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

• ClinicalTrials.gov Identifier: NCT01564537
• Recruitment Status: Completed
• First Posted: March 28, 2012
• Results First Posted: January 27, 2016
• Last Update Posted: March 10, 2023
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Relapsed Multiple Myeloma; Refractory Multiple Myeloma
• Interventions: Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Placebo
• Enrollment: 722

Participant Flow

Recruitment Details	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.
Pre-assignment Details	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.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	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).	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).
Period Title: Overall Study
Started	360	362
Intent-to-Treat (ITT) Population [1]	360	362
Safety Population [2]	361	359
Response Evaluable Population [3]	345	348
Completed	259	263
Not Completed	101	99
Reason Not Completed
Site Terminated by Sponsor	1	0
Withdrawal by Subject	12	14
Lost to Follow-up	7	3
Reason not specified	81	82
[1] ITT population was defined as all randomized participants.; [2] Safety population included all randomized participants who received at least 1 dose of any study drug, regardless of their randomized treatment.; [3] 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.

Baseline Characteristics

Arm/Group Title		Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone	Total
Arm/Group Description		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).	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 of all reporting groups
Overall Number of Baseline Participants		360	362	722
Baseline Analysis Population Description		Intent-to-Treat (ITT) population was defined as all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	360 participants	362 participants	722 participants
		65.5 (9.13)	65.8 (9.70)	65.7 (9.41)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
≤65 years		168	176	344
>65-≤75 years		145	125	270
>75 years		47	61	108
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	360 participants	362 participants	722 participants
	Female	153 42.5%	160 44.2%	313 43.4%
	Male	207 57.5%	202 55.8%	409 56.6%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
White		312	303	615
Black or African American		7	6	13
Native Hawaiian/Other Pacific Islander		2	2	4
Asian		30	34	64
American Indian/Alaska native		0	1	1
Other		4	3	7
Not reported		5	13	18
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
Hispanic or Latino		9	12	21
Not Hispanic or Latino		341	333	674
Not Reported		8	15	23
Missing		2	2	4
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
Russian Federation		21	18	39
Singapore		2	4	6
United States		28	23	51
Portugal		7	8	15
Austria		5	4	9
Netherlands		3	6	9
Sweden		15	12	27
China		3	3	6
Korea, Republic of		4	2	6
Poland		21	20	41
France		36	45	81
Romania		6	6	12
Hungary		18	21	39
United Kingdom		12	8	20
Spain		16	14	30
New Zealand		28	39	67
Canada		19	26	45
Czech Republic		15	21	36
Turkey		4	3	7
Belgium		7	7	14
Denmark		10	7	17
Italy		24	15	39
Israel		19	14	33
Australia		9	8	17
Germany		8	7	15
Japan		20	21	41
Stratification Factor: Lines of Prior Therapy; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
1 Line		212	213	425
2 or 3 Lines		148	149	297
Stratification Factor: Proteasome Inhibitor; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
Exposed		250	253	503
Naïve		110	109	219
Stratification Factor: International Staging System (ISS) Stag at Screening [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	360 participants	362 participants	722 participants
Stage I or Stage II		314	318	632
Stage III		46	44	90
		[1] Measure Description: Stage I: Serum beta2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL; Stage II: Neither Stage I or III, meaning that either: beta2-microglobulin level ≥3.5 and <5.5 mg/L (with any albumin level), OR albumin <3.5 g/dL with beta2-microglobulin <3.5 mg/L; Stage III: Serum beta2-microglobulin ≥5.5 mg/L. Normal serum beta2-microglobulin: <3.0 mg/L; normal albumin: 3.5-5.0 g/dL.

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) as Assessed by the Independent Review Committee (IRC)
Description	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.
Time Frame	From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	360	362
Median (95% Confidence Interval); Unit of Measure: months
	20.6 [1]; (17.02 to NA)	14.7; (12.91 to 17.58)

[1]

The upper limit of 95% confidence interval was not estimable due to low number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ixazomib+ Lenalidomide + Dexamethasone, Placebo + Lenalidomide + Dexamethasone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.012
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.742
	Confidence Interval	(2-Sided) 95%; 0.587 to 0.939
	Estimation Comments	HR is estimated from Cox Regression.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	From date of randomization until death (up to approximately 97 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	360	362
Median (95% Confidence Interval); Unit of Measure: months
	53.6; (49.25 to 62.95)	51.6; (44.78 to 59.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ixazomib+ Lenalidomide + Dexamethasone, Placebo + Lenalidomide + Dexamethasone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.495
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.939
	Confidence Interval	(2-Sided) 95%; 0.784 to 1.125
	Estimation Comments	HR:estimated from Cox Regression with stratification factors: prior therapies, proteasome inhibitor, and ISS Stage at Screening with treatment as factor in model. <1 hazard ratio for treatment=better prevention of death in drug arm vs control.

3. Secondary Outcome

Title	Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)]
Description	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).
Time Frame	From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	36	33
Median (95% Confidence Interval); Unit of Measure: months
	42.2; (27.56 to 56.74)	29.4; (16.99 to 44.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ixazomib+ Lenalidomide + Dexamethasone, Placebo + Lenalidomide + Dexamethasone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.764
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.916
	Confidence Interval	(2-Sided) 95%; 0.516 to 1.626
	Estimation Comments	HR:estimated from Cox Regression with stratification factors: prior therapies, proteasome inhibitor, and ISS Stage at Screening with treatment as factor in model. <1 hazard ratio for treatment=better prevention of death in drug arm vs control.

4. Secondary Outcome

Title	Overall Response Rate (ORR) as Assessed by the IRC
Description	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.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months(approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	360	362
Measure Type: Number; Unit of Measure: percentage of participants
	78.3	71.5

5. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC
Description	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.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Ixazomib + Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	360	362
Measure Type: Number; Unit of Measure: percentage of participants
	48.1	39.0

6. Secondary Outcome

Title	Duration of Response (DOR)
Description	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.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 38 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	281	252
Median (95% Confidence Interval); Unit of Measure: months
	26.0 [1]; (22.51 to NA)	21.7 [1]; (17.77 to NA)

[1]

The upper limit of CI was not estimable due to insufficient number of participants with events.

