Trial Outcomes & Findings for A Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Participants With Multiple Myeloma Following Autologous Stem Cell Transplant (NCT NCT02181413)

NCT ID: NCT02181413

Last Updated: 2024-11-19

Results Overview

PFS was defined as the time from the date of randomization to the date of first documentation of PD, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be \>10 milligrams per deciliter (mg/dL); participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must have been ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size increase; hypercalcemia development.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 656 participants
• Primary outcome timeframe: Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks (up to 45 months)
• Results posted on: 2024-11-19

Participant Flow

Participants enrolled at 167 sites globally to take part in this study from 16 July 2014 to 8 September 2023.

Participants with newly diagnosed multiple myeloma (NDMM) who underwent induction therapy according to regional standard of care (SoC), followed by high-dose melphalan (200 milligrams per meter square [mg/m^2]) and Autologous Stem Cell Transplant (ASCT) were enrolled in a 3:2 ratio to receive ixazomib citrate or placebo.

Participant milestones

Measure	Placebo Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.
Overall Study STARTED	261	395
Overall Study Intent-to-Treat (ITT) Population	261	395
Overall Study Safety Population	259	394
Overall Study Per Protocol (PP) Population	256	387
Overall Study COMPLETED	206	322
Overall Study NOT COMPLETED	55	73

Reasons for withdrawal

Measure	Placebo Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.
Overall Study Withdrawal by Subject	45	61
Overall Study Reason Not Specified	2	5
Overall Study Lost to Follow-up	8	7

Baseline Characteristics

Number analyzed is the number of participants with available height data.

