A Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Participants With Multiple Myeloma Following Autologous Stem Cell Transplant

• ClinicalTrials.gov Identifier: NCT02181413
• Recruitment Status: Active, not recruiting
• First Posted: July 4, 2014
• Results First Posted: May 7, 2019
• Last Update Posted: June 30, 2022
• 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: Multiple Myeloma; Autologous Stem Cell Transplant
• Interventions: Drug: Ixazomib Citrate; Drug: Placebo
• Enrollment: 656

Participant Flow

Recruitment Details	Participants enrolled at 167 sites in Australia, Japan, Korea, Singapore, Taiwan, Thailand, Austria, Belgium, Czech Republic, Denmark,France, Germany, Greece, Hungary, Israel, Italy, Netherlands, Norway, Poland, Portugal, South Africa, Spain, Sweden, Switzerland, Turkey, Ukraine, UK, Argentina, Brazil, US from 01-Jul-14 to 16-Apr-18 (data cut-off).
Pre-assignment Details	Participants with newly diagnosed multiple myeloma (NDMM) who had undergone induction therapy according to regional standard of care (SoC), followed by high-dose melphalan (200 mg/m^2) and Autologous Stem Cell Transplant (ASCT) were enrolled in a 3:2 ratio to receive ixazomib citrate 3 mg for 4 cycles followed by 4 mg for 22 cycles, or placebo.

Arm/Group Title	Placebo	Ixazomib Citrate
Arm/Group Description	Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.
Period Title: Overall Study
Started	261	395
Intent-to-Treat (ITT) Population	261	395
Safety Population	259	394
Per Protocol (PP) Population	256	387
Completed [1]	109	198
Not Completed	152	197
Reason Not Completed
Adverse Event	7	24
Progressive Disease	121	143
Withdrawal by Subject	5	8
Reason Not Specified	19	20
Ongoing Study Treatment	0	1
Lost to Follow-up	0	1
[1] Completed indicates participants who completed maximum number of cycles per protocol