7. Secondary Outcome

Title	Time to Progression (TTP) as Assessed by the IRC
Description	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.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	360	362
Median (95% Confidence Interval); Unit of Measure: months
	22.4; (18.73 to 27.66)	17.6; (14.52 to 20.27)

8. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	361	359
Measure Type: Count of Participants; Unit of Measure: Participants
TEAEs	359 99.4%	357 99.4%
SAEs	205 56.8%	201 56.0%

9. Secondary Outcome

Title	Number of Participants With Change From Baseline in Pain Response
Description	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).
Time Frame	Baseline and end of treatment (EOT) (up to approximately 38 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	360	362
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline	345	351
EOT	145	153

10. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30)
Description	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.
Time Frame	Baseline, EOT and follow-up (up to approximately 97 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:		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).	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 Number of Participants Analyzed		356	360
Mean (Standard Deviation); Unit of Measure: score on a scale
Global Health Index: Baseline	Number Analyzed	355 participants	359 participants
		58.4 (22.60)	56.4 (22.12)
Global Health Index: End of Treatment	Number Analyzed	251 participants	255 participants
		-6.0 (24.6)	-6.0 (23.85)
Global Health Index: Last Follow-up	Number Analyzed	0 participants	1 participants
			16.7 [1] (NA)
Physical Functioning: Baseline	Number Analyzed	356 participants	359 participants
		70.0 (21.74)	67.3 (23.54)
Physical Functioning: EOT	Number Analyzed	253 participants	261 participants
		-4.7 (22.61)	-6.2 (23.36)
Physical Functioning: Last Follow-up	Number Analyzed	0 participants	1 participants
			0.0 [1] (NA)
Role Functioning: Baseline	Number Analyzed	356 participants	360 participants
		68.4 (28.75)	64.4 (30.24)
Role Functioning: EOT	Number Analyzed	253 participants	261 participants
		-8.6 (31.27)	-8.6 (32.90)
Role Functioning: Last Follow-up	Number Analyzed	0 participants	1 participants
			-16.7 [1] (NA)
Emotional Functioning: Baseline	Number Analyzed	355 participants	360 participants
		75.1 (23.47)	75.3 (22.22)
Emotional Functioning: EOT	Number Analyzed	251 participants	256 participants
		-2.1 (20.09)	-6.1 (23.16)
Emotional Functioning: Last Follow-up	Number Analyzed	0 participants	1 participants
			-25.0 [1] (NA)
Cognitive Functioning: Baseline	Number Analyzed	355 participants	360 participants
		81.9 (20.42)	81.6 (19.79)
Cognitive Functioning: EOT	Number Analyzed	251 participants	256 participants
		-7.6 (20.61)	-5.8 (22.24)
Cognitive Functioning: Last Follow-up	Number Analyzed	0 participants	1 participants
			-50.0 [1] (NA)
Social Functioning: Baseline	Number Analyzed	354 participants	360 participants
		77.9 (26.07)	75.3 (26.47)
Social Functioning: EOT	Number Analyzed	250 participants	256 participants
		-6.9 (29.44)	-7.9 (29.37)
Social Functioning: Last Follow-up	Number Analyzed	0 participants	1 participants
			0.0 [1] (NA)
Fatigue: Baseline	Number Analyzed	356 participants	360 participants
		38.4 (23.98)	39.5 (25.14)
Fatigue: EOT	Number Analyzed	253 participants	261 participants
		6.0 (25.38)	6.7 (26.61)
Fatigue: Last Follow-up	Number Analyzed	0 participants	1 participants
			22.2 [1] (NA)
Pain: Baseline	Number Analyzed	356 participants	360 participants
		38.0 (28.30)	38.5 (30.99)
Pain: EOT	Number Analyzed	253 participants	261 participants
		2.7 (26.65)	3.8 (30.07)
Pain: Last Follow-up	Number Analyzed	0 participants	1 participants
			0.0 [1] (NA)
Nausea and Vomiting: Baseline	Number Analyzed	356 participants	360 participants
		5.0 (12.89)	6.0 (13.31)
Nausea and Vomiting: EOT	Number Analyzed	252 participants	261 participants
		3.4 (16.85)	0.6 (19.22)
Nausea and Vomiting: Last Follow-up	Number Analyzed	0 participants	1 participants
			33.3 [1] (NA)
Dyspnea: Baseline	Number Analyzed	356 participants	360 participants
		21.2 (26.74)	23.7 (26.68)
Dyspnea: EOT	Number Analyzed	252 participants	261 participants
		5.7 (31.04)	2.3 (27.33)
Dyspnea: Last Follow-up	Number Analyzed	0 participants	1 participants
			0.0 [1] (NA)
Insomnia: Baseline	Number Analyzed	356 participants	360 participants
		27.4 (31.04)	30.5 (31.59)
Insomnia: EOT	Number Analyzed	252 participants	260 participants
		0.9 (31.41)	-0.5 (33.26)
Insomnia: Last Follow-up	Number Analyzed	0 participants	1 participants
			33.3 [1] (NA)
Appetite Loss: Baseline	Number Analyzed	356 participants	360 participants
		16.9 (25.70)	15.3 (25.21)
Appetite Loss: EOT	Number Analyzed	253 participants	260 participants
		4.7 (31.49)	6.5 (28.47)
Appetite Loss: Last Follow-up	Number Analyzed	0 participants	1 participants
			0.0 [1] (NA)
Constipation: Baseline	Number Analyzed	355 participants	360 participants
		12.2 (22.58)	13.5 (24.30)
Constipation: EOT	Number Analyzed	249 participants	259 participants
		-1.3 (26.57)	2.2 (27.05)
Constipation: Last Follow-up	Number Analyzed	0 participants	1 participants
			33.3 [1] (NA)
Diarrhea: Baseline	Number Analyzed	355 participants	360 participants
		6.3 (16.38)	8.1 (18.49)
Diarrhea: EOT	Number Analyzed	250 participants	256 participants
		17.2 (31.08)	10.8 (31.53)
Diarrhea: Last Follow-up	Number Analyzed	0 participants	1 participants
			0.0 [1] (NA)
Financial Difficulties: Baseline	Number Analyzed	352 participants	360 participants
		16.7 (26.15)	18.6 (28.30)
Financial Difficulties: EOT	Number Analyzed	250 participants	256 participants
		0.5 (20.69)	1.3 (26.54)
Financial Difficulties: Last Follow-up	Number Analyzed	0 participants	1 participants
			-33.3 [1] (NA)

[1]

The SD was not estimable due to single participant with event.

11. Secondary Outcome

Title	Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20)
Description	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.
Time Frame	Baseline, EOT and follow-up (up to approximately 97 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:		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).	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 Number of Participants Analyzed		354	359
Mean (Standard Deviation); Unit of Measure: score on a scale
Disease Symptoms: Baseline	Number Analyzed	354 participants	359 participants
		29.71 (20.850)	30.41 (23.072)
Disease Symptoms: EOT	Number Analyzed	248 participants	255 participants
		-2.35 (20.752)	-2.58 (21.372)
Disease Symptoms: Last Follow-up	Number Analyzed	1 participants	0 participants
		1.11 [1] (NA)
Side Effects of Treatment: Baseline	Number Analyzed	354 participants	359 participants
		17.23 (14.289)	17.97 (14.682)
Side Effects of Treatment: EOT	Number Analyzed	249 participants	255 participants
		4.52 (14.435)	4.43 (13.955)
Side Effects of Treatment: Last Follow-up	Number Analyzed	0 participants	1 participants
			37.04 [1] (NA)
Body Image: Baseline	Number Analyzed	353 participants	359 participants
		78.00 (29.259)	79.48 (27.233)
Body Image: EOT	Number Analyzed	245 participants	254 participants
		-0.27 (29.102)	-5.38 (29.368)
Body Image: Last Follow-up	Number Analyzed	0 participants	1 participants
			-33.3 [1] (NA)
Future Perspective: Baseline	Number Analyzed	353 participants	359 participants
		56.99 (25.170)	60.26 (25.064)
Future Perspective: EOT	Number Analyzed	248 participants	255 participants
		2.76 (22.90)	-2.75 (22.842)
Future Perspective: Last Follow-up	Number Analyzed	0 participants	1 participants
			-11.11 [1] (NA)

[1]

The SD was not estimable due to single participant with event.