Baseline characteristics by cohort

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.	Total n=656 Participants Total of all reporting groups
Age, Continuous	58.2 years STANDARD_DEVIATION 7.92 • n=261 Participants	56.8 years STANDARD_DEVIATION 8.17 • n=395 Participants	57.4 years STANDARD_DEVIATION 8.10 • n=656 Participants
Age, Customized <60 years	127 Participants n=261 Participants	229 Participants n=395 Participants	356 Participants n=656 Participants
Age, Customized ≥60 and <75 years	134 Participants n=261 Participants	166 Participants n=395 Participants	300 Participants n=656 Participants
Sex: Female, Male Female	99 Participants n=261 Participants	143 Participants n=395 Participants	242 Participants n=656 Participants
Sex: Female, Male Male	162 Participants n=261 Participants	252 Participants n=395 Participants	414 Participants n=656 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=261 Participants	14 Participants n=395 Participants	25 Participants n=656 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	240 Participants n=261 Participants	362 Participants n=395 Participants	602 Participants n=656 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	10 Participants n=261 Participants	19 Participants n=395 Participants	29 Participants n=656 Participants
Race/Ethnicity, Customized White	213 Participants n=261 Participants	315 Participants n=395 Participants	528 Participants n=656 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=261 Participants	7 Participants n=395 Participants	10 Participants n=656 Participants
Race/Ethnicity, Customized Asian	36 Participants n=261 Participants	59 Participants n=395 Participants	95 Participants n=656 Participants
Race/Ethnicity, Customized Other	1 Participants n=261 Participants	2 Participants n=395 Participants	3 Participants n=656 Participants
Race/Ethnicity, Customized Not Reported	8 Participants n=261 Participants	12 Participants n=395 Participants	20 Participants n=656 Participants
Region of Enrollment Australia	11 Participants n=261 Participants	17 Participants n=395 Participants	28 Participants n=656 Participants
Region of Enrollment Japan	9 Participants n=261 Participants	13 Participants n=395 Participants	22 Participants n=656 Participants
Region of Enrollment Korea, Republic Of	17 Participants n=261 Participants	23 Participants n=395 Participants	40 Participants n=656 Participants
Region of Enrollment Singapore	4 Participants n=261 Participants	8 Participants n=395 Participants	12 Participants n=656 Participants
Region of Enrollment Taiwan, Province Of China	3 Participants n=261 Participants	10 Participants n=395 Participants	13 Participants n=656 Participants
Region of Enrollment Thailand	1 Participants n=261 Participants	5 Participants n=395 Participants	6 Participants n=656 Participants
Region of Enrollment Austria	2 Participants n=261 Participants	2 Participants n=395 Participants	4 Participants n=656 Participants
Region of Enrollment Belgium	5 Participants n=261 Participants	5 Participants n=395 Participants	10 Participants n=656 Participants
Region of Enrollment Czech Republic	12 Participants n=261 Participants	30 Participants n=395 Participants	42 Participants n=656 Participants
Region of Enrollment Denmark	11 Participants n=261 Participants	20 Participants n=395 Participants	31 Participants n=656 Participants
Region of Enrollment France	7 Participants n=261 Participants	11 Participants n=395 Participants	18 Participants n=656 Participants
Region of Enrollment Germany	26 Participants n=261 Participants	50 Participants n=395 Participants	76 Participants n=656 Participants
Region of Enrollment Greece	22 Participants n=261 Participants	38 Participants n=395 Participants	60 Participants n=656 Participants
Region of Enrollment Hungary	9 Participants n=261 Participants	16 Participants n=395 Participants	25 Participants n=656 Participants
Region of Enrollment Israel	12 Participants n=261 Participants	10 Participants n=395 Participants	22 Participants n=656 Participants
Region of Enrollment Italy	26 Participants n=261 Participants	24 Participants n=395 Participants	50 Participants n=656 Participants
Region of Enrollment Netherlands	11 Participants n=261 Participants	8 Participants n=395 Participants	19 Participants n=656 Participants
Region of Enrollment Norway	6 Participants n=261 Participants	13 Participants n=395 Participants	19 Participants n=656 Participants
Region of Enrollment Poland	5 Participants n=261 Participants	10 Participants n=395 Participants	15 Participants n=656 Participants
Region of Enrollment Portugal	2 Participants n=261 Participants	8 Participants n=395 Participants	10 Participants n=656 Participants
Region of Enrollment South Africa	4 Participants n=261 Participants	3 Participants n=395 Participants	7 Participants n=656 Participants
Region of Enrollment Spain	19 Participants n=261 Participants	19 Participants n=395 Participants	38 Participants n=656 Participants
Region of Enrollment Sweden	4 Participants n=261 Participants	7 Participants n=395 Participants	11 Participants n=656 Participants
Region of Enrollment Switzerland	3 Participants n=261 Participants	0 Participants n=395 Participants	3 Participants n=656 Participants
Region of Enrollment Turkey	10 Participants n=261 Participants	10 Participants n=395 Participants	20 Participants n=656 Participants
Region of Enrollment Ukraine	2 Participants n=261 Participants	1 Participants n=395 Participants	3 Participants n=656 Participants
Region of Enrollment United Kingdom	14 Participants n=261 Participants	21 Participants n=395 Participants	35 Participants n=656 Participants
Region of Enrollment Argentina	0 Participants n=261 Participants	3 Participants n=395 Participants	3 Participants n=656 Participants
Region of Enrollment Brazil	3 Participants n=261 Participants	5 Participants n=395 Participants	8 Participants n=656 Participants
Region of Enrollment United States	1 Participants n=261 Participants	5 Participants n=395 Participants	6 Participants n=656 Participants
Height	168.73 cm STANDARD_DEVIATION 10.347 • n=256 Participants • Number analyzed is the number of participants with available height data.	169.71 cm STANDARD_DEVIATION 10.004 • n=388 Participants • Number analyzed is the number of participants with available height data.	169.32 cm STANDARD_DEVIATION 10.145 • n=644 Participants • Number analyzed is the number of participants with available height data.
Weight	75.18 kg STANDARD_DEVIATION 14.648 • n=261 Participants • Number analyzed is the number of participants with available weight data.	75.93 kg STANDARD_DEVIATION 15.989 • n=395 Participants • Number analyzed is the number of participants with available weight data.	75.63 kg STANDARD_DEVIATION 15.463 • n=656 Participants • Number analyzed is the number of participants with available weight data.
Body Surface Area (BSA)	1.87 m^2 STANDARD_DEVIATION 0.221 • n=256 Participants • Number analyzed is the number of participants with available BSA data.	1.88 m^2 STANDARD_DEVIATION 0.235 • n=388 Participants • Number analyzed is the number of participants with available BSA data.	1.88 m^2 STANDARD_DEVIATION 0.229 • n=644 Participants • Number analyzed is the number of participants with available BSA data.

PRIMARY outcome

Timeframe: Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks (up to 45 months)

Population: Intent-to-Treat (ITT) population was defined as all participants who were randomized and had post randomization data.

