Trial Outcomes & Findings for A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Participants With Relapsed and/or Refractory Multiple Myeloma (NCT NCT01564537)

Last Updated: 2023-03-10

Results Overview

Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurs first. Response including PD was assessed by independent review committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. PD requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl); Urine M-component (absolute increase ≥ 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 10 mg/dl); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease. Status evaluated every 4 weeks until disease progression (PD) was confirmed.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

722 participants

Primary outcome timeframe

From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months)

Results posted on

2023-03-10

Participant Flow

Participants were enrolled at 187 sites in Australia, Austria, Belgium, Canada, China, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Republic of Korea, Netherlands, New Zealand, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Sweden, Turkey, United Kingdom and US from 01 August 2012 to 08 February 2022.

Participants with a diagnosis of relapsed and/or refractory multiple myeloma were enrolled in 1 of 2 treatment groups: Ixazomib 4 mg or Ixazomib placebo-matching tablets in combination with lenalidomide, and dexamethasone.

Participant milestones

Participant milestones
Measure	Ixazomib+ Lenalidomide + Dexamethasone Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Overall Study STARTED	360	362
Overall Study Intent-to-Treat (ITT) Population	360	362
Overall Study Safety Population	361	359
Overall Study Response Evaluable Population	345	348
Overall Study COMPLETED	259	263
Overall Study NOT COMPLETED	101	99

Reasons for withdrawal

Reasons for withdrawal
Measure	Ixazomib+ Lenalidomide + Dexamethasone Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Overall Study Site Terminated by Sponsor	1	0
Overall Study Withdrawal by Subject	12	14
Overall Study Lost to Follow-up	7	3
Overall Study Reason not specified	81	82

Baseline Characteristics

A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Participants With Relapsed and/or Refractory Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).	Total n=722 Participants Total of all reporting groups
Age, Continuous	65.5 years STANDARD_DEVIATION 9.13 • n=5 Participants	65.8 years STANDARD_DEVIATION 9.70 • n=7 Participants	65.7 years STANDARD_DEVIATION 9.41 • n=5 Participants
Age, Customized ≤65 years	168 participants n=5 Participants	176 participants n=7 Participants	344 participants n=5 Participants
Age, Customized >65-≤75 years	145 participants n=5 Participants	125 participants n=7 Participants	270 participants n=5 Participants
Age, Customized >75 years	47 participants n=5 Participants	61 participants n=7 Participants	108 participants n=5 Participants
Sex: Female, Male Female	153 Participants n=5 Participants	160 Participants n=7 Participants	313 Participants n=5 Participants
Sex: Female, Male Male	207 Participants n=5 Participants	202 Participants n=7 Participants	409 Participants n=5 Participants
Race/Ethnicity, Customized White	312 participants n=5 Participants	303 participants n=7 Participants	615 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	7 participants n=5 Participants	6 participants n=7 Participants	13 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Race/Ethnicity, Customized Asian	30 participants n=5 Participants	34 participants n=7 Participants	64 participants n=5 Participants
Race/Ethnicity, Customized American Indian/Alaska native	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Race/Ethnicity, Customized Not reported	5 participants n=5 Participants	13 participants n=7 Participants	18 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	9 participants n=5 Participants	12 participants n=7 Participants	21 participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	341 participants n=5 Participants	333 participants n=7 Participants	674 participants n=5 Participants
Race/Ethnicity, Customized Not Reported	8 participants n=5 Participants	15 participants n=7 Participants	23 participants n=5 Participants
Race/Ethnicity, Customized Missing	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Russian Federation	21 participants n=5 Participants	18 participants n=7 Participants	39 participants n=5 Participants
Region of Enrollment Singapore	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment United States	28 participants n=5 Participants	23 participants n=7 Participants	51 participants n=5 Participants
Region of Enrollment Portugal	7 participants n=5 Participants	8 participants n=7 Participants	15 participants n=5 Participants
Region of Enrollment Austria	5 participants n=5 Participants	4 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Netherlands	3 participants n=5 Participants	6 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Sweden	15 participants n=5 Participants	12 participants n=7 Participants	27 participants n=5 Participants
Region of Enrollment China	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Korea, Republic of	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Poland	21 participants n=5 Participants	20 participants n=7 Participants	41 participants n=5 Participants
Region of Enrollment France	36 participants n=5 Participants	45 participants n=7 Participants	81 participants n=5 Participants
Region of Enrollment Romania	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Hungary	18 participants n=5 Participants	21 participants n=7 Participants	39 participants n=5 Participants
Region of Enrollment United Kingdom	12 participants n=5 Participants	8 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment Spain	16 participants n=5 Participants	14 participants n=7 Participants	30 participants n=5 Participants
Region of Enrollment New Zealand	28 participants n=5 Participants	39 participants n=7 Participants	67 participants n=5 Participants
Region of Enrollment Canada	19 participants n=5 Participants	26 participants n=7 Participants	45 participants n=5 Participants
Region of Enrollment Czech Republic	15 participants n=5 Participants	21 participants n=7 Participants	36 participants n=5 Participants
Region of Enrollment Turkey	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Belgium	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Denmark	10 participants n=5 Participants	7 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Italy	24 participants n=5 Participants	15 participants n=7 Participants	39 participants n=5 Participants
Region of Enrollment Israel	19 participants n=5 Participants	14 participants n=7 Participants	33 participants n=5 Participants
Region of Enrollment Australia	9 participants n=5 Participants	8 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Germany	8 participants n=5 Participants	7 participants n=7 Participants	15 participants n=5 Participants
Region of Enrollment Japan	20 participants n=5 Participants	21 participants n=7 Participants	41 participants n=5 Participants
Stratification Factor: Lines of Prior Therapy 1 Line	212 participants n=5 Participants	213 participants n=7 Participants	425 participants n=5 Participants
Stratification Factor: Lines of Prior Therapy 2 or 3 Lines	148 participants n=5 Participants	149 participants n=7 Participants	297 participants n=5 Participants
Stratification Factor: Proteasome Inhibitor Exposed	250 participants n=5 Participants	253 participants n=7 Participants	503 participants n=5 Participants
Stratification Factor: Proteasome Inhibitor Naïve	110 participants n=5 Participants	109 participants n=7 Participants	219 participants n=5 Participants
Stratification Factor: International Staging System (ISS) Stag at Screening Stage I or Stage II	314 participants n=5 Participants	318 participants n=7 Participants	632 participants n=5 Participants
Stratification Factor: International Staging System (ISS) Stag at Screening Stage III	46 participants n=5 Participants	44 participants n=7 Participants	90 participants n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months)