12. Secondary Outcome

Title	OS in High-Risk Participants
Description	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.
Time Frame	From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	75	62
Median (95% Confidence Interval); Unit of Measure: months
	46.9; (34.04 to 64.53)	30.9; (24.77 to 42.25)

13. Secondary Outcome

Title	PFS in High-Risk Participants
Description	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.
Time Frame	From date of randomization until disease progression or death up to approximately 38 months (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 Number of Participants Analyzed	75	62
Median (95% Confidence Interval); Unit of Measure: months
	18.7 [1]; (13.24 to NA)	9.3; (7.36 to 15.70)

[1]

The upper limit of CI was not estimable due to insufficient number of participants with events.

14. Secondary Outcome

Title	Plasma Concentration Over Time for Ixazomib
Description	[Not Specified]
Time Frame	Pre-dose and post-dose at multiple timepoints up to Cycle 10 Day 1 (each cycle length = 28 days)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:		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).	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 Number of Participants Analyzed		335	5
Mean (Standard Deviation); Unit of Measure: μg/mL
Cycle 1 Day 1	Number Analyzed	1 participants	0 participants
		4.79 [1] (NA)
Cycle 1 Day 1, 1 Hour Post-Dose	Number Analyzed	330 participants	4 participants
		36.3 (31.3)	0 (0)
Cycle 1 Day 1, 4 Hours Post-Dose	Number Analyzed	321 participants	4 participants
		15.6 (11.1)	0 (0)
Cycle 1 Day 14, Pre-Dose	Number Analyzed	335 participants	4 participants
		6.83 (10.5)	0 (0)
Cycle 2 Day 1, Pre-Dose	Number Analyzed	331 participants	5 participants
		2.4 (2.4)	0 (0)
Cycle 2 Day 14, Pre-Dose	Number Analyzed	324 participants	5 participants
		7.12 (8.44)	0 (0)
Cycle 3 Day 1, Pre-Dose	Number Analyzed	329 participants	5 participants
		2.48 (1.69)	0 (0)
Cycle 4 Day 1, Pre-Dose	Number Analyzed	319 participants	4 participants
		2.41 (1.35)	0 (0)
Cycle 5 Day 1, Pre-Dose	Number Analyzed	307 participants	4 participants
		2.42 (1.49)	0 (0)
Cycle 6 Day 1, Pre-Dose	Number Analyzed	290 participants	4 participants
		2.57 (3.89)	0 (0)
Cycle 7 Day 1, Pre-Dose	Number Analyzed	279 participants	3 participants
		2.71 (4.79)	0 (0)
Cycle 8 Day 1, Pre-Dose	Number Analyzed	268 participants	2 participants
		2.37 (1.47)	0 (0)
Cycle 9 Day 1, Pre-Dose	Number Analyzed	262 participants	4 participants
		2.51 (2.13)	0 (0)
Cycle 10 Day 1, Pre-Dose	Number Analyzed	239 participants	2 participants
		2.82 (5.98)	0 (0)

[1]

The SD was not estimable due to single participant with event.

15. Secondary Outcome

Title	Overall Response Rate in Participants Defined by Polymorphism
Description	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.
Time Frame	Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description:	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).	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 progressive disease (PD) or unacceptable toxicity, whichever occurred first up to (up to approximately 41 months).
Overall Number of Participants Analyzed	117	115
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	80.3; (72.0 to 87.1)	75.7; (66.8 to 83.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ixazomib+ Lenalidomide + Dexamethasone, Placebo + Lenalidomide + Dexamethasone
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.332
	Comments	P-value is from Cochran-Mantel-Haenszel stratified by: prior therapies (1, 2 or 3), proteasome inhibitor (exposed, naïve), and ISS Stage at Screening (I or II, III).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.69 to 2.45
	Estimation Comments	Odds ratio is from logistic regression model with prognostic factors: prior therapies (1, 2 or 3), proteasome inhibitor (exposed, naïve),and ISS Stage at Screening (I or II, III). Odds ratio > 1 favors Ixazomib.