Baseline Characteristics

Arm/Group Title		Placebo	Ixazomib Citrate	Total
Arm/Group Description		Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.	Total of all reporting groups
Overall Number of Baseline Participants		261	395	656
Baseline Analysis Population Description		Intent-to-Treat (ITT) population was defined as all participants who were randomized and had post randomization data.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	261 participants	395 participants	656 participants
		58.2 (7.92)	56.8 (8.17)	57.4 (8.10)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	395 participants	656 participants
	<60 years	127 48.7%	229 58.0%	356 54.3%
	≥60 and <75 years	134 51.3%	166 42.0%	300 45.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	395 participants	656 participants
	Female	99 37.9%	143 36.2%	242 36.9%
	Male	162 62.1%	252 63.8%	414 63.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	395 participants	656 participants
	Hispanic or Latino	11 4.2%	14 3.5%	25 3.8%
	Not Hispanic or Latino	240 92.0%	362 91.6%	602 91.8%
	Unknown or Not Reported	10 3.8%	19 4.8%	29 4.4%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	261 participants	395 participants	656 participants
	White	213 81.6%	315 79.7%	528 80.5%
	Black or African American	3 1.1%	7 1.8%	10 1.5%
	Asian	36 13.8%	59 14.9%	95 14.5%
	Other	1 0.4%	2 0.5%	3 0.5%
	Not Reported	8 3.1%	12 3.0%	20 3.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
Australia	Number Analyzed	261 participants	395 participants	656 participants
		11 4.2%	17 4.3%	28 4.3%
Japan	Number Analyzed	261 participants	395 participants	656 participants
		9 3.4%	13 3.3%	22 3.4%
Korea, Republic Of	Number Analyzed	261 participants	395 participants	656 participants
		17 6.5%	23 5.8%	40 6.1%
Singapore	Number Analyzed	261 participants	395 participants	656 participants
		4 1.5%	8 2.0%	12 1.8%
Taiwan, Province Of China	Number Analyzed	261 participants	395 participants	656 participants
		3 1.1%	10 2.5%	13 2.0%
Thailand	Number Analyzed	261 participants	395 participants	656 participants
		1 0.4%	5 1.3%	6 0.9%
Austria	Number Analyzed	261 participants	395 participants	656 participants
		2 0.8%	2 0.5%	4 0.6%
Belgium	Number Analyzed	261 participants	395 participants	656 participants
		5 1.9%	5 1.3%	10 1.5%
Czech Republic	Number Analyzed	261 participants	395 participants	656 participants
		12 4.6%	30 7.6%	42 6.4%
Denmark	Number Analyzed	261 participants	395 participants	656 participants
		11 4.2%	20 5.1%	31 4.7%
France	Number Analyzed	261 participants	395 participants	656 participants
		7 2.7%	11 2.8%	18 2.7%
Germany	Number Analyzed	261 participants	395 participants	656 participants
		26 10.0%	50 12.7%	76 11.6%
Greece	Number Analyzed	261 participants	395 participants	656 participants
		22 8.4%	38 9.6%	60 9.1%
Hungary	Number Analyzed	261 participants	395 participants	656 participants
		9 3.4%	16 4.1%	25 3.8%
Israel	Number Analyzed	261 participants	395 participants	656 participants
		12 4.6%	10 2.5%	22 3.4%
Italy	Number Analyzed	261 participants	395 participants	656 participants
		26 10.0%	24 6.1%	50 7.6%
Netherlands	Number Analyzed	261 participants	395 participants	656 participants
		11 4.2%	8 2.0%	19 2.9%
Norway	Number Analyzed	261 participants	395 participants	656 participants
		6 2.3%	13 3.3%	19 2.9%
Poland	Number Analyzed	261 participants	395 participants	656 participants
		5 1.9%	10 2.5%	15 2.3%
Portugal	Number Analyzed	261 participants	395 participants	656 participants
		2 0.8%	8 2.0%	10 1.5%
South Africa	Number Analyzed	261 participants	395 participants	656 participants
		4 1.5%	3 0.8%	7 1.1%
Spain	Number Analyzed	261 participants	395 participants	656 participants
		19 7.3%	19 4.8%	38 5.8%
Sweden	Number Analyzed	261 participants	395 participants	656 participants
		4 1.5%	7 1.8%	11 1.7%
Switzerland	Number Analyzed	261 participants	395 participants	656 participants
		3 1.1%	0 0.0%	3 0.5%
Turkey	Number Analyzed	261 participants	395 participants	656 participants
		10 3.8%	10 2.5%	20 3.0%
Ukraine	Number Analyzed	261 participants	395 participants	656 participants
		2 0.8%	1 0.3%	3 0.5%
United Kingdom	Number Analyzed	261 participants	395 participants	656 participants
		14 5.4%	21 5.3%	35 5.3%
Argentina	Number Analyzed	261 participants	395 participants	656 participants
		0 0.0%	3 0.8%	3 0.5%
Brazil	Number Analyzed	261 participants	395 participants	656 participants
		3 1.1%	5 1.3%	8 1.2%
United States	Number Analyzed	261 participants	395 participants	656 participants
		1 0.4%	5 1.3%	6 0.9%
Height [1]; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	256 participants	388 participants	644 participants
		168.73 (10.347)	169.71 (10.004)	169.32 (10.145)
		[1] Measure Analysis Population Description: Number analyzed is the number of participants with available height data.
Weight [1]; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	261 participants	395 participants	656 participants
		75.18 (14.648)	75.93 (15.989)	75.63 (15.463)
		[1] Measure Analysis Population Description: Number analyzed is the number of participants with available weight data.
Body Surface Area (BSA) [1]; Mean (Standard Deviation); Unit of measure: M^2
	Number Analyzed	256 participants	388 participants	644 participants
		1.87 (0.221)	1.88 (0.235)	1.88 (0.229)
		[1] Measure Analysis Population Description: Number analyzed is the number of participants with available BSA data.

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD), as evaluated by an independent review committee according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occured first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be >10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must have been ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size increase; hypercalcemia development.
Time Frame	Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks until progression of disease or death (to data cutoff: approximately 4 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population was defined as all participants who were randomized and had post randomization data. Participants without documentation of PD were censored at the date of last response assessment that was stable disease (SD) or better.

