablets; Drug: Prednisone; Prednisone tablets

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1) [Cycle 1, phase 1 (Up to 42 days)]

   The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).

2. Very Good Partial Response (VGPR) or Better Response Rate (Phase 2) [Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)]

   VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) < 5% plasma cells in bone marrow. VGPR: 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 hour.

Secondary Outcome Measures

1. Maximum Inhibition Rate (Emax) (Phase 1) [At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study]

   Whole blood 20S proteasome inhibition parameters

2. Time of Occurrence of Emax (TEmax) (Phase 1) [At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study]

   Whole blood 20S proteasome inhibition parameters

3. Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1) [Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D]

4. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1) [Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D]

5. AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1) [Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D]

6. Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1) [Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D]

   Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.

7. Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1) [Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D]

   Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

8. Observed Accumulation Ratio for AUCtau (Rac) (Phase 1) [Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D]

   Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1.

9. Overall Response Rate (ORR) [Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years)]

   ORR is defined as percentage of participants with overall response including CR, VGPR, and partial response (PR). Per IMWG criteria, CR:1)Negative immunofixation on serum and urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. If serum+urine M-protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

10. Time to First Response (Phase 2) [From the date of enrollment to the date of the first documented response for up to 5.5 years]

    Response is defined as CR, VGPR and PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

11. Duration of Response (DOR) (Phase 2) [From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years]

    DOR is defined as time of first documentation of a confirmed PR or better response to first documented PD or start of alternative therapy. DOR was presented for those achieving CR+VGPR+PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.

12. Time to Progression (TTP) (Phase 2) [From the date of enrollment to the date of the first documented disease progression for up to 5.5 years]

    TTP is defined as time from date of enrollment to date of first documented disease progression (PD). Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.

13. Time to Next Therapy (Phase 2) [From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years]

    Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy.

14. Progression Free Survival (Phase 2) [From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years]

    Progression Free Survival is defined as time in months from start of study treatment to first documentation of objective tumor progression per investigator assessment or up to death due to any cause, whichever occurs first. Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.

15. Overall Survival (Phase 2) [From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)]

    Overall Survival is the time in months from start of study treatment to date of death due to any cause.

16. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years]

    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.

17. Assessments of Quality of Life (Phase 2) [Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Is indicated with standard melphalan prednisone (MP) treatment and is not a candidate for high-dose therapy plus stem cell transplantation (HDT-SCT) for 1 of the following reasons: the participant is 65 years of age or older OR the participant is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT

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

• Has measurable disease as specified in study protocol

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

• Has adequate hematologic, liver, and renal function

Exclusion Criteria

• Has peripheral neuropathy that is greater or equal to Grade 2

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

• Has uncontrolled infection requiring systematic antibiotics

• Has diarrhea (> Grade 1)

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

• Has central nervous system involvement

• Has cardiac status as described in protocol

• Has known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of IXAZOMIB - Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome

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

• Is 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Lebanon	New Hampshire	United States
2		Morgantown	West Virginia	United States
3		Vancouver	British Columbia	Canada
4		Toronto	Ontario	Canada
5		Quebec		Canada
6		Brno		Czechia
7		Praha 2		Czechia
8		Badalona		Spain
9		Barcelona		Spain
10		Madrid		Spain
11		Salamanca		Spain
12		San Sebastian		Spain
13		Sevilla		Spain
14		Bournemouth		United Kingdom
15		Brighton		United Kingdom
16		Cambridge		United Kingdom
17		London		United Kingdom
18		Nottingham		United Kingdom
19		Oxford		United Kingdom
20		Uxbridge		United Kingdom

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: NCT01335685
• Other Study ID Numbers: C16006; 2010-023772-71
• First Posted: Apr 14, 2011
• Last Update Posted: Jan 23, 2018
• Last Verified: Dec 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug Therapy
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Prednisone; Melphalan; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 14 investigative sites in United States Canada, United Kingdom, Spain, and Czech Republic from 27 June 2011 to 29 December 2016.
Pre-assignment Detail	Participants with a diagnosis of multiple myeloma (previously untreated) were enrolled to receive ixazomib orally at various doses in Phase 1. Only Arm B: Ixazomib 4.0 mg continued in Phase 2.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Period Title: Overall Study
STARTED	7	4	3	26	5	6	4	6
COMPLETED	4	3	1	15	5	1	2	3
NOT COMPLETED	3	1	2	11	0	5	2	3