Adverse Events

Time Frame	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
Adverse Event Reporting Description	The investigator had to document any occurrence of adverse events including abnormal laboratory findings. Any event spontaneously reported by the participant or observed by investigator was recorded, irrespective of the relation to study treatment. Safety population included all randomized participants who received at least 1 dose of any study drug, regardless of their randomized treatment.
Arm/Group Title	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
Arm/Group Description	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).	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).
All-Cause Mortality
	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	Affected / at Risk (%)
Total	250/361 (69.25%)	251/359 (69.92%)
Serious Adverse Events
	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	Affected / at Risk (%)
Total	205/361 (56.79%)	202/359 (56.27%)
Blood and lymphatic system disorders
Anaemia † 1	5/361 (1.39%)	10/359 (2.79%)
Disseminated intravascular coagulation † 1	2/361 (0.55%)	0/359 (0.00%)
Febrile neutropenia † 1	2/361 (0.55%)	9/359 (2.51%)
Hyperviscosity syndrome † 1	0/361 (0.00%)	1/359 (0.28%)
Immune thrombocytopenia † 1	1/361 (0.28%)	0/359 (0.00%)
Leukopenia † 1	0/361 (0.00%)	1/359 (0.28%)
Neutropenia † 1	2/361 (0.55%)	2/359 (0.56%)
Pancytopenia † 1	3/361 (0.83%)	1/359 (0.28%)
Thrombocytopenia † 1	5/361 (1.39%)	6/359 (1.67%)
Thrombotic microangiopathy † 1	1/361 (0.28%)	0/359 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	1/361 (0.28%)	1/359 (0.28%)
Acute myocardial infarction † 1	1/361 (0.28%)	2/359 (0.56%)
Angina pectoris † 1	2/361 (0.55%)	3/359 (0.84%)
Angina unstable † 1	0/361 (0.00%)	1/359 (0.28%)
Arrhythmia † 1	0/361 (0.00%)	1/359 (0.28%)
Atrial fibrillation † 1	6/361 (1.66%)	7/359 (1.95%)
Atrial flutter † 1	2/361 (0.55%)	0/359 (0.00%)
Atrioventricular block complete † 1	0/361 (0.00%)	1/359 (0.28%)
Cardiac arrest † 1	3/361 (0.83%)	3/359 (0.84%)
Cardiac failure † 1	4/361 (1.11%)	6/359 (1.67%)
Cardiac failure acute † 1	1/361 (0.28%)	1/359 (0.28%)
Cardiac failure congestive † 1	2/361 (0.55%)	3/359 (0.84%)
Cardio-respiratory arrest † 1	1/361 (0.28%)	0/359 (0.00%)
Cardiogenic shock † 1	0/361 (0.00%)	1/359 (0.28%)
Cardiovascular insufficiency † 1	1/361 (0.28%)	0/359 (0.00%)
Coronary artery disease † 1	1/361 (0.28%)	0/359 (0.00%)
Coronary artery thrombosis † 1	0/361 (0.00%)	1/359 (0.28%)
Diastolic dysfunction † 1	1/361 (0.28%)	0/359 (0.00%)
Left ventricular dysfunction † 1	1/361 (0.28%)	0/359 (0.00%)
Myocardial infarction † 1	5/361 (1.39%)	2/359 (0.56%)
Myocardial ischaemia † 1	4/361 (1.11%)	0/359 (0.00%)
Supraventricular tachycardia † 1	1/361 (0.28%)	0/359 (0.00%)
Trifascicular block † 1	1/361 (0.28%)	0/359 (0.00%)
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy † 1	0/361 (0.00%)	1/359 (0.28%)
Ear and labyrinth disorders
Acute vestibular syndrome † 1	0/361 (0.00%)	1/359 (0.28%)
Endocrine disorders
Toxic goitre † 1	1/361 (0.28%)	0/359 (0.00%)
Eye disorders
Cataract † 1	5/361 (1.39%)	7/359 (1.95%)
Retinal vein thrombosis † 1	1/361 (0.28%)	0/359 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	1/361 (0.28%)	0/359 (0.00%)
Abdominal pain lower † 1	1/361 (0.28%)	0/359 (0.00%)
Abdominal pain upper † 1	1/361 (0.28%)	0/359 (0.00%)
Colitis † 1	1/361 (0.28%)	1/359 (0.28%)
Colitis ischaemic † 1	1/361 (0.28%)	0/359 (0.00%)
Constipation † 1	1/361 (0.28%)	1/359 (0.28%)
Diarrhoea † 1	12/361 (3.32%)	3/359 (0.84%)
Diverticular perforation † 1	1/361 (0.28%)	0/359 (0.00%)
Dyspepsia † 1	2/361 (0.55%)	0/359 (0.00%)
Femoral hernia incarcerated † 1	1/361 (0.28%)	0/359 (0.00%)
Gastrointestinal haemorrhage † 1	0/361 (0.00%)	1/359 (0.28%)
Gastrooesophageal reflux disease † 1	1/361 (0.28%)	0/359 (0.00%)
Haematochezia † 1	0/361 (0.00%)	1/359 (0.28%)
Ileus † 1	1/361 (0.28%)	0/359 (0.00%)
Ileus paralytic † 1	2/361 (0.55%)	0/359 (0.00%)
Inguinal hernia † 1	3/361 (0.83%)	2/359 (0.56%)
Intestinal obstruction † 1	1/361 (0.28%)	0/359 (0.00%)
Large intestinal obstruction † 1	1/361 (0.28%)	0/359 (0.00%)
Nausea † 1	2/361 (0.55%)	0/359 (0.00%)
Oesophageal achalasia † 1	1/361 (0.28%)	0/359 (0.00%)
Oesophageal ulcer † 1	0/361 (0.00%)	1/359 (0.28%)
Pancreatitis † 1	1/361 (0.28%)	0/359 (0.00%)
Pancreatitis acute † 1	0/361 (0.00%)	1/359 (0.28%)
Rectal haemorrhage † 1	1/361 (0.28%)	0/359 (0.00%)
Small intestinal haemorrhage † 1	1/361 (0.28%)	0/359 (0.00%)
Small intestinal obstruction † 1	1/361 (0.28%)	0/359 (0.00%)
Vomiting † 1	2/361 (0.55%)	0/359 (0.00%)
General disorders
Asthenia † 1	2/361 (0.55%)	0/359 (0.00%)
Chills † 1	1/361 (0.28%)	0/359 (0.00%)
Death † 1	0/361 (0.00%)	3/359 (0.84%)
Fatigue † 1	2/361 (0.55%)	1/359 (0.28%)
General physical health deterioration † 1	1/361 (0.28%)	3/359 (0.84%)
Hyperthermia † 1	1/361 (0.28%)	0/359 (0.00%)
Influenza like illness † 1	1/361 (0.28%)	0/359 (0.00%)
Malaise † 1	2/361 (0.55%)	1/359 (0.28%)
Multiple organ dysfunction syndrome † 1	1/361 (0.28%)	0/359 (0.00%)
Non-cardiac chest pain † 1	2/361 (0.55%)	1/359 (0.28%)
Oedema peripheral † 1	0/361 (0.00%)	1/359 (0.28%)
Performance status decreased † 1	1/361 (0.28%)	0/359 (0.00%)
Peripheral swelling † 1	1/361 (0.28%)	0/359 (0.00%)
Pyrexia † 1	12/361 (3.32%)	18/359 (5.01%)
Soft tissue inflammation † 1	0/361 (0.00%)	1/359 (0.28%)
Sudden death † 1	1/361 (0.28%)	0/359 (0.00%)
Hepatobiliary disorders
Cholecystitis † 1	1/361 (0.28%)	1/359 (0.28%)
Cholecystitis acute † 1	2/361 (0.55%)	5/359 (1.39%)
Cholecystitis chronic † 1	0/361 (0.00%)	1/359 (0.28%)
Hyperbilirubinaemia † 1	0/361 (0.00%)	1/359 (0.28%)
Infections and infestations
Abscess limb † 1	1/361 (0.28%)	0/359 (0.00%)
Arthritis bacterial † 1	1/361 (0.28%)	1/359 (0.28%)
Atypical pneumonia † 1	0/361 (0.00%)	1/359 (0.28%)
Bacterial infection † 1	0/361 (0.00%)	1/359 (0.28%)
Bacterial sepsis † 1	1/361 (0.28%)	1/359 (0.28%)
Bronchitis † 1	6/361 (1.66%)	10/359 (2.79%)