Population: ITT population was defined as all randomized participants.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)	20.6 months Interval 17.02 to The upper limit of 95% confidence interval was not estimable due to low number of participants with events.	14.7 months Interval 12.91 to 17.58

SECONDARY outcome

Timeframe: From date of randomization until death (up to approximately 97 months)

Population: ITT population was defined as all randomized participants.

Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Overall Survival (OS)	53.6 months Interval 49.25 to 62.95	51.6 months Interval 44.78 to 59.14

SECONDARY outcome

Timeframe: From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

Population: ITT population was defined as all randomized participants. Overall number analyzed is the number of participants available for analysis.

Overall survival is defined as the time from the date of randomization to the date of death. The high-risk participants whose myeloma carried del(17) subgroup was defined as the cases reported as positive for del(17) by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17) by local laboratory. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. Data is only reported high-risk participants with Del(17).

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=36 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=33 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)]	42.2 months Interval 27.56 to 56.74	29.4 months Interval 16.99 to 44.22

SECONDARY outcome

Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months(approximate median follow-up 15 months)

Population: ITT population included all randomized participants.

ORR was defined as the percentage of participants with Complete Response (CR) including stringent complete response (sCR), very good partial response (VGPR) and Partial Response (PR) assessed by the IRC using IMWG criteria. Percentages are rounded off to single decimal.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Overall Response Rate (ORR) as Assessed by the IRC	78.3 percentage of participants	71.5 percentage of participants

SECONDARY outcome

Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Population: ITT population included all randomized participants.

Response was assessed by the IRC using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; \< 5% plasma cells in bone marrow. VGPR is defined as Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours. Percentages are rounded off to single decimal.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC	48.1 percentage of participants	39.0 percentage of participants

SECONDARY outcome

Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 38 months

Population: Response-Evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment. Overall number analyzed is the number of participants available for analysis.