Arm/Group Title	Placebo	Ixazomib Citrate
Arm/Group Description:	Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.
Overall Number of Participants Analyzed	261	395
Median (95% Confidence Interval); Unit of Measure: months
	21.3; (17.97 to 24.67)	26.5; (23.69 to 33.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ixazomib Citrate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	Log Rank
	Comments	P-value was based on log-rank test stratified by pre-induction regimen, International Staging System (ISS) stage and response after transplantation.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.720
	Confidence Interval	(2-Sided) 95%; 0.582 to 0.890
	Estimation Comments	HR was based on Cox's proportional hazard regression model stratified by pre-induction regimen, pre-induction ISS stage and response after transplantation. <1 HR indicates better prevention of progression in Ixazomib arm compared to Placebo.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was measured as the time from the date of randomization to the date of death.
Time Frame	Baseline up to Follow up period (107 months)

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy
Description	Response was assessed according to IMWG criteria. Best response includes PR, VGPR and CR. PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by greater than or equal to (>=) 90% or to less than (<) 200 milligram (mg) per 24 hours. VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or >= 90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. CR is negative immunofixation of serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent CR (sCR) is CR and normal FLC ratio and absence of clonal PCs by immunohistochemistry or 2- to 4-color flow cytometry.
Time Frame	Baseline up to EOT (24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months)

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP is defined as the time from the date of randomization to the date of first documentation of PD , using IMWG criteria. PD is defined as >=25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be >=10%;new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development.
Time Frame	Baseline until PD (Month 107)

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	Second Progression Free Survival (PFS2)
Description	PFS2 is defined as the time from the date of randomization to the date of objective disease progression on next line treatment or death from any cause (whichever occurs first). PD is defined as >=25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be >=10%;new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development.
Time Frame	Baseline up to EOT (24 months); thereafter followed up every 4 weeks until initiation of next-line therapy and then every 12 weeks until second progressive disease (PD2) or death (up to Month 107)

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	Time to Start of the Next Line of Therapy
Description	Time to start of the next line of therapy was defined as the time from the date of randomization to the date of initiation dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurs first.
Time Frame	Baseline up to start of next line of therapy (after 24 months treatment period followed by every 4 weeks PFS and PD follow up period)

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Time to End of the Next Line of Therapy
Description	Time to end of the next line of therapy is defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurs first.
Time Frame	Baseline up to end of next line of therapy (Month 107)

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Duration of the Next Line of Therapy
Description	Duration of the next line of therapy is defined as the time from the date of the first dose of the next line of therapy to the date of the last dose of the next antineoplastic therapy following study treatment or death due to any cause, whichever occurs first. Duration of the next line of therapy will be analyzed on those participants who actually received the next line of therapy following the study treatment and duration would be summarized using Kaplan-Meier method. Participants who are still on treatment on the next line of therapy will be censored at last visit.
Time Frame	From the start of next line therapy after PD to the last dose of next line therapy (up to Month 107)

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	Percentage of Participants Who Develop A New Primary Malignancy
Description	[Not Specified]
Time Frame	Baseline until death or termination of the study (up to Month 107)

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	Number of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative, and Maintenance of MRD Negativity
Description	MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. The conversion rate from MRD positive to MRD negative and the maintenance of MRD negativity will be assessed and reported. Bone marrow aspirates and blood samples will be sent to a central laboratory and will be assessed for MRD using flow cytometry and a sequencing methodology.
Time Frame	Baseline up to EOT (24 months)

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	Correlation Between MRD Status and Progression Free Survival (PFS) and Overall Survival (OS)
Description	Degree of correlation will be determined between 2 methodologies for MRD assessment (8-color flow cytometry, next-generation sequencing and bone marrow aspirates and blood samples). Association between MRD status with PFS and OS will be evaluated independently from the methodology used for the assessment. The association between MRD status and PFS and OS will be evaluated in both study arms, and concordance between flow cytometry and sequencing readouts will be assessed.
Time Frame	Baseline up to Month 107

Outcome Measure Data Not Reported

12. Secondary Outcome

Title	OS Benefits in a High-Risk Population
Description	High-risk population will include but not be limited to participants carrying deletion (del)17, t(4:14), t(14:16), amplification (ampl) 1q, del13, or del1p. OS will be measured as the time from the date of randomization to the date of death.
Time Frame	Randomization up to Month 107