Bronchitis bacterial † 1	1/361 (0.28%)	0/359 (0.00%)
Bronchopulmonary aspergillosis † 1	1/361 (0.28%)	0/359 (0.00%)
COVID-19 pneumonia † 1	2/361 (0.55%)	3/359 (0.84%)
Campylobacter colitis † 1	0/361 (0.00%)	1/359 (0.28%)
Campylobacter gastroenteritis † 1	2/361 (0.55%)	1/359 (0.28%)
Candida pneumonia † 1	1/361 (0.28%)	0/359 (0.00%)
Cellulitis † 1	4/361 (1.11%)	2/359 (0.56%)
Chronic sinusitis † 1	0/361 (0.00%)	1/359 (0.28%)
Clostridium difficile colitis † 1	0/361 (0.00%)	1/359 (0.28%)
Complicated appendicitis † 1	0/361 (0.00%)	1/359 (0.28%)
Cytomegalovirus colitis † 1	0/361 (0.00%)	1/359 (0.28%)
Dermo-hypodermitis † 1	0/361 (0.00%)	1/359 (0.28%)
Diarrhoea infectious † 1	0/361 (0.00%)	1/359 (0.28%)
Diverticulitis † 1	0/361 (0.00%)	1/359 (0.28%)
Endocarditis † 1	0/361 (0.00%)	1/359 (0.28%)
Endocarditis staphylococcal † 1	0/361 (0.00%)	1/359 (0.28%)
Enteritis infectious † 1	0/361 (0.00%)	1/359 (0.28%)
Escherichia bacteraemia † 1	2/361 (0.55%)	1/359 (0.28%)
Escherichia sepsis † 1	0/361 (0.00%)	1/359 (0.28%)
Gastroenteritis † 1	5/361 (1.39%)	1/359 (0.28%)
Gastroenteritis caliciviral † 1	0/361 (0.00%)	1/359 (0.28%)
Gastroenteritis viral † 1	2/361 (0.55%)	1/359 (0.28%)
Gastrointestinal infection † 1	1/361 (0.28%)	1/359 (0.28%)
H1N1 influenza † 1	0/361 (0.00%)	1/359 (0.28%)
Haemophilus infection † 1	1/361 (0.28%)	0/359 (0.00%)
Herpes zoster † 1	3/361 (0.83%)	3/359 (0.84%)
Infection † 1	4/361 (1.11%)	3/359 (0.84%)
Influenza † 1	8/361 (2.22%)	5/359 (1.39%)
Intervertebral discitis † 1	1/361 (0.28%)	0/359 (0.00%)
Large intestine infection † 1	1/361 (0.28%)	1/359 (0.28%)
Localised infection † 1	0/361 (0.00%)	2/359 (0.56%)
Lower respiratory tract infection † 1	6/361 (1.66%)	4/359 (1.11%)
Meningitis pneumococcal † 1	1/361 (0.28%)	0/359 (0.00%)
Metapneumovirus infection † 1	0/361 (0.00%)	3/359 (0.84%)
Moraxella infection † 1	0/361 (0.00%)	1/359 (0.28%)
Parainfluenzae virus infection † 1	1/361 (0.28%)	2/359 (0.56%)
Pharyngitis † 1	1/361 (0.28%)	0/359 (0.00%)
Pilonidal cyst † 1	0/361 (0.00%)	1/359 (0.28%)
Pneumococcal infection † 1	0/361 (0.00%)	1/359 (0.28%)
Pneumococcal sepsis † 1	0/361 (0.00%)	1/359 (0.28%)
Pneumonia † 1	47/361 (13.02%)	46/359 (12.81%)
Pneumonia escherichia † 1	1/361 (0.28%)	0/359 (0.00%)
Pneumonia fungal † 1	1/361 (0.28%)	0/359 (0.00%)
Pneumonia haemophilus † 1	2/361 (0.55%)	0/359 (0.00%)
Pneumonia influenzal † 1	1/361 (0.28%)	1/359 (0.28%)
Pneumonia moraxella † 1	1/361 (0.28%)	0/359 (0.00%)
Pneumonia pneumococcal † 1	0/361 (0.00%)	2/359 (0.56%)
Pneumonia pseudomonal † 1	0/361 (0.00%)	1/359 (0.28%)
Postoperative wound infection † 1	1/361 (0.28%)	1/359 (0.28%)
Progressive multifocal leukoencephalopathy † 1	1/361 (0.28%)	1/359 (0.28%)
Proteus infection † 1	1/361 (0.28%)	0/359 (0.00%)
Pseudomonal sepsis † 1	0/361 (0.00%)	2/359 (0.56%)
Pseudomonas infection † 1	1/361 (0.28%)	0/359 (0.00%)
Pulmonary tuberculosis † 1	1/361 (0.28%)	0/359 (0.00%)
Pyelonephritis † 1	0/361 (0.00%)	1/359 (0.28%)
Respiratory syncytial virus infection † 1	1/361 (0.28%)	2/359 (0.56%)
Respiratory tract infection † 1	3/361 (0.83%)	7/359 (1.95%)
Rhinovirus infection † 1	0/361 (0.00%)	3/359 (0.84%)
Salmonella sepsis † 1	1/361 (0.28%)	0/359 (0.00%)
Sepsis † 1	4/361 (1.11%)	5/359 (1.39%)
Septic shock † 1	4/361 (1.11%)	5/359 (1.39%)
Sinusitis † 1	1/361 (0.28%)	0/359 (0.00%)
Skin infection † 1	1/361 (0.28%)	3/359 (0.84%)
Staphylococcal infection † 1	0/361 (0.00%)	1/359 (0.28%)
Subcutaneous abscess † 1	0/361 (0.00%)	1/359 (0.28%)
Tooth infection † 1	1/361 (0.28%)	0/359 (0.00%)
Typhoid fever † 1	1/361 (0.28%)	0/359 (0.00%)
Upper respiratory tract infection † 1	4/361 (1.11%)	3/359 (0.84%)
Urinary tract infection † 1	3/361 (0.83%)	6/359 (1.67%)
Urinary tract infection bacterial † 1	1/361 (0.28%)	0/359 (0.00%)
Urosepsis † 1	1/361 (0.28%)	2/359 (0.56%)
Viral upper respiratory tract infection † 1	0/361 (0.00%)	1/359 (0.28%)
Visceral leishmaniasis † 1	0/361 (0.00%)	1/359 (0.28%)
Injury, poisoning and procedural complications
Accidental overdose † 1	2/361 (0.55%)	0/359 (0.00%)
Clavicle fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Concussion † 1	0/361 (0.00%)	1/359 (0.28%)
Contusion † 1	0/361 (0.00%)	1/359 (0.28%)
Fall † 1	2/361 (0.55%)	4/359 (1.11%)
Femoral neck fracture † 1	3/361 (0.83%)	2/359 (0.56%)
Femur fracture † 1	3/361 (0.83%)	1/359 (0.28%)
Foot fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Hip fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Humerus fracture † 1	0/361 (0.00%)	1/359 (0.28%)
Incisional hernia † 1	1/361 (0.28%)	0/359 (0.00%)
Ligament rupture † 1	1/361 (0.28%)	0/359 (0.00%)
Lower limb fracture † 1	0/361 (0.00%)	1/359 (0.28%)
Lumbar vertebral fracture † 1	1/361 (0.28%)	1/359 (0.28%)
Overdose † 1	1/361 (0.28%)	3/359 (0.84%)
Pelvic fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Periprosthetic fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Procedural pain † 1	1/361 (0.28%)	0/359 (0.00%)
Radius fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Rib fracture † 1	2/361 (0.55%)	0/359 (0.00%)
Road traffic accident † 1	1/361 (0.28%)	0/359 (0.00%)
Spinal compression fracture † 1	1/361 (0.28%)	5/359 (1.39%)
Spinal fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Sternal fracture † 1	0/361 (0.00%)	1/359 (0.28%)
Subcutaneous haematoma † 1	1/361 (0.28%)	0/359 (0.00%)
Tendon rupture † 1	0/361 (0.00%)	1/359 (0.28%)
Thoracic vertebral fracture † 1	0/361 (0.00%)	1/359 (0.28%)
Tibia fracture † 1	1/361 (0.28%)	0/359 (0.00%)
Traumatic intracranial haemorrhage † 1	0/361 (0.00%)	1/359 (0.28%)
Investigations
Blood creatinine increased † 1	1/361 (0.28%)	1/359 (0.28%)
Influenza A virus test positive † 1	1/361 (0.28%)	2/359 (0.56%)
Platelet count decreased † 1	3/361 (0.83%)	1/359 (0.28%)
Weight decreased † 1	1/361 (0.28%)	0/359 (0.00%)
Metabolism and nutrition disorders
Cachexia † 1	0/361 (0.00%)	1/359 (0.28%)
Decreased appetite † 1	0/361 (0.00%)	1/359 (0.28%)
Dehydration † 1	1/361 (0.28%)	0/359 (0.00%)