Baseline Characteristics

Arm/Group Title	Arm A: Ixazomib 3.0 - 3.7 mg	Arm B: Ixazomib 3.0 - 5.5 mg	Arm C: Ixazomib 3.0 - 4.0 mg	Arm D: Ixazomib 4.0 mg	Total
Arm/Group Description	Ixazomib 3.0 - 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles).	Ixazomib 3.0 - 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1-4 for in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles).	Ixazomib 3.0 - 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles).	Total of all reporting groups
Overall Participants	11	34	10	6	61
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.2 (6.68)	74.3 (4.79)	76.3 (4.27)	73.2 (9.66)	74.5 (5.60)
Age, Customized (Count of Participants)
<75	6 54.5%	19 55.9%	2 20%	4 66.7%	31 50.8%
>=75	5 45.5%	15 44.1%	8 80%	2 33.3%	30 49.2%
Sex: Female, Male (Count of Participants)
Female	3 27.3%	12 35.3%	5 50%	3 50%	23 37.7%
Male	8 72.7%	22 64.7%	5 50%	3 50%	38 62.3%
Race/Ethnicity, Customized (Count of Participants)
Missing	2 18.2%	3 8.8%	0 0%	0 0%	5 8.2%
Not Hispanic or Latino	9 81.8%	31 91.2%	10 100%	6 100%	56 91.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	0 0%	1 10%	0 0%	1 1.6%
Black or African American	0 0%	1 2.9%	0 0%	0 0%	1 1.6%
White	10 90.9%	32 94.1%	9 90%	6 100%	57 93.4%
Other	1 9.1%	1 2.9%	0 0%	0 0%	2 3.3%
Region of Enrollment (Count of Participants)
Canada	0 0%	6 17.6%	2 20%	0 0%	8 13.1%
Czech Republic	6 54.5%	8 23.5%	0 0%	1 16.7%	15 24.6%
Spain	3 27.3%	15 44.1%	7 70%	5 83.3%	30 49.2%
United Kingdom	1 9.1%	2 5.9%	1 10%	0 0%	4 6.6%
United States	1 9.1%	3 8.8%	0 0%	0 0%	4 6.6%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	162.24 (7.872)	162.68 (12.087)	164.50 (11.413)	160.50 (16.897)	162.65 (11.615)
Weight at Baseline (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	70.58 (9.389)	73.43 (16.642)	72.77 (20.532)	66.97 (21.404)	72.17 (16.509)
Body Surface Area at Baseline (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.782 (0.1426)	1.813 (0.2638)	1.799 (0.3337)	1.718 (0.3650)	1.795 (0.2638)

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)
Description	The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).
Time Frame	Cycle 1, phase 1 (Up to 42 days)

Outcome Measure Data

Analysis Population Description

Dose Limiting Toxicity population included participants who received at least 80% of doses of MLN9708 and melphalan during Cycle 1 in Arms A or all doses of MLN9708 and melphalan during Cycle 1 in Arm B, C, D, or experience a DLT in Cycle 1 in the phase 1 dose escalation portion.

Arm/Group Title	Arm A: Ixazomib 3.0 - 3.7 mg	Arm B: Ixazomib 3.0 - 5.5 mg	Arm C: Ixazomib 3.0 - 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 - 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles).	Ixazomib 3.0 - 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1-4 for in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles).	Ixazomib 3.0 - 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles).
Measure Participants	11	34	10	6
Number [mg]	3	4	3	4

2. Primary Outcome

Title	Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)
Description	VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) < 5% plasma cells in bone marrow. VGPR: 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 hour.
Time Frame	Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)