Outcome Measure Data Not Reported

13. Secondary Outcome

Title	PFS Benefits in a High-Risk Population
Description	High-risk population will include but not be limited to participants carrying deletion (del)17, t(4:14), t(14:16), amplification (ampl) 1q, del13, or del1p. PFS is defined as the time from the date of randomization to the date of first documentation of PD, as evaluated by an independent review committee according to IMWG criteria, or death due to any cause (whichever occurs first). PD is defined as >=25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be >=10%;new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development.
Time Frame	Randomization up to Month 107

Outcome Measure Data Not Reported

14. Secondary Outcome

Title	Eastern Cooperative Oncology Group (ECOG) Performance Score
Description	The ECOG performance is a 6-point scale used by doctors to assess how a participant's disease is progressing, how the disease affects the participant's daily life, and to determine appropriate treatment and prognosis. The scale is 0=Normal activity. Fully active, able to carry on all pre disease performance without restriction (best) to 5=Dead.
Time Frame	Baseline up to EOT (24 months), thereafter every 4 weeks until initiation of next line therapy

Outcome Measure Data Not Reported

15. Secondary Outcome

Title	Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)
Description	[Not Specified]
Time Frame	First dose of study drug through 30 days after last dose of study drug (up to 24 months)

Outcome Measure Data Not Reported

16. Secondary Outcome

Title	Number of Participants With Markedly Abnormal Clinical Laboratory Values
Description	[Not Specified]
Time Frame	Baseline through 30 days after the last dose of study drug (up to 24 months)

Outcome Measure Data Not Reported

17. Secondary Outcome

Title	Health-related Quality of Life (HRQL) Score Based on The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Domain
Description	EORTC QLQ-C30 is completed by the participants. The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best).
Time Frame	Baseline up to PD (up to Month 107)

Outcome Measure Data Not Reported

18. Secondary Outcome

Title	Plasma Concentration of Ixazomib
Description	Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) will be measured using a validated Liquid Chromatography-tandem Mass Spectrometry (LC/MS/MS) assay.
Time Frame	Day 1 of Cycle 1 at multiple time points (up to 4 hours) post-dose; Days 8 and 15 of Cycle 1, Days 1 and 8 of Cycle 2, Day 1 of Cycles 3 through 10 (each cycle of 28 days) predose

Outcome Measure Data Not Reported

19. Secondary Outcome

Title	Time to Resolution of Peripheral Neuropathy (PN) Events
Description	Peripheral neuropathy is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as improved if the event improves from the maximum grade. That is, all the grades recorded after the maximum grade is less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first.
Time Frame	From randomization date through 30 days after the last dose of drug (up to 24 months)

Outcome Measure Data Not Reported

20. Secondary Outcome

Title	Time to Improvement of PN Events
Description	PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. A PN event is considered as improved if the event improves from the maximum grade. That is, all the grades recorded after the maximum grade is less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first.
Time Frame	From randomization date through 30 days after the last dose of drug (up to 24 months)