DOR was measured as the time in months from the date of first documentation of a confirmed response of PR or better (CR \[including sCR\] + PR+ VGPR) to the date of the first documented disease progression (PD) among participants who responded to the treatment. Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=281 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=252 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Duration of Response (DOR)	26.0 months Interval 22.51 to The upper limit of CI was not estimable due to insufficient number of participants with events.	21.7 months Interval 17.77 to The upper limit of CI was not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Population: ITT population included all randomized participants

TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD) as assessed by the IRC using IMWG criteria.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Time to Progression (TTP) as Assessed by the IRC	22.4 months Interval 18.73 to 27.66	17.6 months Interval 14.52 to 20.27

SECONDARY outcome

Timeframe: From the date of signing of the informed consent form through 30 days after the last dose of study drug up to approximately 115 months

Population: Safety population included all randomized participants who received at least 1 dose of any study drug, regardless of their randomized treatment.

Eastern Cooperative Oncology Group (ECOG) performance score, laboratory values, vital sign measurements and reported adverse events (AEs) were collected and assessed to evaluate the safety of therapy throughout the study. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=361 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=359 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) TEAEs	359 Participants	357 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	205 Participants	201 Participants

SECONDARY outcome

Timeframe: Baseline and end of treatment (EOT) (up to approximately 38 months)

Population: ITT population included all randomized participants.

Pain response was defined as 30% reduction from Baseline in Brief Pain Inventory-Short Form (BPI-SF) worst pain score over the last 24 hours without an increase in analgesic (oral morphine equivalents) use at 2 consecutive evaluations. The BPI-SF contains 15 items designed to capture the pain severity ("worst," "least," "average," and "now" \[current pain\]), pain location, medication to relieve the pain, and the interference of pain with various daily activities including general activity, mood, walking activity, normal work, relations with other people, sleep, and enjoyment of life. The pain severity items are rated on a 0 to 10 scale where: 0=no pain and 10=pain as bad as you can imagine and averaged for a total score of 0 (best) to 10 (Worst).

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=360 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=362 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Number of Participants With Change From Baseline in Pain Response EOT	145 Participants	153 Participants
Number of Participants With Change From Baseline in Pain Response Baseline	345 Participants	351 Participants

SECONDARY outcome

Timeframe: Baseline, EOT and follow-up (up to approximately 97 months)

Population: ITT population included all randomized participants. Overall number analyzed is the number of participants available for analysis. Number analyzed is the number of participants available for analysis at the given timepoint.