Outcome Measure Data

Analysis Population Description

The response-evaluable population is defined as participants who received at least 5 of 8 MLN9708 doses in Arm A, at least 2 of 3 MLN9708 doses in Arm B, at least 4 of 5 MLN9708 doses in Arm C, or at least 3 of 4 MLN9708 doses in Arm D and had measurable disease at baseline and at least 1 post-baseline response assessment.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	23
Number [percentage of participants]	48 436.4%

3. Secondary Outcome

Title	Maximum Inhibition Rate (Emax) (Phase 1)
Description	Whole blood 20S proteasome inhibition parameters
Time Frame	At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

Outcome Measure Data

Analysis Population Description

Due to the change in the planned analysis, the efficacy endpoint of maximum inhibition rate was not performed.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	0	0	0	0	0	0	0	0

4. Secondary Outcome

Title	Time of Occurrence of Emax (TEmax) (Phase 1)
Description	Whole blood 20S proteasome inhibition parameters
Time Frame	At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study

Outcome Measure Data

Analysis Population Description

The efficacy endpoint of maximum inhibition rate was not performed due to the change in the planned analysis.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	0	0	0	0	0	0	0	0

5. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)
Time Frame	Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Outcome Measure Data

Analysis Population Description

The pharmacokinetics (PK) population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	1	3	20	4	6	4	5
Cycle 1, Day 1	26.791 (18.2608)	39.300 (NA)	22.950 (NA)	53.278 (41.1963)	104.225 (46.9148)	55.367 (43.8052)	50.875 (20.6487)	72.080 (54.3984)
Cycle 1, Day 11	69.214 (30.1985)	22.000 (NA)
Cycle 1, Day 15	30.267 (13.7173)	85.636 (64.6346)	285.000 (NA)
Cycle 1, Day 29	59.560 (37.2229)	109.000 (NA)	146.400 (90.1703)

6. Secondary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)
Time Frame	Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Outcome Measure Data

Analysis Population Description

The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	1	3	20	4	6	4	5
Cycle 1, Day 1	1.020	0.517	1.750	1.000	1.302	1.560	1.282	0.567
Cycle 1, Day 11	1.050	8.000
Cycle 1, Day 15	0.833	1.000	0.500
Cycle 1, Day 29	1.500	1.275	0.760

7. Secondary Outcome

Title	AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)
Time Frame	Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Outcome Measure Data

Analysis Population Description

The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	1	3	20	4	6	4	5
Cycle 1, Day 1	319.714 (104.6721)	287.000 (NA)	450.000 (NA)	806.824 (472.7173)	1612.250 (1009.5816)	662.833 (414.5178)	1037.500 (397.8748)	934.800 (390.2598)
Cycle 1, Day 11	1227.143 (338.9550)	1180.000 (NA)
Cycle 1, Day 15	705.667 (92.5005)	1610.500 (770.2156)	1680.000 (NA)
Cycle 1, Day 29	1527.800 (975.9914)	2680.000 (NA)	2435.000 (1107.5047)

8. Secondary Outcome

Title	Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)
Description	Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time Frame	Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Outcome Measure Data

Analysis Population Description

The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	1	3	20	4	6	4	5
Cycle 1, Day 15	0.004 (NA)	0.006 (0.0018)	0.007 (NA)	NA (NA)
Cycle 1, Day 29	0.005 (0.0021)	0.005 (NA)	0.006 (0.0025)

9. Secondary Outcome

Title	Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)
Description	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time Frame	Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Outcome Measure Data

Analysis Population Description

The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	1	3	20	4	6	4	5
Cycle 1, Day 15	167.000 (NA)	130.362 (45.0672)	98.900 (NA)	NA (NA)
Cycle 1, Day 29	140.575 (49.3760)	163.500 (NA)	120.050 (45.6024)

10. Secondary Outcome

Title	Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)
Description	Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1.
Time Frame	Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D

Outcome Measure Data

Analysis Population Description

The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	1	3	20	4	6	4	5
Cycle 1, Day 11	4.019 (1.1349)	4.120 (NA)
Cycle 1, Day 15	1.700 (NA)	2.288 (0.6246)	1.970 (NA)
Cycle 1, Day 29	2.632 (0.6732)	2.560 (NA)	2.540 (0.2061)

11. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR is defined as percentage of participants with overall response including CR, VGPR, and partial response (PR). Per IMWG criteria, CR:1)Negative immunofixation on serum and urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. If serum+urine M-protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.
Time Frame	Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years)

Outcome Measure Data

Analysis Population Description

The response-evaluable population is defined as participants who received at least 5 of 8 MLN9708 doses in Arm A, at least 2 of 3 MLN9708 doses in Arm B, at least 4 of 5 MLN9708 doses in Arm C, or at least 3 of 4 MLN9708 doses in Arm D and had measurable disease at baseline and at least 1 post-baseline response assessment.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	3	3	23	5	5	3	4
Number (95% Confidence Interval) [percentage of participants]	86 781.8%	67 197.1%	100 1000%	65 1083.3%	60 98.4%	40 NaN	67 NaN	50 NaN

12. Secondary Outcome

Title	Time to First Response (Phase 2)
Description	Response is defined as CR, VGPR and PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.
Time Frame	From the date of enrollment to the date of the first documented response for up to 5.5 years

Outcome Measure Data

Analysis Population Description

The safety population consisted of participants who received at least 1 dose of any study drug.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	15
Median (95% Confidence Interval) [months]	1.9

13. Secondary Outcome

Title	Duration of Response (DOR) (Phase 2)
Description	DOR is defined as time of first documentation of a confirmed PR or better response to first documented PD or start of alternative therapy. DOR was presented for those achieving CR+VGPR+PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.
Time Frame	From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years

Outcome Measure Data

Analysis Population Description

The safety population consisted of participants who received at least 1 dose of any study drug.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	23
Median (95% Confidence Interval) [months]	25.2

14. Secondary Outcome

Title	Time to Progression (TTP) (Phase 2)
Description	TTP is defined as time from date of enrollment to date of first documented disease progression (PD). Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.
Time Frame	From the date of enrollment to the date of the first documented disease progression for up to 5.5 years

Outcome Measure Data

Analysis Population Description

The safety population consisted of participants who received at least 1 dose of any study drug.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	26
Median (95% Confidence Interval) [months]	22.1

15. Secondary Outcome

Title	Time to Next Therapy (Phase 2)
Description	Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy.
Time Frame	From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years

Outcome Measure Data

Analysis Population Description

Time to next therapy was not analyzed due to the change in the planned analysis.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	0

16. Secondary Outcome

Title	Progression Free Survival (Phase 2)
Description	Progression Free Survival is defined as time in months from start of study treatment to first documentation of objective tumor progression per investigator assessment or up to death due to any cause, whichever occurs first. Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.
Time Frame	From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years

Outcome Measure Data

Analysis Population Description

The safety population consisted of participants who received at least 1 dose of any study drug.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	26
Median (95% Confidence Interval) [months]	18.4

17. Secondary Outcome

Title	Overall Survival (Phase 2)
Description	Overall Survival is the time in months from start of study treatment to date of death due to any cause.
Time Frame	From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)

Outcome Measure Data

Analysis Population Description

The safety population consisted of participants who received at least 1 dose of any study drug.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	26
Median (95% Confidence Interval) [months]	NA

18. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
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.
Time Frame	From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years

Outcome Measure Data

Analysis Population Description

The safety population consisted of participants who received at least 1 dose of any study drug.

Arm/Group Title	Arm A: Ixazomib 3.0 mg	Arm A: Ixazomib 3.7 mg	Arm B: Ixazomib 3.0 mg	Arm B: Ixazomib 4.0 mg	Arm B: Ixazomib 5.5 mg	Arm C: Ixazomib 3.0 mg	Arm C: Ixazomib 4.0 mg	Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).	Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).	Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).	Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
Measure Participants	7	4	3	26	5	6	4	6
During Entire Study Any Adverse Event	7 63.6%	4 11.8%	3 30%	26 433.3%	5 8.2%	6 NaN	4 NaN	6 NaN
Grade 3 or Higher Adverse Event	7 63.6%	4 11.8%	3 30%	21 350%	5 8.2%	5 NaN	4 NaN	5 NaN
Serious Adverse Event	2 18.2%	4 11.8%	3 30%	12 200%	3 4.9%	4 NaN	2 NaN	1 NaN
Adverse Event With Any Study Drug Discontinuation	0 0%	0 0%	0 0%	8 133.3%	2 3.3%	2 NaN	1 NaN	2 NaN
Adverse Event With Any Study Drug Reduction	4 36.4%	2 5.9%	1 10%	13 216.7%	3 4.9%	3 NaN	2 NaN	4 NaN