Diabetes mellitus † 1	0/361 (0.00%)	1/359 (0.28%)
Diabetes mellitus inadequate control † 1	0/361 (0.00%)	1/359 (0.28%)
Diabetic metabolic decompensation † 1	0/361 (0.00%)	1/359 (0.28%)
Gout † 1	1/361 (0.28%)	0/359 (0.00%)
Hypercalcaemia † 1	4/361 (1.11%)	2/359 (0.56%)
Hyperglycaemia † 1	1/361 (0.28%)	3/359 (0.84%)
Hypokalaemia † 1	3/361 (0.83%)	1/359 (0.28%)
Hyponatraemia † 1	2/361 (0.55%)	0/359 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/361 (0.00%)	1/359 (0.28%)
Arthritis reactive † 1	0/361 (0.00%)	1/359 (0.28%)
Back pain † 1	2/361 (0.55%)	8/359 (2.23%)
Bone pain † 1	2/361 (0.55%)	1/359 (0.28%)
Groin pain † 1	0/361 (0.00%)	2/359 (0.56%)
Intervertebral disc degeneration † 1	0/361 (0.00%)	1/359 (0.28%)
Intervertebral disc protrusion † 1	1/361 (0.28%)	1/359 (0.28%)
Lumbar spinal stenosis † 1	1/361 (0.28%)	0/359 (0.00%)
Muscular weakness † 1	1/361 (0.28%)	0/359 (0.00%)
Musculoskeletal chest pain † 1	1/361 (0.28%)	1/359 (0.28%)
Musculoskeletal pain † 1	0/361 (0.00%)	1/359 (0.28%)
Neck pain † 1	1/361 (0.28%)	1/359 (0.28%)
Osteoarthritis † 1	0/361 (0.00%)	1/359 (0.28%)
Osteolysis † 1	1/361 (0.28%)	1/359 (0.28%)
Osteoporotic fracture † 1	0/361 (0.00%)	1/359 (0.28%)
Pain in extremity † 1	1/361 (0.28%)	0/359 (0.00%)
Pathological fracture † 1	5/361 (1.39%)	4/359 (1.11%)
Rotator cuff syndrome † 1	1/361 (0.28%)	0/359 (0.00%)
Spinal pain † 1	1/361 (0.28%)	2/359 (0.56%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	3/361 (0.83%)	1/359 (0.28%)
Basal cell carcinoma † 1	2/361 (0.55%)	3/359 (0.84%)
Bladder adenocarcinoma stage unspecified † 1	1/361 (0.28%)	0/359 (0.00%)
Bladder transitional cell carcinoma † 1	0/361 (0.00%)	1/359 (0.28%)
Bowen's disease † 1	2/361 (0.55%)	2/359 (0.56%)
Breast cancer † 1	1/361 (0.28%)	1/359 (0.28%)
Colon adenoma † 1	1/361 (0.28%)	0/359 (0.00%)
Lobular breast carcinoma in situ † 1	0/361 (0.00%)	1/359 (0.28%)
Lung neoplasm malignant † 1	0/361 (0.00%)	1/359 (0.28%)
Metastatic gastric cancer † 1	1/361 (0.28%)	0/359 (0.00%)
Myelodysplastic syndrome † 1	2/361 (0.55%)	1/359 (0.28%)
Neuroendocrine carcinoma † 1	1/361 (0.28%)	0/359 (0.00%)
Pancreatic neuroendocrine tumour † 1	0/361 (0.00%)	1/359 (0.28%)
Penile squamous cell carcinoma † 1	0/361 (0.00%)	1/359 (0.28%)
Plasma cell leukaemia † 1	0/361 (0.00%)	2/359 (0.56%)
Plasma cell myeloma † 1	3/361 (0.83%)	3/359 (0.84%)
Plasmacytoma † 1	4/361 (1.11%)	0/359 (0.00%)
Prostate cancer † 1	1/361 (0.28%)	1/359 (0.28%)
Prostate cancer metastatic † 1	0/361 (0.00%)	1/359 (0.28%)
Second primary malignancy † 1	1/361 (0.28%)	0/359 (0.00%)
Squamous cell carcinoma of skin † 1	5/361 (1.39%)	7/359 (1.95%)
T-cell lymphoma † 1	0/361 (0.00%)	1/359 (0.28%)
Nervous system disorders
Acute polyneuropathy † 1	0/361 (0.00%)	1/359 (0.28%)
Central nervous system lesion † 1	0/361 (0.00%)	1/359 (0.28%)
Cerebral haemorrhage † 1	0/361 (0.00%)	2/359 (0.56%)
Cerebral infarction † 1	1/361 (0.28%)	1/359 (0.28%)
Cerebral small vessel ischaemic disease † 1	1/361 (0.28%)	0/359 (0.00%)
Cerebrovascular accident † 1	2/361 (0.55%)	1/359 (0.28%)
Coma † 1	1/361 (0.28%)	0/359 (0.00%)
Generalised tonic-clonic seizure † 1	1/361 (0.28%)	0/359 (0.00%)
Haemorrhagic stroke † 1	1/361 (0.28%)	0/359 (0.00%)
Headache † 1	1/361 (0.28%)	0/359 (0.00%)
Ischaemic stroke † 1	1/361 (0.28%)	3/359 (0.84%)
Lethargy † 1	0/361 (0.00%)	1/359 (0.28%)
Neuralgia † 1	1/361 (0.28%)	0/359 (0.00%)
Seizure † 1	0/361 (0.00%)	1/359 (0.28%)
Spinal cord compression † 1	3/361 (0.83%)	0/359 (0.00%)
Subarachnoid haemorrhage † 1	0/361 (0.00%)	1/359 (0.28%)
Syncope † 1	6/361 (1.66%)	4/359 (1.11%)
Transient ischaemic attack † 1	1/361 (0.28%)	0/359 (0.00%)
Vascular encephalopathy † 1	1/361 (0.28%)	0/359 (0.00%)
Psychiatric disorders
Completed suicide † 1	0/361 (0.00%)	2/359 (0.56%)
Confusional state † 1	2/361 (0.55%)	2/359 (0.56%)
Delirium † 1	1/361 (0.28%)	0/359 (0.00%)
Mental disorder † 1	1/361 (0.28%)	0/359 (0.00%)
Mental status changes † 1	0/361 (0.00%)	1/359 (0.28%)
Psychotic disorder † 1	0/361 (0.00%)	1/359 (0.28%)
Renal and urinary disorders
Acute kidney injury † 1	5/361 (1.39%)	6/359 (1.67%)
Atonic urinary bladder † 1	0/361 (0.00%)	1/359 (0.28%)
Chronic kidney disease † 1	0/361 (0.00%)	2/359 (0.56%)
Haematuria † 1	0/361 (0.00%)	2/359 (0.56%)
Nephrolithiasis † 1	2/361 (0.55%)	1/359 (0.28%)
Neurogenic bladder † 1	1/361 (0.28%)	0/359 (0.00%)
Renal failure † 1	1/361 (0.28%)	3/359 (0.84%)
Renal impairment † 1	0/361 (0.00%)	2/359 (0.56%)
Urethral haemorrhage † 1	1/361 (0.28%)	0/359 (0.00%)
Urethral meatus stenosis † 1	0/361 (0.00%)	1/359 (0.28%)
Urinary retention † 1	0/361 (0.00%)	2/359 (0.56%)
Urinary tract obstruction † 1	0/361 (0.00%)	1/359 (0.28%)
Reproductive system and breast disorders
Bartholin's cyst † 1	0/361 (0.00%)	1/359 (0.28%)
Benign prostatic hyperplasia † 1	1/361 (0.28%)	0/359 (0.00%)
Endometrial hyperplasia † 1	0/361 (0.00%)	1/359 (0.28%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	1/361 (0.28%)	1/359 (0.28%)
Asthma † 1	2/361 (0.55%)	2/359 (0.56%)
Chronic obstructive pulmonary disease † 1	2/361 (0.55%)	1/359 (0.28%)
Dyspnoea † 1	3/361 (0.83%)	4/359 (1.11%)
Emphysema † 1	0/361 (0.00%)	1/359 (0.28%)
Epistaxis † 1	0/361 (0.00%)	1/359 (0.28%)
Haemoptysis † 1	1/361 (0.28%)	0/359 (0.00%)
Hypoxia † 1	0/361 (0.00%)	1/359 (0.28%)
Interstitial lung disease † 1	1/361 (0.28%)	1/359 (0.28%)
Lung disorder † 1	0/361 (0.00%)	1/359 (0.28%)
Lung infiltration † 1	0/361 (0.00%)	1/359 (0.28%)
Organising pneumonia † 1	1/361 (0.28%)	1/359 (0.28%)
Orthopnoea † 1	0/361 (0.00%)	1/359 (0.28%)
Pleural effusion † 1	2/361 (0.55%)	0/359 (0.00%)
Pneumonia aspiration † 1	1/361 (0.28%)	1/359 (0.28%)
Pneumonitis † 1	0/361 (0.00%)	3/359 (0.84%)
Pulmonary congestion † 1	1/361 (0.28%)	0/359 (0.00%)
Pulmonary embolism † 1	7/361 (1.94%)	9/359 (2.51%)
Pulmonary hypertension † 1	1/361 (0.28%)	0/359 (0.00%)
Pulmonary microemboli † 1	1/361 (0.28%)	0/359 (0.00%)
Respiratory failure † 1	1/361 (0.28%)	1/359 (0.28%)
Skin and subcutaneous tissue disorders