PFS was defined as the time from the date of randomization to the date of first documentation of PD, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be >10 milligrams per deciliter (mg/dL); participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must have been ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size increase; hypercalcemia development.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Progression Free Survival (PFS)	21.3 months Interval 17.97 to 24.67	26.5 months Interval 23.69 to 33.81

SECONDARY outcome

Timeframe: Randomization up to end of follow up period (up to 107 months)

Population: ITT population was defined as all participants who were randomized and had post randomization data.

OS was measured as the time from the date of randomization to the date of death.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Overall Survival (OS)	NA months Interval 96.95 to Median and upper limit of 95% confidence interval (CI) were not estimable due to low number of participants with events.	NA months Interval 104.97 to Median and upper limit of 95% confidence interval (CI) were not estimable due to low number of participants with events.

SECONDARY outcome

Timeframe: Randomization up to EOT (up to 24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months)

Population: ITT population was defined as all participants who were randomized and had post randomization data.

Response was assessed according to IMWG criteria. Best response includes partial response (PR), very good partial response (VGPR) and complete response (CR). PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to less than (<)200 milligrams (mg) per 24 hours. VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. CR is negative immunofixation of serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent CR (sCR) is CR and normal FLC ratio and absence of clonal plasma cells (PCs) by immunohistochemistry or 2- to 4-color flow cytometry. The decimal values of percentages were subjected to rounding off.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy PR	10 percentage of participants	12 percentage of participants
Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy VGPR	45 percentage of participants	40 percentage of participants
Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy CR	42 percentage of participants	44 percentage of participants

SECONDARY outcome

Timeframe: Randomization up to PD (up to 107 months)

Population: ITT Population was defined as all participants who were randomized and had post randomization data.

TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria. PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%;new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. Participants without documentation of PD at the time of analysis were censored at the date of last response assessment that is stable disease or better.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Time to Progression (TTP)	21.4 months Interval 18.1 to 24.67	26.6 months Interval 23.69 to 33.81

SECONDARY outcome

Timeframe: Randomization up to EOT (24 months); thereafter followed up every 4 weeks until initiation of next-line therapy and then every 12 weeks until second progressive disease (PD2) or death (up to 107 months)

Population: ITT population was defined as all participants who were randomized and had post randomization data.

PFS2 is defined as the time from the date of randomization to the date of objective disease progression on next line treatment or death from any cause (whichever occurs first). PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Second Progression Free Survival (PFS2)	80.4 months Interval 68.7 to Upper limit of 95% CI was not estimable due to low number of participants with events.	84.0 months Interval 67.22 to Upper limit of 95% CI was not estimable due to low number of participants with events.

SECONDARY outcome

Timeframe: Randomization up to 107 months

Population: ITT population was defined as all participants who were randomized and had post randomization data.

Time to start of the next line of therapy was defined as the time from the date of randomization to the date of initiation dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurred first. Participants who never took antineoplastic therapy were censored at the date of last contact or death.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Time to Start of the Next Line of Therapy	27.6 months Interval 24.48 to 31.61	33.1 months Interval 29.14 to 36.34

SECONDARY outcome

Timeframe: Randomization up to 107 months

Population: ITT Population was defined as all participants who were randomized and had post randomization data.

Time to end of the next line of therapy was defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurred first or date of last contact for participants who never took antineoplastic therapy.

Outcome measures

Measure	Placebo n=261 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=395 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Time to End of the Next Line of Therapy	50.4 months Interval 42.84 to 61.01	55.9 months Interval 49.61 to 61.86

SECONDARY outcome

Timeframe: Up to 107 months

Population: ITT Population was defined as all participants who were randomized and had post randomization data. Overall number of participants analyzed indicates the number of participants who started next line of therapy.

Duration of the next line of therapy was defined as the time from the date of the first dose of the next line of therapy to the date of the last dose of the next antineoplastic therapy following study treatment or death due to any cause, whichever occurred first. Duration of the next line of therapy was analyzed on those participants who received the next line of therapy following the study treatment and duration was summarized using Kaplan-Meier method.

Outcome measures

Measure	Placebo n=187 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=278 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Duration of the Next Line of Therapy	12.3 months Interval 9.82 to 16.53	9.6 months Interval 7.49 to 12.06

SECONDARY outcome

Timeframe: Up to 107 months

Population: Safety Population was defined as participants who received at least 1 dose of ixzaomib citrate or placebo.

The decimal values of percentages were subjected to rounding off.