19. Secondary Outcome

Title	Assessments of Quality of Life (Phase 2)
Time Frame	Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years

Outcome Measure Data

Analysis Population Description

Assessments of quality of life parameters were not analyzed due to change in planned analysis.

Arm/Group Title	Arm B: Ixazomib 4.0 mg (RP2D)
Arm/Group Description	Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).
Measure Participants	0

Adverse Events

Time Frame	From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years
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	Arm A: Ixazomib 3.0 mg		Arm A: Ixazomib 3.7 mg		Arm B: Ixazomib 3.0 mg		Arm B: Ixazomib 4.0 mg		Arm B: Ixazomib 5.5 mg		Arm C: Ixazomib 3.0 mg		Arm C: Ixazomib 4.0 mg		Arm D: Ixazomib 4.0 mg
Arm/Group Description	Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).		Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).		Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).		Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).		Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).		Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).		Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).		Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).
All Cause Mortality
	Arm A: Ixazomib 3.0 mg		Arm A: Ixazomib 3.7 mg		Arm B: Ixazomib 3.0 mg		Arm B: Ixazomib 4.0 mg		Arm B: Ixazomib 5.5 mg		Arm C: Ixazomib 3.0 mg		Arm C: Ixazomib 4.0 mg		Arm D: Ixazomib 4.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: Ixazomib 3.0 mg		Arm A: Ixazomib 3.7 mg		Arm B: Ixazomib 3.0 mg		Arm B: Ixazomib 4.0 mg		Arm B: Ixazomib 5.5 mg		Arm C: Ixazomib 3.0 mg		Arm C: Ixazomib 4.0 mg		Arm D: Ixazomib 4.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)		4/4 (100%)		3/3 (100%)		12/26 (46.2%)		3/5 (60%)		4/6 (66.7%)		2/4 (50%)		1/6 (16.7%)
Blood and lymphatic system disorders
Neutropenia	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Thrombocytopenia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Cardiac disorders
Atrial fibrillation	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Supraventricular tachycardia	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Gastrointestinal disorders
Ileus	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Subileus	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Constipation	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Diarrhoea	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Rectal haemorrhage	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Vomiting	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Oesophageal ulcer haemorrhage	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
General disorders
Pyrexia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Asthenia	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hepatobiliary disorders
Cholecystitis	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Cholecystitis acute	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Infections and infestations
Pneumonia	0/7 (0%)		1/4 (25%)		0/3 (0%)		2/26 (7.7%)		1/5 (20%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)
Bronchitis	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Respiratory tract infection	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Diverticulitis	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Influenza	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Septic shock	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hip fracture	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Chest injury	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Overdose	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Face injury	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Lumbar vertebral fracture	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Diabetes mellitus	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Cachexia	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Back pain	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Nervous system disorders
Peripheral sensory neuropathy	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Polyneuropathy	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Cerebrovascular accident	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Syncope	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Dizziness	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Seizure	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Neuralgia	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Transient ischaemic attack	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Psychiatric disorders
Depression	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Renal and urinary disorders
Neurogenic bladder	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Acute kidney injury	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Pulmonary embolism	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Generalised erythema	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: Ixazomib 3.0 mg		Arm A: Ixazomib 3.7 mg		Arm B: Ixazomib 3.0 mg		Arm B: Ixazomib 4.0 mg		Arm B: Ixazomib 5.5 mg		Arm C: Ixazomib 3.0 mg		Arm C: Ixazomib 4.0 mg		Arm D: Ixazomib 4.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		4/4 (100%)		3/3 (100%)		26/26 (100%)		5/5 (100%)		6/6 (100%)		4/4 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	6/7 (85.7%)		4/4 (100%)		2/3 (66.7%)		16/26 (61.5%)		3/5 (60%)		5/6 (83.3%)		4/4 (100%)		6/6 (100%)
Neutropenia	5/7 (71.4%)		4/4 (100%)		2/3 (66.7%)		12/26 (46.2%)		2/5 (40%)		2/6 (33.3%)		4/4 (100%)		6/6 (100%)
Anaemia	4/7 (57.1%)		2/4 (50%)		1/3 (33.3%)		9/26 (34.6%)		5/5 (100%)		3/6 (50%)		3/4 (75%)		4/6 (66.7%)
Lymphopenia	3/7 (42.9%)		2/4 (50%)		1/3 (33.3%)		8/26 (30.8%)		2/5 (40%)		3/6 (50%)		2/4 (50%)		2/6 (33.3%)