Outcome Measure Data Not Reported

Adverse Events

Time Frame	First dose of study drug through 30 days after last dose of study drug (up to 24 months)
Adverse Event Reporting Description	At each visit the investigator was to document any occurrence of adverse events including abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo	Ixazomib Citrate
Arm/Group Description	Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.	Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.
All-Cause Mortality
	Placebo	Ixazomib Citrate
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/259 (0.00%)	1/394 (0.25%)
Serious Adverse Events
	Placebo	Ixazomib Citrate
	Affected / at Risk (%)	Affected / at Risk (%)
Total	51/259 (19.69%)	108/394 (27.41%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	1/259 (0.39%)	1/394 (0.25%)
Anaemia † 1	1/259 (0.39%)	0/394 (0.00%)
Haemolytic anaemia † 1	1/259 (0.39%)	0/394 (0.00%)
Cardiac disorders
Myocardial ischaemia † 1	0/259 (0.00%)	2/394 (0.51%)
Myocardial infarction † 1	1/259 (0.39%)	0/394 (0.00%)
Atrial fibrillation † 1	1/259 (0.39%)	1/394 (0.25%)
Cardiac failure † 1	0/259 (0.00%)	1/394 (0.25%)
Eye disorders
Diplopia † 1	0/259 (0.00%)	1/394 (0.25%)
Gastrointestinal disorders
Diarrhoea † 1	0/259 (0.00%)	4/394 (1.02%)
Pancreatitis † 1	0/259 (0.00%)	1/394 (0.25%)
Pancreatitis acute † 1	0/259 (0.00%)	1/394 (0.25%)
Colitis ischaemic † 1	0/259 (0.00%)	1/394 (0.25%)
Periodontal disease † 1	0/259 (0.00%)	1/394 (0.25%)
Diaphragmatic hernia † 1	0/259 (0.00%)	1/394 (0.25%)
Gastritis † 1	0/259 (0.00%)	1/394 (0.25%)
Abdominal pain upper † 1	1/259 (0.39%)	0/394 (0.00%)
Constipation † 1	0/259 (0.00%)	1/394 (0.25%)
Enteritis † 1	1/259 (0.39%)	0/394 (0.00%)
Inguinal hernia † 1	0/259 (0.00%)	1/394 (0.25%)
Vomiting † 1	0/259 (0.00%)	1/394 (0.25%)
Haematemesis † 1	0/259 (0.00%)	1/394 (0.25%)
Umbilical hernia † 1	0/259 (0.00%)	1/394 (0.25%)
General disorders
Pyrexia † 1	2/259 (0.77%)	5/394 (1.27%)
Non-cardiac chest pain † 1	1/259 (0.39%)	0/394 (0.00%)
Pain † 1	0/259 (0.00%)	1/394 (0.25%)
Chills † 1	1/259 (0.39%)	0/394 (0.00%)
Hepatobiliary disorders
Hepatic function abnormal † 1	0/259 (0.00%)	1/394 (0.25%)
Immune system disorders
Drug hypersensitivity † 1	1/259 (0.39%)	0/394 (0.00%)
Infections and infestations
Pneumonia † 1 [1]	10/259 (3.86%)	24/394 (6.09%)
Lower respiratory tract infection † 1	1/259 (0.39%)	3/394 (0.76%)
Bronchitis † 1	0/259 (0.00%)	3/394 (0.76%)
Atypical pneumonia † 1	1/259 (0.39%)	1/394 (0.25%)
Lung infection † 1	0/259 (0.00%)	1/394 (0.25%)
Herpes zoster † 1	2/259 (0.77%)	4/394 (1.02%)
Herpes zoster disseminated † 1	0/259 (0.00%)	1/394 (0.25%)
Varicella † 1	1/259 (0.39%)	0/394 (0.00%)
Sinusitis † 1	1/259 (0.39%)	3/394 (0.76%)
Pharyngitis † 1	1/259 (0.39%)	1/394 (0.25%)
Upper respiratory tract infection † 1	0/259 (0.00%)	2/394 (0.51%)
Tonsillitis † 1	0/259 (0.00%)	1/394 (0.25%)
Gastroenteritis † 1	1/259 (0.39%)	2/394 (0.51%)
Appendicitis † 1	0/259 (0.00%)	1/394 (0.25%)
Diverticulitis † 1	0/259 (0.00%)	1/394 (0.25%)
Influenza † 1	1/259 (0.39%)	4/394 (1.02%)
Metapneumovirus infection † 1	0/259 (0.00%)	2/394 (0.51%)
Picornavirus infection † 1	0/259 (0.00%)	1/394 (0.25%)
Pneumonia viral † 1	0/259 (0.00%)	1/394 (0.25%)
Viral upper respiratory tract infection † 1	1/259 (0.39%)	0/394 (0.00%)
Cellulitis † 1	0/259 (0.00%)	2/394 (0.51%)
Bacterial infection † 1	0/259 (0.00%)	1/394 (0.25%)
Parainfluenzae virus infection † 1	0/259 (0.00%)	1/394 (0.25%)
Pneumonia parainfluenzae viral † 1	0/259 (0.00%)	1/394 (0.25%)
Pneumococcal sepsis † 1	0/259 (0.00%)	1/394 (0.25%)
Pneumonia pneumococcal † 1	0/259 (0.00%)	1/394 (0.25%)