Outcome measures

Measure	Placebo n=259 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=394 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Percentage of Participants Who Develop a New Primary Malignancy	8 percentage of participants	7 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to EOT (up to 24 months)

Population: ITT population was defined as all participants who were randomized and had post randomization data. Overall number of participants analyzed indicates the number of participants with MRD+ at Baseline.

MRD negativity (MRD-) is defined as absence of MRD and MRD positivity (MRD+) is defined as presence of MRD. The conversion rate from MRD positive to MRD negative was assessed and reported. Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry and a sequencing methodology.

Outcome measures

Measure	Placebo n=139 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=225 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative	27 Participants	39 Participants

SECONDARY outcome

Timeframe: Up to EOT (up to 24 months)

Population: ITT population was defined as all participants who were randomized and had post randomization data. Overall number analyzed is the number of participants who converted from MRD+ at Baseline to MRD negative.

MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. The maintenance of MRD negativity up to the end of treatment was assessed and reported in participants converting from MRD+ at Baseline to MRD negative. Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry and a sequencing methodology.

Outcome measures

Measure	Placebo n=27 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=39 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Number of Participants With Maintenance of MRD Negativity	25 Participants	37 Participants

SECONDARY outcome

Timeframe: From randomization up to 107 months

Population: ITT population was defined as all participants who were randomized and had post randomization data. Overall number analyzed is the number of participants with data available for analyses. Number analyzed indicates the number of participants available for analysis in the specified category.

PFS is defined as the time from the date of randomization to the date of first documentation of PD as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 107 months in this outcome measure.

Outcome measures

Measure	Placebo n=214 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=342 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Correlation Between MRD Status and Progression Free Survival (PFS) MRD- at Study Entry	32.5 months Interval 19.32 to Upper limit of 95% CI was not estimable due to censoring.	38.6 months Interval 33.81 to Upper limit of 95% CI was not estimable due to censoring.
Correlation Between MRD Status and Progression Free Survival (PFS) MRD+ at Study Entry	18.5 months Interval 15.7 to 21.91	23.1 months Interval 20.24 to 25.69

SECONDARY outcome

Timeframe: From randomization up to 107 months

Population: ITT population was defined as all participants who were randomized and had post randomization data. Overall number analyzed is the number of participants with data available for analyses. Number analyzed indicates the number of participants available for analysis in the specified category.

OS was measured as the time from the date of randomization to the date of death, assessed for up to 107 months in this outcome measure.

Outcome measures

Measure	Placebo n=214 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=342 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Correlation Between MRD Status and Overall Survival (OS) MRD- at Study Entry	NA months Interval 84.9 to Median and upper limit of 95% CI were not estimable due to censoring.	NA months Median, lower limit, and upper limit of 95% CI were not estimable due to censoring.
Correlation Between MRD Status and Overall Survival (OS) MRD+ at Study Entry	NA months Interval 90.74 to Median and upper limit of 95% CI were not estimable due to censoring.	105.0 months Interval 91.47 to Upper limit of 95% CI was not estimable due to censoring.

SECONDARY outcome

Timeframe: Randomization up to 107 months

Population: ITT population was defined as all participants who were randomized and had post randomization data. Overall number analyzed is the number of participants present in the high-risk group.

High-risk population included but was not limited to participants carrying deletion (del)17, t(4:14), t(14:16), amplification (ampl) 1q, del13, or del1p. OS was measured as the time from the date of randomization to the date of death.

Outcome measures

Measure	Placebo n=54 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=61 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
OS Benefits in a High-Risk Population	69.0 months Interval 33.25 to 92.98	64.2 months Interval 40.97 to Upper limit of 95% CI was not estimable due to low number of participants with events.

SECONDARY outcome

Timeframe: Randomization up to 107 months

Population: ITT population was defined as all participants who were randomized and had post randomization data. Overall number of participants analyzed is the number of participants present in the high-risk group.

High-risk population included but not be limited to participants carrying deletion (del)17, t(4:14), t(14:16), amplification (ampl) 1q, del13, or del1p. PFS was defined as the time from the date of randomization to the date of first documentation of PD, as evaluated by an independent review committee according to IMWG criteria, or death due to any cause (whichever occurs first). PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%;new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development.