Leukopenia	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		7/26 (26.9%)		2/5 (40%)		2/6 (33.3%)		2/4 (50%)		4/6 (66.7%)
Iron deficiency anaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Cardiac disorders
Atrial fibrillation	0/7 (0%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		1/4 (25%)		1/6 (16.7%)
Atrial flutter	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Atrial tachycardia	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Cardiac failure	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Supraventricular extrasystoles	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Tachycardia	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Endocrine disorders
Cushingoid	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Eye disorders
Blepharitis	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Eyelid oedema	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Erythema of eyelid	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Eye pruritus	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Eye swelling	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Ulcerative keratitis	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Visual acuity reduced	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Vitreous floaters	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Gastrointestinal disorders
Diarrhoea	4/7 (57.1%)		3/4 (75%)		1/3 (33.3%)		17/26 (65.4%)		5/5 (100%)		2/6 (33.3%)		3/4 (75%)		3/6 (50%)
Nausea	6/7 (85.7%)		2/4 (50%)		2/3 (66.7%)		11/26 (42.3%)		3/5 (60%)		3/6 (50%)		2/4 (50%)		4/6 (66.7%)
Vomiting	4/7 (57.1%)		4/4 (100%)		1/3 (33.3%)		11/26 (42.3%)		4/5 (80%)		1/6 (16.7%)		1/4 (25%)		2/6 (33.3%)
Constipation	2/7 (28.6%)		2/4 (50%)		2/3 (66.7%)		6/26 (23.1%)		3/5 (60%)		3/6 (50%)		3/4 (75%)		4/6 (66.7%)
Abdominal pain	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		5/26 (19.2%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Abdominal pain upper	2/7 (28.6%)		1/4 (25%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		2/6 (33.3%)
Dyspepsia	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		2/6 (33.3%)		0/4 (0%)		0/6 (0%)
Abdominal discomfort	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Mouth ulceration	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)
Dry mouth	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Dysphagia	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Flatulence	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Haemorrhoids	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Odynophagia	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Stomatitis	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Tongue ulceration	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)
Toothache	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)
Abdominal distension	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Abdominal hernia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Colitis	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Gastric disorder	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Gastrointestinal motility disorder	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Gastrooesophageal reflux disease	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Haematemesis	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Oral pain	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Rectal haemorrhage	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Tongue eruption	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
General disorders
Asthenia	1/7 (14.3%)		3/4 (75%)		1/3 (33.3%)		9/26 (34.6%)		2/5 (40%)		1/6 (16.7%)		2/4 (50%)		3/6 (50%)
Pyrexia	3/7 (42.9%)		3/4 (75%)		1/3 (33.3%)		6/26 (23.1%)		2/5 (40%)		1/6 (16.7%)		0/4 (0%)		3/6 (50%)
Fatigue	6/7 (85.7%)		0/4 (0%)		1/3 (33.3%)		9/26 (34.6%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Oedema peripheral	0/7 (0%)		0/4 (0%)		2/3 (66.7%)		7/26 (26.9%)		2/5 (40%)		2/6 (33.3%)		3/4 (75%)		1/6 (16.7%)
Peripheral swelling	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Gait disturbance	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Feeling cold	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Inflammation	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Malaise	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Pain	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Chest discomfort	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Chronic fatigue syndrome	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Feeling hot	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Localised oedema	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Immune system disorders
Drug hypersensitivity	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Infections and infestations
Respiratory tract infection	0/7 (0%)		2/4 (50%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		3/6 (50%)		0/4 (0%)		2/6 (33.3%)
Urinary tract infection	0/7 (0%)		1/4 (25%)		0/3 (0%)		6/26 (23.1%)		2/5 (40%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Bronchitis	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		3/26 (11.5%)		1/5 (20%)		2/6 (33.3%)		0/4 (0%)		0/6 (0%)
Upper respiratory tract infection	1/7 (14.3%)		1/4 (25%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Pharyngitis	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		3/26 (11.5%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Herpes zoster	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		1/4 (25%)		1/6 (16.7%)
