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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02181413
Recruitment Status : Active, not recruiting
First Posted : July 4, 2014
Results First Posted : May 7, 2019
Last Update Posted : March 6, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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
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
Hide 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
Arm/Group Title Placebo Ixazomib Citrate Total
Hide 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
Hide 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.
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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)
Hide 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
Hide 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)
Hide 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)
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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)
Hide 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
Hide 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
Hide 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
Hide 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)
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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
Hide 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
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
Hide 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%) 
Hide 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.
Hide 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
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
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Takeda
Phone: +1-866-835-2233
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
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: March 6, 2020