Outcome measures

Measure	Placebo n=54 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=61 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
PFS Benefits in a High-Risk Population	16.8 months Interval 12.81 to 18.5	18.5 months Interval 12.06 to 31.15

SECONDARY outcome

Timeframe: Baseline up to EOT (up to Month 24)

Population: Safety population was defined as participants who received at least 1 dose of ixazomib citrate or placebo. Overall number of participants analyzed indicates the number of participants with data available for analysis.

ECOG performance status assesses a participant's performance status on a 6-point scale ranging from 0=fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead. Lower scores indicate improvement.

Outcome measures

Measure	Placebo n=252 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=371 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score	0.1 score on a scale Standard Deviation 0.63	0.0 score on a scale Standard Deviation 0.54

SECONDARY outcome

Timeframe: Up to 107 months

Population: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject administered a drug. An AE can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital abnormality or birth defect, an important medical event.

Outcome measures

Measure	Placebo n=259 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=394 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs) TEAEs	241 Participants	382 Participants
Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs) SAEs	51 Participants	108 Participants

SECONDARY outcome

Timeframe: Up to 107 months

Population: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.

Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug.

Outcome measures

Measure	Placebo n=259 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=394 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs	36 Participants	81 Participants

SECONDARY outcome

Timeframe: Baseline up to EOT (up to Month 24)

Population: ITT Population was defined as all participants who were randomized and had post randomization data. Overall number of participants analyzed indicates the number of participants with data available for analysis.

The EORTC QLQ-C30 is a 30-item questionnaire used to assess the health-related quality of life of cancer patients. GHS/QoL domain is based on questions 29 ("How would you rate your overall health during the past week?") and 30 ("How would you rate your overall quality of life during the past week?") of the EORTC QLQ-C30 where the study participants' self-reported responses to the questions on a 7-point scale (1=very poor to 7=excellent). The raw GHS/QoL domain scores were linearly transformed to a scale ranging 0 (worse outcome) to 100 (best outcome), with higher scores indicating better quality of life. The change from baseline in EORTC QLQ-C30 GHS/QoL domain was evaluated by treatment group.

Outcome measures

Measure	Placebo n=237 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=349 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Domain Score	-1.7 score on a scale Standard Error 1.57	-4.1 score on a scale Standard Error 1.43

SECONDARY outcome

Timeframe: Day 1 of Cycle 1: 1 hour and 4 hours post-dose; Predose on Days 8 and 15 of Cycle 1, Days 1 and 8 of Cycle 2, Day 1 of Cycles 3 through 10 (each cycle length= 28 days)

Population: The Pharmacokinetic (PK) Analysis Population was defined as participants with at least one PK sample that was collected and analyzed. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) were measured using a validated Liquid Chromatography-tandem Mass Spectrometry (LC/MS/MS) assay.

Outcome measures

Measure	Placebo n=393 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Plasma Concentration of Ixazomib Cycle 1 Day 1: 1 Hour Post-dose	27.919 nanograms per milliliter (ng/mL) Standard Deviation 24.7787	—
Plasma Concentration of Ixazomib Cycle 1 Day 1: 4 Hours Post-dose	10.352 nanograms per milliliter (ng/mL) Standard Deviation 9.8078	—
Plasma Concentration of Ixazomib Cycle 1 Day 8	1.584 nanograms per milliliter (ng/mL) Standard Deviation 1.6707	—
Plasma Concentration of Ixazomib Cycle 1 Day 15	2.611 nanograms per milliliter (ng/mL) Standard Deviation 1.4305	—
Plasma Concentration of Ixazomib Cycle 2 Day 1	1.946 nanograms per milliliter (ng/mL) Standard Deviation 1.0984	—
Plasma Concentration of Ixazomib Cycle 2 Day 8	3.232 nanograms per milliliter (ng/mL) Standard Deviation 2.0069	—
Plasma Concentration of Ixazomib Cycle 3 Day 1	2.258 nanograms per milliliter (ng/mL) Standard Deviation 1.1508	—
Plasma Concentration of Ixazomib Cycle 4 Day 1	2.396 nanograms per milliliter (ng/mL) Standard Deviation 1.7822	—
Plasma Concentration of Ixazomib Cycle 5 Day 1	2.400 nanograms per milliliter (ng/mL) Standard Deviation 1.4921	—
Plasma Concentration of Ixazomib Cycle 6 Day 1	2.623 nanograms per milliliter (ng/mL) Standard Deviation 1.6994	—
Plasma Concentration of Ixazomib Cycle 7 Day 1	2.691 nanograms per milliliter (ng/mL) Standard Deviation 1.9842	—
Plasma Concentration of Ixazomib Cycle 8 Day 1	2.637 nanograms per milliliter (ng/mL) Standard Deviation 1.7074	—
Plasma Concentration of Ixazomib Cycle 9 Day 1	2.610 nanograms per milliliter (ng/mL) Standard Deviation 1.9380	—
Plasma Concentration of Ixazomib Cycle 10 Day 1	2.594 nanograms per milliliter (ng/mL) Standard Deviation 1.9509	—