Oral candidiasis	0/7 (0%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Oral herpes	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Rhinitis	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Viral infection	1/7 (14.3%)		1/4 (25%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Conjunctivitis	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Klebsiella infection	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Diverticulitis	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hordeolum	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Oesophageal candidiasis	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Streptococcal infection	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Urethritis	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Vulvovaginal candidiasis	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Wound infection	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Nasopharyngitis	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		4/26 (15.4%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)
Injury, poisoning and procedural complications
Fall	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Contusion	1/7 (14.3%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Clavicle fracture	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Compression fracture	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Face injury	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Injury	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Ligament sprain	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Overdose	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Spinal compression fracture	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Synovial rupture	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Wrist fracture	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Investigations
Weight decreased	3/7 (42.9%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)
Alanine aminotransferase increased	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Blood creatinine increased	0/7 (0%)		0/4 (0%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Platelet count decreased	0/7 (0%)		0/4 (0%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
C-reactive protein increased	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Electrocardiogram QT prolonged	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Blood electrolytes decreased	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Body temperature increased	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hepatic enzyme increased	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Influenza A virus test positive	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Liver function test increased	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
White blood cell count decreased	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Lymphocyte count decreased	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Metabolism and nutrition disorders
Decreased appetite	4/7 (57.1%)		1/4 (25%)		1/3 (33.3%)		8/26 (30.8%)		3/5 (60%)		0/6 (0%)		2/4 (50%)		3/6 (50%)
Hypokalaemia	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Hyponatraemia	1/7 (14.3%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Hyperglycaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Hypocalcaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Hypophosphataemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Electrolyte imbalance	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hypercalcaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hyperuricaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hypoalbuminaemia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hypomagnesaemia	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Malnutrition	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Type 2 diabetes mellitus	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		10/26 (38.5%)		1/5 (20%)		0/6 (0%)		3/4 (75%)		0/6 (0%)
Pain in extremity	3/7 (42.9%)		1/4 (25%)		2/3 (66.7%)		5/26 (19.2%)		1/5 (20%)		1/6 (16.7%)		1/4 (25%)		1/6 (16.7%)
Arthralgia	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		6/26 (23.1%)		0/5 (0%)		3/6 (50%)		0/4 (0%)		1/6 (16.7%)
Musculoskeletal chest pain	1/7 (14.3%)		1/4 (25%)		0/3 (0%)		6/26 (23.1%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Arthritis	1/7 (14.3%)		1/4 (25%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Myalgia	2/7 (28.6%)		1/4 (25%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Bone pain	0/7 (0%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		1/5 (20%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Musculoskeletal pain	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Flank pain	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Muscular weakness	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Polyarthritis	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Spinal pain	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Joint swelling	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Muscle spasms	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Muscle swelling	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Neck pain	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Osteoarthritis	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Plasmacytoma	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Nervous system disorders
Peripheral sensory neuropathy	4/7 (57.1%)		2/4 (50%)		0/3 (0%)		7/26 (26.9%)		2/5 (40%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)
Dizziness	2/7 (28.6%)		1/4 (25%)		1/3 (33.3%)		4/26 (15.4%)		0/5 (0%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)
Paraesthesia	2/7 (28.6%)		2/4 (50%)		0/3 (0%)		5/26 (19.2%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Headache	1/7 (14.3%)		3/4 (75%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)