Pneumonia streptococcal † 1	0/259 (0.00%)	1/394 (0.25%)
Escherichia sepsis † 1	0/259 (0.00%)	1/394 (0.25%)
Dengue fever † 1	1/259 (0.39%)	0/394 (0.00%)
Respiratory tract infection † 1	1/259 (0.39%)	0/394 (0.00%)
Respiratory syncytial virus infection † 1	1/259 (0.39%)	0/394 (0.00%)
Sepsis † 1	0/259 (0.00%)	1/394 (0.25%)
Injury, poisoning and procedural complications
Meniscus injury † 1	0/259 (0.00%)	2/394 (0.51%)
Ankle fracture † 1	1/259 (0.39%)	0/394 (0.00%)
Lower limb fracture † 1	1/259 (0.39%)	0/394 (0.00%)
Subarachnoid haemorrhage † 1	0/259 (0.00%)	1/394 (0.25%)
Joint dislocation † 1	0/259 (0.00%)	1/394 (0.25%)
Ligament sprain † 1	0/259 (0.00%)	1/394 (0.25%)
Bone contusion † 1	0/259 (0.00%)	1/394 (0.25%)
Overdose † 1	0/259 (0.00%)	1/394 (0.25%)
Ulnar nerve injury † 1	0/259 (0.00%)	1/394 (0.25%)
Investigations
Light chain analysis increased † 1	1/259 (0.39%)	1/394 (0.25%)
Alanine aminotransferase increased † 1	1/259 (0.39%)	0/394 (0.00%)
Aspartate aminotransferase increased † 1	1/259 (0.39%)	0/394 (0.00%)
Gamma-glutamyltransferase increased † 1	1/259 (0.39%)	0/394 (0.00%)
C-reactive protein increased † 1	0/259 (0.00%)	1/394 (0.25%)
Blood alkaline phosphatase increased † 1	1/259 (0.39%)	0/394 (0.00%)
Influenza B virus test positive † 1	1/259 (0.39%)	0/394 (0.00%)
Metabolism and nutrition disorders
Hypokalaemia † 1	1/259 (0.39%)	1/394 (0.25%)
Hypercalcaemia † 1	0/259 (0.00%)	1/394 (0.25%)
Tumour lysis syndrome † 1	1/259 (0.39%)	0/394 (0.00%)
Hyperglycaemia † 1	1/259 (0.39%)	0/394 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	1/259 (0.39%)	3/394 (0.76%)
Musculoskeletal chest pain † 1	0/259 (0.00%)	1/394 (0.25%)
Pain in extremity † 1	0/259 (0.00%)	1/394 (0.25%)
Pathological fracture † 1	1/259 (0.39%)	4/394 (1.02%)
Osteonecrosis of jaw † 1	0/259 (0.00%)	3/394 (0.76%)
Osteonecrosis † 1	0/259 (0.00%)	1/394 (0.25%)
Bone pain † 1	1/259 (0.39%)	0/394 (0.00%)
Rotator cuff syndrome † 1	0/259 (0.00%)	1/394 (0.25%)
Osteoarthritis † 1	0/259 (0.00%)	1/394 (0.25%)
Kyphosis † 1	0/259 (0.00%)	1/394 (0.25%)
Ankylosing spondylitis † 1	1/259 (0.39%)	0/394 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma † 1	2/259 (0.77%)	2/394 (0.51%)
Plasma cell leukaemia † 1	1/259 (0.39%)	0/394 (0.00%)
Plasmacytoma † 1	1/259 (0.39%)	0/394 (0.00%)
Prostate cancer † 1	1/259 (0.39%)	1/394 (0.25%)
Basal cell carcinoma † 1	0/259 (0.00%)	2/394 (0.51%)
Invasive ductal breast carcinoma † 1	1/259 (0.39%)	0/394 (0.00%)
Adenocarcinoma of colon † 1	1/259 (0.39%)	0/394 (0.00%)
Squamous cell carcinoma of lung † 1	0/259 (0.00%)	1/394 (0.25%)
Tumour pain † 1	1/259 (0.39%)	0/394 (0.00%)
Bronchial carcinoma † 1	0/259 (0.00%)	1/394 (0.25%)
Malignant melanoma † 1	0/259 (0.00%)	1/394 (0.25%)
Leiomyoma † 1	1/259 (0.39%)	0/394 (0.00%)
Uterine cancer † 1	0/259 (0.00%)	1/394 (0.25%)
Nervous system disorders
Spinal cord compression † 1	0/259 (0.00%)	1/394 (0.25%)
Cerebral ischaemia † 1	0/259 (0.00%)	1/394 (0.25%)
Somnolence † 1	0/259 (0.00%)	1/394 (0.25%)
Post herpetic neuralgia † 1	0/259 (0.00%)	1/394 (0.25%)
Transient ischaemic attack † 1	1/259 (0.39%)	0/394 (0.00%)
Radicular pain † 1	0/259 (0.00%)	1/394 (0.25%)
Product Issues
Device dislocation † 1	0/259 (0.00%)	1/394 (0.25%)
Psychiatric disorders
Delirium † 1	1/259 (0.39%)	0/394 (0.00%)
Depression † 1	1/259 (0.39%)	0/394 (0.00%)
Renal and urinary disorders
Urinary retention † 1	1/259 (0.39%)	0/394 (0.00%)
Renal impairment † 1	1/259 (0.39%)	0/394 (0.00%)
Reproductive system and breast disorders
Prostatitis † 1	1/259 (0.39%)	0/394 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	0/259 (0.00%)	1/394 (0.25%)