Cutaneous vasculitis † 1	1/361 (0.28%)	0/359 (0.00%)
Psoriasis † 1	1/361 (0.28%)	0/359 (0.00%)
Rash † 1	1/361 (0.28%)	0/359 (0.00%)
Vascular disorders
Aortic aneurysm † 1	1/361 (0.28%)	0/359 (0.00%)
Aortic dissection † 1	0/361 (0.00%)	1/359 (0.28%)
Aortic thrombosis † 1	0/361 (0.00%)	1/359 (0.28%)
Circulatory collapse † 1	0/361 (0.00%)	1/359 (0.28%)
Deep vein thrombosis † 1	5/361 (1.39%)	7/359 (1.95%)
Hypotension † 1	2/361 (0.55%)	0/359 (0.00%)
Hypovolaemic shock † 1	0/361 (0.00%)	1/359 (0.28%)
Orthostatic hypotension † 1	1/361 (0.28%)	1/359 (0.28%)
Peripheral artery aneurysm † 1	1/361 (0.28%)	0/359 (0.00%)
Peripheral vascular disorder † 1	0/361 (0.00%)	1/359 (0.28%)
Phlebitis superficial † 1	1/361 (0.28%)	0/359 (0.00%)
Thrombophlebitis † 1	0/361 (0.00%)	1/359 (0.28%)
Thrombophlebitis superficial † 1	0/361 (0.00%)	1/359 (0.28%)
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ixazomib+ Lenalidomide + Dexamethasone	Placebo + Lenalidomide + Dexamethasone
	Affected / at Risk (%)	Affected / at Risk (%)
Total	350/361 (96.95%)	342/359 (95.26%)
Blood and lymphatic system disorders
Anaemia † 1	123/361 (34.07%)	105/359 (29.25%)
Leukopenia † 1	28/361 (7.76%)	19/359 (5.29%)
Neutropenia † 1	112/361 (31.02%)	99/359 (27.58%)
Thrombocytopenia † 1	95/361 (26.32%)	44/359 (12.26%)
Cardiac disorders
Atrial fibrillation † 1	17/361 (4.71%)	19/359 (5.29%)
Eye disorders
Cataract † 1	50/361 (13.85%)	61/359 (16.99%)
Dry eye † 1	22/361 (6.09%)	6/359 (1.67%)
Vision blurred † 1	26/361 (7.20%)	18/359 (5.01%)
Gastrointestinal disorders
Abdominal pain † 1	37/361 (10.25%)	36/359 (10.03%)
Abdominal pain upper † 1	26/361 (7.20%)	17/359 (4.74%)
Constipation † 1	125/361 (34.63%)	99/359 (27.58%)
Diarrhoea † 1	186/361 (51.52%)	153/359 (42.62%)
Dry mouth † 1	16/361 (4.43%)	25/359 (6.96%)
Dyspepsia † 1	33/361 (9.14%)	31/359 (8.64%)
Nausea † 1	114/361 (31.58%)	83/359 (23.12%)
Vomiting † 1	93/361 (25.76%)	47/359 (13.09%)
General disorders
Asthenia † 1	62/361 (17.17%)	66/359 (18.38%)
Fatigue † 1	113/361 (31.30%)	103/359 (28.69%)
Influenza like illness † 1	25/361 (6.93%)	15/359 (4.18%)
Oedema peripheral † 1	97/361 (26.87%)	76/359 (21.17%)
Peripheral swelling † 1	20/361 (5.54%)	7/359 (1.95%)
Pyrexia † 1	55/361 (15.24%)	71/359 (19.78%)
Infections and infestations
Bronchitis † 1	76/361 (21.05%)	53/359 (14.76%)
Conjunctivitis † 1	34/361 (9.42%)	10/359 (2.79%)
Gastroenteritis † 1	26/361 (7.20%)	17/359 (4.74%)
Herpes zoster † 1	20/361 (5.54%)	7/359 (1.95%)
Influenza † 1	27/361 (7.48%)	26/359 (7.24%)
Lower respiratory tract infection † 1	16/361 (4.43%)	18/359 (5.01%)
Nasopharyngitis † 1	90/361 (24.93%)	86/359 (23.96%)
Oral candidiasis † 1	17/361 (4.71%)	19/359 (5.29%)
Pharyngitis † 1	16/361 (4.43%)	22/359 (6.13%)
Pneumonia † 1	46/361 (12.74%)	33/359 (9.19%)
Respiratory tract infection † 1	23/361 (6.37%)	30/359 (8.36%)
Sinusitis † 1	25/361 (6.93%)	21/359 (5.85%)
Upper respiratory tract infection † 1	97/361 (26.87%)	83/359 (23.12%)
Urinary tract infection † 1	43/361 (11.91%)	34/359 (9.47%)
Injury, poisoning and procedural complications
Contusion † 1	23/361 (6.37%)	22/359 (6.13%)
Fall † 1	35/361 (9.70%)	40/359 (11.14%)
Investigations
Neutrophil count decreased † 1	26/361 (7.20%)	28/359 (7.80%)
Platelet count decreased † 1	36/361 (9.97%)	22/359 (6.13%)
Weight decreased † 1	36/361 (9.97%)	28/359 (7.80%)
Metabolism and nutrition disorders
Decreased appetite † 1	51/361 (14.13%)	42/359 (11.70%)
Hyperglycaemia † 1	18/361 (4.99%)	23/359 (6.41%)
Hypocalcaemia † 1	24/361 (6.65%)	21/359 (5.85%)
Hypokalaemia † 1	60/361 (16.62%)	51/359 (14.21%)
Hypomagnesaemia † 1	18/361 (4.99%)	26/359 (7.24%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	79/361 (21.88%)	71/359 (19.78%)
Back pain † 1	97/361 (26.87%)	82/359 (22.84%)
Bone pain † 1	33/361 (9.14%)	34/359 (9.47%)
Muscle spasms † 1	70/361 (19.39%)	102/359 (28.41%)
Muscular weakness † 1	21/361 (5.82%)	28/359 (7.80%)
Musculoskeletal chest pain † 1	33/361 (9.14%)	39/359 (10.86%)
Myalgia † 1	22/361 (6.09%)	16/359 (4.46%)
Neck pain † 1	14/361 (3.88%)	21/359 (5.85%)
Pain in extremity † 1	54/361 (14.96%)	41/359 (11.42%)
Nervous system disorders
Dizziness † 1	58/361 (16.07%)	43/359 (11.98%)
Dysgeusia † 1	23/361 (6.37%)	15/359 (4.18%)
Headache † 1	53/361 (14.68%)	56/359 (15.60%)
Neuropathy peripheral † 1	35/361 (9.70%)	26/359 (7.24%)
Paraesthesia † 1	33/361 (9.14%)	19/359 (5.29%)
Peripheral sensory neuropathy † 1	88/361 (24.38%)	61/359 (16.99%)
Tremor † 1	22/361 (6.09%)	38/359 (10.58%)
Psychiatric disorders
Anxiety † 1	18/361 (4.99%)	23/359 (6.41%)
Depression † 1	19/361 (5.26%)	18/359 (5.01%)
Insomnia † 1	82/361 (22.71%)	106/359 (29.53%)
Mood altered † 1	12/361 (3.32%)	21/359 (5.85%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	73/361 (20.22%)	65/359 (18.11%)
Dysphonia † 1	7/361 (1.94%)	21/359 (5.85%)
Dyspnoea † 1	44/361 (12.19%)	40/359 (11.14%)
Dyspnoea exertional † 1	17/361 (4.71%)	24/359 (6.69%)
Epistaxis † 1	20/361 (5.54%)	16/359 (4.46%)
Oropharyngeal pain † 1	16/361 (4.43%)	21/359 (5.85%)
Skin and subcutaneous tissue disorders
Erythema † 1	22/361 (6.09%)	13/359 (3.62%)
Hyperhidrosis † 1	14/361 (3.88%)	18/359 (5.01%)
Pruritus † 1	45/361 (12.47%)	32/359 (8.91%)
Rash † 1	20/361 (5.54%)	11/359 (3.06%)
Rash macular † 1	26/361 (7.20%)	29/359 (8.08%)
Rash maculo-papular † 1	34/361 (9.42%)	15/359 (4.18%)
Vascular disorders
Deep vein thrombosis † 1	11/361 (3.05%)	18/359 (5.01%)
Hypertension † 1	29/361 (8.03%)	27/359 (7.52%)
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Study Director
• Organization: Takeda
• Phone: +1-877-825-3327
• EMail: trialdisclosures@takeda.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Richardson PG, Kumar SK, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Gimsing P, Garderet L, Touzeau C, Buadi FK, Laubach JP, Cavo M, Darif M, Labotka R, Berg D, Moreau P. Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2021 Aug 1;39(22):2430-2442. doi: 10.1200/JCO.21.00972. Epub 2021 Jun 11.