Neuropathy peripheral	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		5/26 (19.2%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Neuralgia	1/7 (14.3%)		2/4 (50%)		0/3 (0%)		2/26 (7.7%)		1/5 (20%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Dysgeusia	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Somnolence	0/7 (0%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Ataxia	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Hypoaesthesia	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Tremor	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Ageusia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Autonomic nervous system imbalance	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Burning sensation	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Cognitive disorder	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Dementia	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Dementia Alzheimer's type	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Dizziness postural	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Dysaesthesia	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Memory impairment	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Polyneuropathy	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Sciatica	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Seizure	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Syncope	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Psychiatric disorders
Insomnia	1/7 (14.3%)		1/4 (25%)		1/3 (33.3%)		4/26 (15.4%)		2/5 (40%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Depression	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		4/26 (15.4%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Anxiety	0/7 (0%)		1/4 (25%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Confusional state	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Hallucination	0/7 (0%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Disorientation	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Renal and urinary disorders
Renal failure	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Urinary incontinence	0/7 (0%)		0/4 (0%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Dysuria	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Pollakiuria	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Urinary retention	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Anuria	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Chromaturia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Reproductive system and breast disorders
Uterine haemorrhage	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Cough	2/7 (28.6%)		2/4 (50%)		1/3 (33.3%)		9/26 (34.6%)		0/5 (0%)		2/6 (33.3%)		0/4 (0%)		1/6 (16.7%)
Dyspnoea	0/7 (0%)		0/4 (0%)		0/3 (0%)		5/26 (19.2%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		2/6 (33.3%)
Catarrh	0/7 (0%)		2/4 (50%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Epistaxis	0/7 (0%)		1/4 (25%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Respiratory failure	0/7 (0%)		1/4 (25%)		1/3 (33.3%)		1/26 (3.8%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Dyspnoea exertional	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Rhinitis allergic	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Rhinorrhoea	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Acute pulmonary oedema	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Acute respiratory distress syndrome	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Dysphonia	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)
Oropharyngeal pain	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Pharyngeal oedema	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Pleural effusion	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Rash macular	4/7 (57.1%)		0/4 (0%)		1/3 (33.3%)		3/26 (11.5%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Rash maculo-papular	3/7 (42.9%)		3/4 (75%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Pruritus	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		4/26 (15.4%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		2/6 (33.3%)
Rash pruritic	2/7 (28.6%)		0/4 (0%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Alopecia	0/7 (0%)		0/4 (0%)		0/3 (0%)		4/26 (15.4%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Erythema	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		1/4 (25%)		1/6 (16.7%)
Rash	0/7 (0%)		0/4 (0%)		0/3 (0%)		3/26 (11.5%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Rash papular	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		2/26 (7.7%)		0/5 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)
Dermatitis	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Hyperhidrosis	0/7 (0%)		1/4 (25%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Pruritus generalised	0/7 (0%)		1/4 (25%)		0/3 (0%)		1/26 (3.8%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Rash erythematous	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Swelling face	0/7 (0%)		0/4 (0%)		0/3 (0%)		2/26 (7.7%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Eczema	0/7 (0%)		1/4 (25%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Erythema nodosum	0/7 (0%)		0/4 (0%)		1/3 (33.3%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Generalised erythema	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Night sweats	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Rash generalised	1/7 (14.3%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Skin hyperpigmentation	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Vascular disorders
Hypotension	3/7 (42.9%)		0/4 (0%)		0/3 (0%)		6/26 (23.1%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)
Hypertension	1/7 (14.3%)		2/4 (50%)		0/3 (0%)		4/26 (15.4%)		1/5 (20%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Peripheral venous disease	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		1/6 (16.7%)		2/4 (50%)		1/6 (16.7%)
Peripheral coldness	2/7 (28.6%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)
Haematoma	0/7 (0%)		0/4 (0%)		0/3 (0%)		0/26 (0%)		0/5 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property