Sleep apnoea syndrome † 1	1/259 (0.39%)	0/394 (0.00%)
Chronic obstructive pulmonary disease † 1	0/259 (0.00%)	2/394 (0.51%)
Pleural effusion † 1	0/259 (0.00%)	2/394 (0.51%)
Organising pneumonia † 1	0/259 (0.00%)	1/394 (0.25%)
Pleurisy † 1	0/259 (0.00%)	1/394 (0.25%)
Skin and subcutaneous tissue disorders
Rash generalised † 1	0/259 (0.00%)	1/394 (0.25%)
Rash macular † 1	0/259 (0.00%)	1/394 (0.25%)
Erythema nodosum † 1	1/259 (0.39%)	0/394 (0.00%)
Vascular disorders
Jugular vein thrombosis † 1	0/259 (0.00%)	1/394 (0.25%)
Subclavian vein thrombosis † 1	0/259 (0.00%)	1/394 (0.25%)
Hypertension † 1	1/259 (0.39%)	0/394 (0.00%)
1 Term from vocabulary, MedDRA version: 19.0; † Indicates events were collected by systematic assessment; [1] One treatment-emergent death occurred in the ixazomib citrate treatment arm and was assessed as being related to study treatment.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Ixazomib Citrate
	Affected / at Risk (%)	Affected / at Risk (%)
Total	229/259 (88.42%)	371/394 (94.16%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	6/259 (2.32%)	41/394 (10.41%)
Neutropenia † 1	15/259 (5.79%)	25/394 (6.35%)
Anaemia † 1	9/259 (3.47%)	29/394 (7.36%)
Gastrointestinal disorders
Diarrhoea † 1	61/259 (23.55%)	136/394 (34.52%)
Nausea † 1	40/259 (15.44%)	154/394 (39.09%)
Vomiting † 1	28/259 (10.81%)	105/394 (26.65%)
Constipation † 1	21/259 (8.11%)	41/394 (10.41%)
Dyspepsia † 1	15/259 (5.79%)	13/394 (3.30%)
General disorders
Fatigue † 1	43/259 (16.60%)	79/394 (20.05%)
Pyrexia † 1	37/259 (14.29%)	79/394 (20.05%)
Influenza like illness † 1	18/259 (6.95%)	36/394 (9.14%)
Asthenia † 1	17/259 (6.56%)	30/394 (7.61%)
Oedema peripheral † 1	11/259 (4.25%)	34/394 (8.63%)
Infections and infestations
Viral upper respiratory tract infection † 1	68/259 (26.25%)	94/394 (23.86%)
Upper respiratory tract infection † 1	54/259 (20.85%)	100/394 (25.38%)
Influenza † 1	29/259 (11.20%)	38/394 (9.64%)
Bronchitis † 1	19/259 (7.34%)	40/394 (10.15%)
Herpes zoster † 1	14/259 (5.41%)	37/394 (9.39%)
Conjunctivitis † 1	10/259 (3.86%)	28/394 (7.11%)
Pneumonia † 1	14/259 (5.41%)	20/394 (5.08%)
Pharyngitis † 1	9/259 (3.47%)	20/394 (5.08%)
Sinusitis † 1	6/259 (2.32%)	20/394 (5.08%)
Metabolism and nutrition disorders
Decreased appetite † 1	17/259 (6.56%)	21/394 (5.33%)
Musculoskeletal and connective tissue disorders
Back pain † 1	48/259 (18.53%)	76/394 (19.29%)
Arthralgia † 1	30/259 (11.58%)	86/394 (21.83%)
Musculoskeletal pain † 1	24/259 (9.27%)	39/394 (9.90%)
Pain in extremity † 1	25/259 (9.65%)	32/394 (8.12%)
Muscle spasms † 1	21/259 (8.11%)	35/394 (8.88%)
Bone pain † 1	18/259 (6.95%)	37/394 (9.39%)
Myalgia † 1	14/259 (5.41%)	22/394 (5.58%)
Musculoskeletal chest pain † 1	15/259 (5.79%)	20/394 (5.08%)
Nervous system disorders
Headache † 1	23/259 (8.88%)	43/394 (10.91%)
Neuropathy peripheral † 1	20/259 (7.72%)	41/394 (10.41%)
Peripheral sensory neuropathy † 1	19/259 (7.34%)	36/394 (9.14%)
Dizziness † 1	18/259 (6.95%)	33/394 (8.38%)
Paraesthesia † 1	8/259 (3.09%)	27/394 (6.85%)
Psychiatric disorders
Insomnia † 1	12/259 (4.63%)	31/394 (7.87%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	55/259 (21.24%)	87/394 (22.08%)
Oropharyngeal pain † 1	19/259 (7.34%)	29/394 (7.36%)
Productive cough † 1	9/259 (3.47%)	26/394 (6.60%)
Skin and subcutaneous tissue disorders
Pruritus † 1	15/259 (5.79%)	28/394 (7.11%)
Rash maculo-papular † 1	9/259 (3.47%)	24/394 (6.09%)
Rash macular † 1	8/259 (3.09%)	24/394 (6.09%)
Vascular disorders
Hypertension † 1	18/259 (6.95%)	21/394 (5.33%)
1 Term from vocabulary, MedDRA version: 19.0; † 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.