SECONDARY outcome

Timeframe: Up to 107 months

Population: Safety population was defined as participants who received at least 1 dose of ixazomib citrate or placebo. Overall number of participants analyzed indicates the number of participants with peripheral neuropathy events.

Peripheral neuropathy is defined as the TEAE in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as improved if the event improves from the maximum grade. That is, all the grades recorded after the maximum grade is less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first.

Outcome measures

Measure	Placebo n=39 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=73 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Time to Resolution of Peripheral Neuropathy (PN) Events	159.0 days Interval 45.0 to 736.0	225.0 days Interval 117.0 to 421.0

SECONDARY outcome

Timeframe: Up to 107 months

Population: Safety population was defined as participants who received at least 1 dose of ixazomib citrate or placebo. Overall number of participants analyzed indicates number of participants with peripheral neuropathy events.

PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. A PN event is considered as improved if the event improves from the maximum grade. That is, all the grades recorded after the maximum grade is less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first.

Outcome measures

Measure	Placebo n=39 Participants Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=73 Participants Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Time to Improvement of PN Events	130.0 days Interval 36.0 to 520.0	134.0 days Interval 70.0 to 252.0

Adverse Events

Placebo

Serious events: 51 serious events

Other events: 229 other events

Deaths: 93 deaths

Ixazomib Citrate

Serious events: 108 serious events

Other events: 371 other events

Deaths: 144 deaths

Serious adverse events

Measure	Placebo n=259 participants at risk Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=394 participants at risk Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Infections and infestations Pharyngitis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Picornavirus infection	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Abdominal pain upper	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations Alanine aminotransferase increased	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Blood and lymphatic system disorders Anaemia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Ankle fracture	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Ankylosing spondylitis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Appendicitis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations Aspartate aminotransferase increased	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Cardiac disorders Atrial fibrillation	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Atypical pneumonia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Back pain	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.76% 3/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Bacterial infection	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations Blood alkaline phosphatase increased	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Bone contusion	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Bone pain	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Bronchitis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.76% 3/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations C-reactive protein increased	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Cardiac disorders Cardiac failure	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Cellulitis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Cerebral ischaemia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Chills	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Colitis ischaemic	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Constipation	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Psychiatric disorders Delirium	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Dengue fever	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Psychiatric disorders Depression	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Product Issues Device dislocation	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Diaphragmatic hernia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Diarrhoea	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	1.0% 4/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Eye disorders Diplopia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Diverticulitis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Immune system disorders Drug hypersensitivity	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Enteritis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Skin and subcutaneous tissue disorders Erythema nodosum	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Escherichia sepsis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations Gamma-glutamyltransferase increased	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Gastritis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Gastroenteritis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Haematemesis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Blood and lymphatic system disorders Haemolytic anaemia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Herpes zoster	0.77% 2/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	1.0% 4/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Herpes zoster disseminated	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Metabolism and nutrition disorders Hyperglycaemia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Vascular disorders Hypertension	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Metabolism and nutrition disorders Hypokalaemia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Influenza	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	1.0% 4/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations Influenza B virus test positive	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Inguinal hernia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Vascular disorders Jugular vein thrombosis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Kyphosis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Leiomyoma	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Investigations Light chain analysis increased	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Lower limb fracture	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Lower respiratory tract infection	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.76% 3/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Metapneumovirus infection	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Cardiac disorders Myocardial infarction	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Cardiac disorders Myocardial ischaemia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Nasopharyngitis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Non-cardiac chest pain	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Organising pneumonia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.76% 3/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Overdose	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Pain	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Pancreatitis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Parainfluenzae virus infection	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Pathological fracture	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	1.0% 4/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Periodontal disease	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasma cell leukaemia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasma cell myeloma	0.77% 2/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasmacytoma	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumococcal sepsis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumonia	3.9% 10/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.3% 25/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumonia parainfluenzae viral	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumonia pneumococcal	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumonia streptococcal	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumonia viral	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Post herpetic neuralgia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Reproductive system and breast disorders Prostatitis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Pyrexia	0.77% 2/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	1.3% 5/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Radicular pain	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Skin and subcutaneous tissue disorders Rash	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Skin and subcutaneous tissue disorders Rash macular	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Renal and urinary disorders Renal impairment	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Respiratory syncytial virus infection	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Respiratory tract infection	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Sepsis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Sinusitis	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.76% 3/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Somnolence	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Spinal cord compression	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of lung	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Vascular disorders Subclavian vein thrombosis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Blood and lymphatic system disorders Thrombocytopenia	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Tonsillitis	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Transient ischaemic attack	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Metabolism and nutrition disorders Tumour lysis syndrome	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Injury, poisoning and procedural complications Ulnar nerve injury	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Umbilical hernia	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Upper respiratory tract infection	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.51% 2/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Renal and urinary disorders Urinary retention	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine cancer	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Varicella	0.39% 1/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.00% 0/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Vomiting	0.00% 0/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	0.25% 1/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.