Di Bacco A, Bahlis NJ, Munshi NC, Avet-Loiseau H, Masszi T, Viterbo L, Pour L, Ganly P, Cavo M, Langer C, Kumar SK, Rajkumar SV, Keats JJ, Berg D, Lin J, Li B, Badola S, Shen L, Zhang J, Esseltine DL, Luptakova K, van de Velde H, Richardson PG, Moreau P. c-MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide-dexamethasone in myeloma. Eur J Haematol. 2020 Jul;105(1):35-46. doi: 10.1111/ejh.13405. Epub 2020 Apr 15.

Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. doi: 10.1182/blood-2017-06-791228. Epub 2017 Oct 20.

Gupta N, Yang H, Hanley MJ, Zhang S, Liu R, Kumar S, Richardson PG, Skacel T, Venkatakrishnan K. Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses. Target Oncol. 2017 Oct;12(5):643-654. doi: 10.1007/s11523-017-0524-3.

Mateos MV, Masszi T, Grzasko N, Hansson M, Sandhu I, Pour L, Viterbo L, Jackson SR, Stoppa AM, Gimsing P, Hamadani M, Borsaru G, Berg D, Lin J, Di Bacco A, van de Velde H, Richardson PG, Moreau P. Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1. Haematologica. 2017 Oct;102(10):1767-1775. doi: 10.3324/haematol.2017.170118. Epub 2017 Jul 27.

Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. doi: 10.1186/s13045-017-0501-4.

Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-34. doi: 10.1056/NEJMoa1516282.

Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. doi: 10.1182/blood-2016-01-693580. Epub 2016 Mar 21.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01564537
• Other Study ID Numbers: C16010; 2011-005496-17 ( EudraCT Number ); CTR20130908 ( Registry Identifier: SFDA CTR ); U1111-1164-7646 ( Registry Identifier: WHO ); NL40132.018.12 ( Registry Identifier: CCMO ); 12/LO/0949 ( Registry Identifier: NRES ); JapicCTI-132345 ( Registry Identifier: JapicCTI ); 1015042370 ( Registry Identifier: TCTIN ); C16010CTIL ( Registry Identifier: Israel )
• First Submitted: March 22, 2012
• First Posted: March 28, 2012
• Results First Submitted: December 19, 2015
• Results First Posted: January 27, 2016
• Last Update Posted: March 10, 2023