The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement. Scores are linearly transformed to a 0-100 scale. High scores for the global and functional domains indicate higher quality of life or functioning. Higher scores on the symptom scales represent higher levels of symptomatology or problems.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=356 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=360 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Global Health Index: Baseline	58.4 score on a scale Standard Deviation 22.60	56.4 score on a scale Standard Deviation 22.12
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Global Health Index: End of Treatment	-6.0 score on a scale Standard Deviation 24.6	-6.0 score on a scale Standard Deviation 23.85
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Global Health Index: Last Follow-up	—	16.7 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Physical Functioning: Baseline	70.0 score on a scale Standard Deviation 21.74	67.3 score on a scale Standard Deviation 23.54
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Physical Functioning: EOT	-4.7 score on a scale Standard Deviation 22.61	-6.2 score on a scale Standard Deviation 23.36
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Physical Functioning: Last Follow-up	—	0.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Role Functioning: Baseline	68.4 score on a scale Standard Deviation 28.75	64.4 score on a scale Standard Deviation 30.24
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Role Functioning: EOT	-8.6 score on a scale Standard Deviation 31.27	-8.6 score on a scale Standard Deviation 32.90
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Role Functioning: Last Follow-up	—	-16.7 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Emotional Functioning: Baseline	75.1 score on a scale Standard Deviation 23.47	75.3 score on a scale Standard Deviation 22.22
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Emotional Functioning: EOT	-2.1 score on a scale Standard Deviation 20.09	-6.1 score on a scale Standard Deviation 23.16
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Emotional Functioning: Last Follow-up	—	-25.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Cognitive Functioning: Baseline	81.9 score on a scale Standard Deviation 20.42	81.6 score on a scale Standard Deviation 19.79
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Cognitive Functioning: EOT	-7.6 score on a scale Standard Deviation 20.61	-5.8 score on a scale Standard Deviation 22.24
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Cognitive Functioning: Last Follow-up	—	-50.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Social Functioning: Baseline	77.9 score on a scale Standard Deviation 26.07	75.3 score on a scale Standard Deviation 26.47
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Social Functioning: EOT	-6.9 score on a scale Standard Deviation 29.44	-7.9 score on a scale Standard Deviation 29.37
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Social Functioning: Last Follow-up	—	0.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Fatigue: Baseline	38.4 score on a scale Standard Deviation 23.98	39.5 score on a scale Standard Deviation 25.14
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Fatigue: EOT	6.0 score on a scale Standard Deviation 25.38	6.7 score on a scale Standard Deviation 26.61
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Fatigue: Last Follow-up	—	22.2 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Pain: Baseline	38.0 score on a scale Standard Deviation 28.30	38.5 score on a scale Standard Deviation 30.99
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Pain: EOT	2.7 score on a scale Standard Deviation 26.65	3.8 score on a scale Standard Deviation 30.07
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Pain: Last Follow-up	—	0.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Nausea and Vomiting: Baseline	5.0 score on a scale Standard Deviation 12.89	6.0 score on a scale Standard Deviation 13.31
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Nausea and Vomiting: EOT	3.4 score on a scale Standard Deviation 16.85	0.6 score on a scale Standard Deviation 19.22
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Nausea and Vomiting: Last Follow-up	—	33.3 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Dyspnea: Baseline	21.2 score on a scale Standard Deviation 26.74	23.7 score on a scale Standard Deviation 26.68
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Dyspnea: EOT	5.7 score on a scale Standard Deviation 31.04	2.3 score on a scale Standard Deviation 27.33
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Dyspnea: Last Follow-up	—	0.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Insomnia: Baseline	27.4 score on a scale Standard Deviation 31.04	30.5 score on a scale Standard Deviation 31.59
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Insomnia: EOT	0.9 score on a scale Standard Deviation 31.41	-0.5 score on a scale Standard Deviation 33.26
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Insomnia: Last Follow-up	—	33.3 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Appetite Loss: Baseline	16.9 score on a scale Standard Deviation 25.70	15.3 score on a scale Standard Deviation 25.21
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Appetite Loss: EOT	4.7 score on a scale Standard Deviation 31.49	6.5 score on a scale Standard Deviation 28.47
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Appetite Loss: Last Follow-up	—	0.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Constipation: Baseline	12.2 score on a scale Standard Deviation 22.58	13.5 score on a scale Standard Deviation 24.30
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Constipation: EOT	-1.3 score on a scale Standard Deviation 26.57	2.2 score on a scale Standard Deviation 27.05
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Constipation: Last Follow-up	—	33.3 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Diarrhea: Baseline	6.3 score on a scale Standard Deviation 16.38	8.1 score on a scale Standard Deviation 18.49
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Diarrhea: EOT	17.2 score on a scale Standard Deviation 31.08	10.8 score on a scale Standard Deviation 31.53
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Diarrhea: Last Follow-up	—	0.0 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Financial Difficulties: Baseline	16.7 score on a scale Standard Deviation 26.15	18.6 score on a scale Standard Deviation 28.30
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Financial Difficulties: EOT	0.5 score on a scale Standard Deviation 20.69	1.3 score on a scale Standard Deviation 26.54
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) Financial Difficulties: Last Follow-up	—	-33.3 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.

SECONDARY outcome

Timeframe: Baseline, EOT and follow-up (up to approximately 97 months)

The EORTC-QLQ-MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement. Scores are linearly transformed to a 0-100 scale. Higher scores on the symptom scales (e.g. Disease Symptoms, Side Effects of Treatment) represent higher levels of symptomatology or problems. High scores for Body Image and Future Perspective represent better quality of life or functioning.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=354 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=359 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Side Effects of Treatment: Last Follow-up	—	37.04 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Disease Symptoms: Baseline	29.71 score on a scale Standard Deviation 20.850	30.41 score on a scale Standard Deviation 23.072
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Disease Symptoms: EOT	-2.35 score on a scale Standard Deviation 20.752	-2.58 score on a scale Standard Deviation 21.372
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Disease Symptoms: Last Follow-up	1.11 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.	—
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Side Effects of Treatment: Baseline	17.23 score on a scale Standard Deviation 14.289	17.97 score on a scale Standard Deviation 14.682
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Side Effects of Treatment: EOT	4.52 score on a scale Standard Deviation 14.435	4.43 score on a scale Standard Deviation 13.955
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Body Image: Baseline	78.00 score on a scale Standard Deviation 29.259	79.48 score on a scale Standard Deviation 27.233
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Body Image: EOT	-0.27 score on a scale Standard Deviation 29.102	-5.38 score on a scale Standard Deviation 29.368
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Body Image: Last Follow-up	—	-33.3 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Future Perspective: Baseline	56.99 score on a scale Standard Deviation 25.170	60.26 score on a scale Standard Deviation 25.064
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Future Perspective: EOT	2.76 score on a scale Standard Deviation 22.90	-2.75 score on a scale Standard Deviation 22.842
Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) Future Perspective: Last Follow-up	—	-11.11 score on a scale Standard Deviation NA The SD was not estimable due to single participant with event.