Other adverse events

Measure	Placebo n=259 participants at risk Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib Citrate n=394 participants at risk Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.
Blood and lymphatic system disorders Thrombocytopenia	2.3% 6/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	10.2% 40/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Upper respiratory tract infection	20.8% 54/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	25.4% 100/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Vomiting	10.8% 28/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	26.6% 105/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Blood and lymphatic system disorders Anaemia	3.1% 8/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	7.1% 28/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Arthralgia	16.6% 43/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	26.6% 105/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Asthenia	6.6% 17/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	7.6% 30/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Back pain	18.1% 47/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	19.5% 77/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Bone pain	7.3% 19/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	9.4% 37/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Bronchitis	7.3% 19/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	10.2% 40/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Conjunctivitis	3.9% 10/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	7.1% 28/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Constipation	8.1% 21/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	10.4% 41/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Cough	21.2% 55/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	22.1% 87/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Metabolism and nutrition disorders Decreased appetite	6.6% 17/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	5.3% 21/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Diarrhoea	23.6% 61/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	34.3% 135/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Dizziness	6.9% 18/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	8.4% 33/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Dyspepsia	5.8% 15/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	3.3% 13/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Fatigue	16.6% 43/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	20.1% 79/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Headache	8.9% 23/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	10.9% 43/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Herpes zoster	5.4% 14/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	9.4% 37/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Vascular disorders Hypertension	7.3% 19/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	5.3% 21/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Influenza	11.2% 29/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	9.6% 38/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Influenza like illness	6.9% 18/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	9.4% 37/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Psychiatric disorders Insomnia	4.6% 12/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	7.9% 31/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Muscle spasms	8.1% 21/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	8.9% 35/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.8% 15/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	5.1% 20/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Myalgia	5.4% 14/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	5.6% 22/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Nasopharyngitis	26.6% 69/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	23.1% 91/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Gastrointestinal disorders Nausea	15.4% 40/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	39.1% 154/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Neuropathy peripheral	7.3% 19/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	10.2% 40/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Blood and lymphatic system disorders Neutropenia	5.8% 15/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.1% 24/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Oedema peripheral	4.2% 11/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	8.6% 34/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.9% 18/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	7.4% 29/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Musculoskeletal and connective tissue disorders Pain in extremity	10.0% 26/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	8.1% 32/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Paraesthesia	3.1% 8/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.9% 27/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Nervous system disorders Peripheral sensory neuropathy	8.9% 23/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	10.4% 41/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pharyngitis	3.5% 9/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	5.1% 20/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Pneumonia	5.8% 15/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.1% 24/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Respiratory, thoracic and mediastinal disorders Productive cough	3.5% 9/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.6% 26/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Skin and subcutaneous tissue disorders Pruritus	7.3% 19/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	8.9% 35/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
General disorders Pyrexia	14.3% 37/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	19.8% 78/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Skin and subcutaneous tissue disorders Rash macular	3.1% 8/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.1% 24/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Skin and subcutaneous tissue disorders Rash maculo-papular	3.5% 9/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	6.1% 24/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
Infections and infestations Sinusitis	2.3% 6/259 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.	5.1% 20/394 • Randomization up to end of follow up period (107 months) All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: TrialDisclosures@takeda.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place