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

Results Point of Contact

• Name/Title: Medical Director
• Organization: Takeda
• Phone: +1-866-835-2233
• EMail: trialdisclosures@takeda.com

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

Kaiser M, Beksac M, Gulbrandsen N, Schjesvold F, Hajek R, Moreau P, de Arriba de la Fuente F, Mateos MV, West S, Spencer A, Rajkumar SV, Suryanarayan K, Czorniak M, Li C, Teng Z, Labotka R, Dimopoulos MA. Adverse event management in the TOURMALINE-MM3 study of post-transplant ixazomib maintenance in multiple myeloma. Ann Hematol. 2020 Aug;99(8):1793-1804. doi: 10.1007/s00277-020-04149-5. Epub 2020 Jul 1. Erratum In: Ann Hematol. 2021 Jan;100(1):297-302.

Schjesvold F, Goldschmidt H, Maisnar V, Spicka I, Abildgaard N, Rowlings P, Cain L, Romanus D, Suryanarayan K, Rajkumar V, Odom D, Gnanasakthy A, Dimopoulos M. Quality of life is maintained with ixazomib maintenance in post-transplant newly diagnosed multiple myeloma: The TOURMALINE-MM3 trial. Eur J Haematol. 2020 May;104(5):443-458. doi: 10.1111/ejh.13379. Epub 2020 Feb 22.

Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, Goldschmidt H, Maisnar V, Moreau P, Min CK, Pluta A, Chng WJ, Kaiser M, Zweegman S, Mateos MV, Spencer A, Iida S, Morgan G, Suryanarayan K, Teng Z, Skacel T, Palumbo A, Dash AB, Gupta N, Labotka R, Rajkumar SV; TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019 Jan 19;393(10168):253-264. doi: 10.1016/S0140-6736(18)33003-4. Epub 2018 Dec 10.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02181413
• Other Study ID Numbers: C16019; U1111-1155-8695 ( Other Identifier: WHO ); 2013-002076-41 ( EudraCT Number ); C16019CTIL ( Registry Identifier: Israel MOH ); NL.47795.029.14 ( Registry Identifier: CCMO ); 173116 ( Registry Identifier: HC-CTD ); 1036024001 ( Registry Identifier: TCTIN ); SNCTP000001745 ( Registry Identifier: SNCTP )
• First Submitted: June 27, 2014
• First Posted: July 4, 2014
• Results First Submitted: April 15, 2019
• Results First Posted: May 7, 2019
• Last Update Posted: June 30, 2022