SECONDARY outcome

Timeframe: From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

Population: ITT population included all randomized participants. Overall number analyzed is the number of participants available for analysis.

Overall survival (OS) is defined as the time from the date of randomization to the date of death. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are not included in the analysis. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. Data is only reported for high-risk participants.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=75 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=62 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
OS in High-Risk Participants	46.9 months Interval 34.04 to 64.53	30.9 months Interval 24.77 to 42.25

SECONDARY outcome

Timeframe: From date of randomization until disease progression or death up to approximately 38 months (approximate median follow-up 15 months)

Population: Participants from the ITT population, all randomized participants, with cytogenic abnormalities. Overall number analyzed is the number of participants available for analysis.

Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Response was assessed by independent review committee (IRC) using IMWG response criteria. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are not included in the analysis.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=75 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=62 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
PFS in High-Risk Participants	18.7 months Interval 13.24 to The upper limit of CI was not estimable due to insufficient number of participants with events.	9.3 months Interval 7.36 to 15.7

SECONDARY outcome

Timeframe: Pre-dose and post-dose at multiple timepoints up to Cycle 10 Day 1 (each cycle length = 28 days)

Population: Safety population is defined as all subjects who received at least 1 dose of any study drug. Overall number analyzed is the number of participants available for analysis. Number analyzed is the number of participants available for analysis at the given timepoint.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=335 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=5 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Plasma Concentration Over Time for Ixazomib Cycle 1 Day 1	4.79 μg/mL Standard Deviation NA The SD was not estimable due to single participant with event.	—
Plasma Concentration Over Time for Ixazomib Cycle 1 Day 1, 1 Hour Post-Dose	36.3 μg/mL Standard Deviation 31.3	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 1 Day 1, 4 Hours Post-Dose	15.6 μg/mL Standard Deviation 11.1	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 1 Day 14, Pre-Dose	6.83 μg/mL Standard Deviation 10.5	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 2 Day 1, Pre-Dose	2.4 μg/mL Standard Deviation 2.4	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 2 Day 14, Pre-Dose	7.12 μg/mL Standard Deviation 8.44	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 3 Day 1, Pre-Dose	2.48 μg/mL Standard Deviation 1.69	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 4 Day 1, Pre-Dose	2.41 μg/mL Standard Deviation 1.35	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 5 Day 1, Pre-Dose	2.42 μg/mL Standard Deviation 1.49	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 6 Day 1, Pre-Dose	2.57 μg/mL Standard Deviation 3.89	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 7 Day 1, Pre-Dose	2.71 μg/mL Standard Deviation 4.79	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 8 Day 1, Pre-Dose	2.37 μg/mL Standard Deviation 1.47	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 9 Day 1, Pre-Dose	2.51 μg/mL Standard Deviation 2.13	0 μg/mL Standard Deviation 0
Plasma Concentration Over Time for Ixazomib Cycle 10 Day 1, Pre-Dose	2.82 μg/mL Standard Deviation 5.98	0 μg/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Population: ITT population included all randomized participants. Overall number analyzed is the number of participants available with data.

Data is reported for percentage of participants defined by polymorphism defined by polymorphisms in proteasome genes, such as polymorphism P11A in PSMB1 gene. Percentages are rounded off to single decimal.

Outcome measures

Outcome measures
Measure	Ixazomib+ Lenalidomide + Dexamethasone n=117 Participants Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to EOT (up to approximately 42.9 months).	Placebo + Lenalidomide + Dexamethasone n=115 Participants Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first (up to approximately 41 months).
Overall Response Rate in Participants Defined by Polymorphism	80.3 percentage of participants Interval 72.0 to 87.1	75.7 percentage of participants Interval 66.8 to 83.2

Adverse Events

Ixazomib+ Lenalidomide + Dexamethasone

Serious events: 205 serious events

Other events: 350 other events

Deaths: 250 deaths

Placebo + Lenalidomide + Dexamethasone

Serious events: 202 serious events

Other events: 342 other events

Deaths: 251 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER