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CompletedNCT02181413Updated Nov 19, 2024Results posted

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

A Phase 3 interventional study of Ixazomib Citrate and Placebo in Multiple Myeloma and Autologous Stem Cell Transplant, sponsored by Takeda. Completed at 227 sites in 33 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-11-19.

Sponsored by Takeda · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
656
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

The purpose of this study is to determine the effect of ixazomib citrate maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with newly diagnosed multiple myeloma (NDMM) who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT).

Read the detailed description

The investigational drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being tested to slow disease progression and improve overall survival in people who have NDMM and who have had any type of positive response to induction therapy followed by HDT and ASCT. This study will look at the effect ixazomib citrate has on the length of time that participants are free of progressive disease (PD) and their overall survival (OS).

The study enrolled 656 participants. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need, or if the disease has progressed and the information is required for planning the next treatment):

  • Ixazomib citrate 3 mg for the first 4 cycles, then 4 mg for the remaining 22 cycles
  • Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient.

All participants will be asked to take one capsule on Days 1, 8 and 15 of each 28-day cycle, for up to 26 cycles (approximately 24 months).

This multi-center trial will be conducted globally. The overall time to participate in this study is up to 107 months. Participants will make 28 visits to the clinic during the treatment period and will continue to make visits after treatment has ended. During this initial follow up period, participants will be assessed for disease status with follow up every 12 weeks. After the next line of therapy begins, follow-up will occur every 12 weeks until death or termination of the study.

02

Conditions studied

  • Multiple Myeloma
  • Autologous Stem Cell Transplant

Keywords

  • Drug therapy
  • Ixazomib citrate
03

In context

Multiple Myeloma

3,632 studies on the registry are indexed under Multiple Myeloma; 745 are open to participants now.

This study's enrollment of 656 is above the median of 41 across 2,907 interventional studies indexed under Multiple Myeloma.

Browse Multiple Myeloma studies →

Lead sponsor

Takeda is the lead sponsor of 1,002 studies on the registry; 92 are open to participants now.

Of its 173 completed or terminated interventional studies of FDA-regulated products, 149 (86%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic multiple myeloma according to standard criteria.
  2. Documented results of cytogenetics/ fluorescence in situ hybridization (FISH) obtained at any time before transplant, and International Staging System (ISS) staging at the time of diagnosis available.
  3. Underwent standard of care (SOC) induction therapy (induction therapy must include proteasome inhibitor (PI) and/or immunomodulating drugs (IMiD)-based regimens as primary therapy for multiple myeloma), followed by a single autologous stem cell transplant (ASCT) with a high-dose melphalan (200 mg/m\^2) conditioning regimen, within 12 months of diagnosis. Vincristine, Adriamycin [doxorubicin], and dexamethasone (VAD) is not an acceptable induction therapy for this trial.
  4. Started screening no earlier than 75 days after transplant, completed screening within 15 days, and randomized no later than 115 days after transplant.
  5. Must have not received post-ASCT consolidation therapy.
  6. Documented response to ASCT (PR, VGPR, CR/stringent complete response [sCR]) according to IMWG criteria.
  7. ECOG performance status of 0 to 2.

  8. Female participants who:

    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, AND
    • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilized (ie, status postvasectomy), who:
    • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, AND
    • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
  9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
  10. Suitable venous access for the study-required blood sampling.
  11. Is willing and able to adhere to the study visit schedule and other protocol requirements.

  12. Must meet the following clinical laboratory criteria at study entry:

    • Absolute neutrophil count (ANC) ≥ 1,000 per cubic milliliter (/mm\^3) and platelet count ≥ 75,000/mm\^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before randomization.
    • Total bilirubin ≤ 1.5 * the upper limit of the normal range (ULN).
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 * ULN.
    • Calculated creatinine clearance ≥ 30 milliliter per minute (mL/min).

Exclusion criteria

Exclusion Criteria:

  1. Multiple myeloma that has relapsed following primary therapy or is not responsive to primary therapy. For this study, stable disease following ASCT will be considered nonresponsive to primary therapy.
  2. Double (tandem) ASCT.
  3. Radiotherapy within 14 days before the first dose of study drug.
  4. Diagnosed or treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy with evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  5. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
  6. Major surgery within 14 days before randomization.
  7. Central nervous system involvement.
  8. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before randomization.
  9. Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
  10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
  11. Systemic treatment with strong cytochrome P450 3A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before randomization in the study.
  12. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
  13. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause).
  14. Psychiatric illness/social situation that would limit compliance with study requirements.
  15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  16. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.
  17. Treatment with any investigational products within 60 days before the first dose of the study drug regimen.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
656 participants (actual)

Study arms

  • Placebo comparator
    Placebo

    Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.

    Drug: Placebo

  • Experimental
    Ixazomib Citrate

    Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who have had any dose reductions due to adverse events (AEs) would not be dose escalated.

    Drug: Ixazomib Citrate

Interventions

  • DrugIxazomib Citrate

    Ixazomib citrate capsules

    Also known as: MLN9708

  • DrugPlacebo

    Ixazomib citrate placebo-matching capsules

06

What researchers measure

Primary outcomes

  1. Progression Free Survival (PFS)

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

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

Secondary outcomes

  1. Overall Survival (OS)

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

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

  2. Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy

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

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

  3. Time to Progression (TTP)

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

    Time frame: Randomization up to PD (up to 107 months)

  4. Second Progression Free Survival (PFS2)

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

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

  5. Time to Start of the Next Line of Therapy

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

    Time frame: Randomization up to 107 months

  6. Time to End of the Next Line of Therapy

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

    Time frame: Randomization up to 107 months

  7. Duration of the Next Line of Therapy

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

    Time frame: Up to 107 months

  8. Percentage of Participants Who Develop a New Primary Malignancy

    The decimal values of percentages were subjected to rounding off.

    Time frame: Up to 107 months

  9. Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative

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

    Time frame: Baseline up to EOT (up to 24 months)

  10. Number of Participants With Maintenance of MRD Negativity

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

    Time frame: Up to EOT (up to 24 months)

  11. Correlation Between MRD Status and Progression Free Survival (PFS)

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

    Time frame: From randomization up to 107 months

  12. Correlation Between MRD Status and Overall Survival (OS)

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

    Time frame: From randomization up to 107 months

  13. OS Benefits in a High-Risk Population

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

    Time frame: Randomization up to 107 months

  14. PFS Benefits in a High-Risk Population

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

    Time frame: Randomization up to 107 months

  15. Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score

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

    Time frame: Baseline up to EOT (up to Month 24)

  16. Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)

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

    Time frame: Up to 107 months

  17. Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs

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

    Time frame: Up to 107 months

  18. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Domain Score

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

    Time frame: Baseline up to EOT (up to Month 24)

  19. Plasma Concentration of Ixazomib

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

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

  20. Time to Resolution of Peripheral Neuropathy (PN) Events

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

    Time frame: Up to 107 months

  21. Time to Improvement of PN Events

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

    Time frame: Up to 107 months

07

Results

Posted May 7, 2019

Participant flow

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

Participant flow — Overall Study
MilestonePlaceboIxazomib Citrate
Started261395
Intent-to-treat (itt) population261395
Safety population259394
Per protocol (pp) population256387
Completed206322
Not completed5573
Withdrew: Withdrawal by subject4561
Withdrew: Reason not specified25
Withdrew: Lost to follow-up87

Outcome measures

PrimaryProgression Free Survival (PFS)

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

Time frame:
Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks (up to 45 months)
Reported as:
Median · months
Progression Free Survival (PFS)
monthsPlaceboIxazomib Citrate
Progression Free Survival (PFS)21.3 (17.97 to 24.67)26.5 (23.69 to 33.81)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.002 · Hazard ratio (hr): 0.720 · 95% CI 0.582 to 0.890HR 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.
SecondaryOverall Survival (OS)

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

Time frame:
Randomization up to end of follow up period (up to 107 months)
Reported as:
Median · months
Overall Survival (OS)
monthsPlaceboIxazomib Citrate
Overall Survival (OS)NA (96.95 to NA)NA (104.97 to NA)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.850 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 1.025 · 95% CI 0.789 to 1.332Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryPercentage of Participants With Any Best Response Category Before PD or Subsequent Therapy

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

Time frame:
Randomization up to EOT (up to 24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months)
Reported as:
Number · percentage of participants
Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy
percentage of participantsPlaceboIxazomib Citrate
PR1012
VGPR4540
CR4244
Statistical analysis
  • Placebo vs Ixazomib Citrate · Cochran-Mantel-Haenszel · p = 0.370 (P-value is based on Cochran-Mantel-Haenszel (CMH) test stratified by pre-induction regimen, pre-induction international staging system (ISS), and response after transplantation at screening.) · Odds ratio (or): 0.732 · 95% CI 0.365 to 1.466Odds ratio and CI are based on a logistic regression model with treatment group as a categorical predictor variable and pre-induction regimen, pre-induction ISS, and response after transplantation at screening as covariates.
SecondaryTime to Progression (TTP)

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

Time frame:
Randomization up to PD (up to 107 months)
Reported as:
Median · months
Time to Progression (TTP)
monthsPlaceboIxazomib Citrate
Time to Progression (TTP)21.4 (18.10 to 24.67)26.6 (23.69 to 33.81)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.002 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 0.716 · 95% CI 0.579 to 0.886Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondarySecond Progression Free Survival (PFS2)

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

Time frame:
Randomization up to EOT (24 months); thereafter followed up every 4 weeks until initiation of next-line therapy and then every 12 weeks until second progressive disease (PD2) or death (up to 107 months)
Reported as:
Median · months
Second Progression Free Survival (PFS2)
monthsPlaceboIxazomib Citrate
Second Progression Free Survival (PFS2)80.4 (68.7 to NA)84.0 (67.22 to NA)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.902 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 1.015 · 95% CI 0.795 to 1.298Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryTime to Start of the Next Line of Therapy

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

Time frame:
Randomization up to 107 months
Reported as:
Median · months
Time to Start of the Next Line of Therapy
monthsPlaceboIxazomib Citrate
Time to Start of the Next Line of Therapy27.6 (24.48 to 31.61)33.1 (29.14 to 36.34)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.056 · Hazard ratio (hr): 0.833 · 95% CI 0.690 to 1.005Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryTime to End of the Next Line of Therapy

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

Time frame:
Randomization up to 107 months
Reported as:
Median · months
Time to End of the Next Line of Therapy
monthsPlaceboIxazomib Citrate
Time to End of the Next Line of Therapy50.4 (42.84 to 61.01)55.9 (49.61 to 61.86)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.431 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage, and response after transplantation.) · Hazard ratio (hr): 0.922 · 95% CI 0.753 to 1.129Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryDuration of the Next Line of Therapy

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

Time frame:
Up to 107 months
Reported as:
Median · months
Duration of the Next Line of Therapy
monthsPlaceboIxazomib Citrate
Duration of the Next Line of Therapy12.3 (9.82 to 16.53)9.6 (7.49 to 12.06)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Hazard ratio (hr): 1.179 · 95% CI 0.959 to 1.450Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryPercentage of Participants Who Develop a New Primary Malignancy

The decimal values of percentages were subjected to rounding off.

Time frame:
Up to 107 months
Reported as:
Number · percentage of participants
Percentage of Participants Who Develop a New Primary Malignancy
percentage of participantsPlaceboIxazomib Citrate
Percentage of Participants Who Develop a New Primary Malignancy87
SecondaryNumber of Participants With Conversion to Minimal Residual Disease (MRD) Negative

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

Time frame:
Baseline up to EOT (up to 24 months)
Reported as:
Count of participants · Participants
Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative
ParticipantsPlaceboIxazomib Citrate
Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative2739
Statistical analysis
  • Placebo vs Ixazomib Citrate · Fisher Exact · p = 0.814 (P-value was based on Fisher's exact test comparing conversion to MRD- at any time post study entry between treatment groups.)
SecondaryNumber of Participants With Maintenance of MRD Negativity

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

Time frame:
Up to EOT (up to 24 months)
Reported as:
Count of participants · Participants
Number of Participants With Maintenance of MRD Negativity
ParticipantsPlaceboIxazomib Citrate
Number of Participants With Maintenance of MRD Negativity2537
Statistical analysis
  • Placebo vs Ixazomib Citrate · Fisher Exact · p = 0.805 (P-value was based on fisher's exact test comparing conversion to MRD- at any time post study entry between treatment groups.)
SecondaryCorrelation Between MRD Status and Progression Free Survival (PFS)

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

Time frame:
From randomization up to 107 months
Reported as:
Median · months
Correlation Between MRD Status and Progression Free Survival (PFS)
monthsPlaceboIxazomib Citrate
MRD- at Study Entry32.5 (19.32 to NA)38.6 (33.81 to NA)
MRD+ at Study Entry18.5 (15.70 to 21.91)23.1 (20.24 to 25.69)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.034 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 0.612 · 95% CI 0.386 to 0.969Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.010 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 0.704 · 95% CI 0.539 to 0.920Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryCorrelation Between MRD Status and Overall Survival (OS)

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

Time frame:
From randomization up to 107 months
Reported as:
Median · months
Correlation Between MRD Status and Overall Survival (OS)
monthsPlaceboIxazomib Citrate
MRD- at Study EntryNA (84.90 to NA)NA (NA to NA)
MRD+ at Study EntryNA (90.74 to NA)105.0 (91.47 to NA)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.182 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 0.7 · 95% CI 0.414 to 1.184Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.847 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 0.966 · 95% CI 0.682 to 1.368Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryOS Benefits in a High-Risk Population

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

Time frame:
Randomization up to 107 months
Reported as:
Median · months
OS Benefits in a High-Risk Population
monthsPlaceboIxazomib Citrate
OS Benefits in a High-Risk Population69.0 (33.25 to 92.98)64.2 (40.97 to NA)
Statistical analysis
  • Placebo vs Ixazomib Citrate · Log Rank · p = 0.905 (P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.) · Hazard ratio (hr): 0.97 · 95% CI 0.583 to 1.613Hazard ratio is based on an unadjusted Cox's proportional hazard regression model stratified by induction regimen, pre-induction ISS, and response after transplantation, comparing the hazard rate of Ixazomib arm over the hazard rate of Placebo arm.
SecondaryPFS Benefits in a High-Risk Population

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

Time frame:
Randomization up to 107 months
Reported as:
Median · months
PFS Benefits in a High-Risk Population
monthsPlaceboIxazomib Citrate
PFS Benefits in a High-Risk Population16.8 (12.81 to 18.50)18.5 (12.06 to 31.15)
SecondaryChange From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score

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

Time frame:
Baseline up to EOT (up to Month 24)
Reported as:
Mean · score on a scale
Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score
score on a scalePlaceboIxazomib Citrate
Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score0.1 ± 0.630.0 ± 0.54
SecondaryNumber of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)

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

Time frame:
Up to 107 months
Reported as:
Count of participants · Participants
Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)
ParticipantsPlaceboIxazomib Citrate
TEAEs241382
SAEs51108
SecondaryNumber of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs

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

Time frame:
Up to 107 months
Reported as:
Count of participants · Participants
Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs
ParticipantsPlaceboIxazomib Citrate
Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs3681
SecondaryChange From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Domain Score

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

Time frame:
Baseline up to EOT (up to Month 24)
Reported as:
Least squares mean · score on a scale
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Domain Score
score on a scalePlaceboIxazomib Citrate
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Domain Score-1.7 ± 1.57-4.1 ± 1.43
Statistical analysis
  • Placebo vs Ixazomib Citrate · t-test, 2 sided · p = 0.074 · Least squares (ls) mean difference: -2.3 · 95% CI -4.9 to 0.2P-value was from the significance test for the coefficient of the interaction between treatment and visit.
SecondaryPlasma Concentration of Ixazomib

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

Time frame:
Day 1 of Cycle 1: 1 hour and 4 hours post-dose; Predose on Days 8 and 15 of Cycle 1, Days 1 and 8 of Cycle 2, Day 1 of Cycles 3 through 10 (each cycle length= 28 days)
Reported as:
Mean · nanograms per milliliter (ng/mL)
Plasma Concentration of Ixazomib
nanograms per milliliter (ng/mL)Ixazomib Citrate
Cycle 1 Day 1: 1 Hour Post-dose27.919 ± 24.7787
Cycle 1 Day 1: 4 Hours Post-dose10.352 ± 9.8078
Cycle 1 Day 81.584 ± 1.6707
Cycle 1 Day 152.611 ± 1.4305
Cycle 2 Day 11.946 ± 1.0984
Cycle 2 Day 83.232 ± 2.0069
Cycle 3 Day 12.258 ± 1.1508
Cycle 4 Day 12.396 ± 1.7822
Cycle 5 Day 12.400 ± 1.4921
Cycle 6 Day 12.623 ± 1.6994
Cycle 7 Day 12.691 ± 1.9842
Cycle 8 Day 12.637 ± 1.7074
Cycle 9 Day 12.610 ± 1.9380
Cycle 10 Day 12.594 ± 1.9509
SecondaryTime to Resolution of Peripheral Neuropathy (PN) Events

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

Time frame:
Up to 107 months
Reported as:
Median · days
Time to Resolution of Peripheral Neuropathy (PN) Events
daysPlaceboIxazomib Citrate
Time to Resolution of Peripheral Neuropathy (PN) Events159.0 (45.0 to 736.0)225.0 (117.0 to 421.0)
SecondaryTime to Improvement of PN Events

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

Time frame:
Up to 107 months
Reported as:
Median · days
Time to Improvement of PN Events
daysPlaceboIxazomib Citrate
Time to Improvement of PN Events130.0 (36.0 to 520.0)134.0 (70.0 to 252.0)

Adverse events

Collected over Randomization up to end of follow up period (107 months). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo93/261 (35.6%)51/259 (19.7%)229/259 (88.4%)
Ixazomib Citrate144/395 (36.5%)108/394 (27.4%)371/394 (94.2%)
Most frequent serious events
Showing 10 of 127
Most frequent serious events
EventPlaceboIxazomib Citrate
PneumoniaInfections and infestations10/25925/394
PyrexiaGeneral disorders2/2595/394
DiarrhoeaGastrointestinal disorders0/2594/394
Herpes zosterInfections and infestations2/2594/394
InfluenzaInfections and infestations1/2594/394
Pathological fractureMusculoskeletal and connective tissue disorders1/2594/394
Plasma cell myelomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)2/2592/394
Back painMusculoskeletal and connective tissue disorders1/2593/394
BronchitisInfections and infestations0/2593/394
Lower respiratory tract infectionInfections and infestations1/2593/394
Most frequent other events
Showing 10 of 43
Most frequent other events
EventPlaceboIxazomib Citrate
NauseaGastrointestinal disorders40/259154/394
DiarrhoeaGastrointestinal disorders61/259135/394
ArthralgiaMusculoskeletal and connective tissue disorders43/259105/394
VomitingGastrointestinal disorders28/259105/394
NasopharyngitisInfections and infestations69/25991/394
Upper respiratory tract infectionInfections and infestations54/259100/394
CoughRespiratory, thoracic and mediastinal disorders55/25987/394
FatigueGeneral disorders43/25979/394
PyrexiaGeneral disorders37/25978/394
Back painMusculoskeletal and connective tissue disorders47/25977/394

Baseline characteristics

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

Age, Continuous
Age, Continuous(years)PlaceboIxazomib CitrateTotal
Mean58.2 ± 7.9256.8 ± 8.1757.4 ± 8.10
Age, Customized
Age, Customized(Participants)PlaceboIxazomib CitrateTotal
<60 years127229356
≥60 and <75 years134166300
Sex: Female, Male
Sex: Female, Male(Participants)PlaceboIxazomib CitrateTotal
Female99143242
Male162252414
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)PlaceboIxazomib CitrateTotal
Hispanic or Latino111425
Not Hispanic or Latino240362602
Unknown or Not Reported101929
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)PlaceboIxazomib CitrateTotal
White213315528
Black or African American3710
Asian365995
Other123
Not Reported81220
Region of Enrollment
Region of Enrollment(Participants)PlaceboIxazomib CitrateTotal
Australia111728
Japan91322
Korea, Republic Of172340
Singapore4812
Taiwan, Province Of China31013
Thailand156
Austria224
Belgium5510
Czech Republic123042
Denmark112031
France71118
Germany265076
Greece223860
Hungary91625
Israel121022
Italy262450
Netherlands11819
Norway61319
Poland51015
Portugal2810
South Africa437
Spain191938
Sweden4711
Switzerland303
Turkey101020
Ukraine213
United Kingdom142135
Argentina033
Brazil358
United States156
Height
Height(cm)PlaceboIxazomib CitrateTotal
Mean168.73 ± 10.347169.71 ± 10.004169.32 ± 10.145
Weight
Weight(kg)PlaceboIxazomib CitrateTotal
Mean75.18 ± 14.64875.93 ± 15.98975.63 ± 15.463

1 further baseline measures are reported on the registry.

08

Study locations

227 sites
  • University of Arkansas for Medical Sciences
    Little Rock, Arkansas 72205, United States
  • Mayo Clinic - PPDS
    Rochester, Minnesota 55905, United States
  • Montefiore Medical Center
    Bronx, New York 10467, United States
  • Penn State Health Milton S. Hershey Medical Center
    Hershey, Pennsylvania 17033, United States
  • Baylor University Medical Center
    Dallas, Texas 75246, United States
  • West Virginia University Hospital
    Morgantown, West Virginia 26506, United States
  • Hospital Italiano de La Plata
    La Plata, Buenos Aires B1900AX, Argentina
  • Instituto de Hematologia Y Medicina Clinica Dr Ruben Davoli
    Rosario, Santa Fe 2000, Argentina
  • Sanatorio Britanico de Rosario
    Rosario, Santa Fe S2000CVB, Argentina
  • Sanatorio Parque de Rosario
    Rosario, Santa Fe S2000DSV, Argentina
  • Hospital Italiano de Buenos Aires
    Ciudad Autonoma de Buenos Aires, C1181ACH, Argentina
  • Hospital Iturraspe
    Santa Fe, S3006FTP, Argentina
  • St George Hospital
    Kogarah, New South Wales 2217, Australia
  • Calvary Mater Newcastle
    Waratah, New South Wales 2298, Australia
  • Westmead Hospital
    Westmead, New South Wales 2145, Australia
  • Icon Cancer Care South Brisbane
    South Brisbane, Queensland 4101, Australia
  • Gold Coast University Hospital
    Southport, Queensland 4215, Australia
  • Royal Adelaide Hospital
    Adelaide, South Australia 5000, Australia
  • The Queen Elizabeth Hospital
    Woodville South, South Australia 5011, Australia
  • Austin Health
    Heidelberg, Victoria 3084, Australia
  • The Alfred Hospital
    Melbourne, Victoria 3004, Australia
  • Elisabethinen Hospital Linz
    Linz, 4020, Austria
  • Salzburger Landeskliniken
    Salzburg, 5020, Austria
  • Allgemeines Krankenhaus der Stadt Wien
    Wien, 1090, Austria
  • Klinik Ottakring (fruher: Wilhelminenspital)
    Wien, 1160, Austria
  • Centre Hospitalier Jolimont-Lobbes
    La Louviere, Hainaut 7100, Belgium
  • Centre Hospitalier Universitaire Ambroise Pare
    Mons, Hainaut 7000, Belgium
  • UZ Gent
    Gent, Oost-Vlaanderen 9000, Belgium
  • AZ Sint-Jan AV
    Brugge, West-Vlaanderen 8000, Belgium
  • ZNA Middelheim
    Antwerpen, 2020, Belgium
  • ZNA Stuivenberg
    Antwerpen, 2060, Belgium
  • Hospital Das Clinicas Da Universidade Federal de Minas Gerais
    Belo Horizonte, Minas Gerais 30130-100, Brazil
  • Instituto de Oncologia Do Parana
    Curitiba, Parana 80530-010, Brazil
  • Liga Paranaense de Combate Ao Cancer - Hospital Erasto Gaertner
    Curitiba, Parana 81520-060, Brazil
  • Hospital de Clinicas de Passo Fundo
    Passo Fundo, Rio Grande Do Sul 99010-260, Brazil
  • Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
    Porto Alegre, Rio Grande Do Sul 90035-903, Brazil
  • Mae de Deus Center Hospital Giovanni Battista
    Porto Alegre, Rio Grande Do Sul 90470-340, Brazil
  • Centro de Pesquisas Oncologicas
    Florianopolis, Santa Catarina 88034000, Brazil
  • Instituto Joinvilense de Hematologia E Oncologia
    Joinville, Santa Catarina 89201-260, Brazil
  • Hospital Amaral Carvalho
    Jau, Sao Paulo 17210-080, Brazil
  • Hospital de Base Da FAMERP
    Sao Jose Do Rio Preto, Sao Paulo 15090-000, Brazil
  • Instituto Nacional de Cancer
    Rio De Janeiro, 20231-050, Brazil
  • Universidade Federal do Rio de Janeiro - UFRJ
    Rio de Janeiro, 21941-913, Brazil
  • Irmandade Da Santa Casa de Misericordia de Sao Paulo
    Sao Paulo, 01223-001, Brazil
  • Hospital Israelita Albert Einstein
    Sao Paulo, 05651-901, Brazil
  • Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
    Sao Paulo, 5403000, Brazil
  • University Health Network
    Toronto, Ontario M5G 2N2, Canada
  • MUHC-Glen Site
    Montreal, Quebec H4A 3J1, Canada
  • Instituto Nacional de Cancerologia Colombia
    Bogota, Cundinamarca, Colombia
  • Fundacion Valle Del Lili
    Cali, Valle Del Cauca, Colombia
  • Hospital Pablo Tobon Uribe
    Medellin, Colombia
  • Fakultni nemocnice Hradec Kralove
    Hradec Kralove, Kralovehradeck Kraj 500 05, Czechia
  • Fakultni nemocnice Brno
    Brno, 625 00, Czechia
  • Fakultni nemocnice Olomouc
    Olomouc, 779 00, Czechia
  • Fakultni nemocnice Ostrava
    Ostrava, 708 52, Czechia
  • Vseobecna Fakultni Nemocnice V Praze
    Praha 2, 128 08, Czechia
  • Fakultni nemocnice Kralovske Vinohrady
    Praha, 100 34, Czechia
  • Herlev Hospital
    Herlev, Capital 2730, Denmark
  • Aalborg Universitetshospital
    Aalborg, Nordjylland DK-9000, Denmark
  • Aarhus Universitetshospital Arhus Sygehus
    Aarhus N, DK-8200, Denmark
  • Rigshospitalet
    Copenhagen, 2100, Denmark
  • Odense Universitetshospital
    Odense, 5000, Denmark
  • Sjallands Universitetshospital, Roskilde
    Roskilde, DK-4000, Denmark
  • Vejle Sygehus
    Vejle, DK-7100, Denmark
  • Hopital Antoine Beclere
    Clamart, Hauts-de-Seine 92140, France
  • Hotel Dieu - Nantes
    Nantes, Loire-Atlantique 44093, France
  • CHRU Lille
    Lille, Nord 59037, France
  • Hopital Universitaire Dupuytren
    Limoges, 87042, France
  • Groupe Hospitalier Necker Enfants Malades
    Paris, 75015, France
  • University Clinic Heidelberg
    Heidelberg, Baden-Wurttemberg 69120, Germany
  • Klinikum Mannheim Universitatsklinikum gGmbH
    Mannheim, Baden-Wurttemberg 68167, Germany
  • Universitatsklinikum Ulm
    Ulm, Baden-Wurttemberg 89081, Germany
  • LMU Klinikum der Universitat Munchen
    Munchen, Bayern 81377, Germany
  • Universitatsklinikum Wurzburg
    Wurzburg, Bayern 97080, Germany
  • Klinikum Darmstadt GmbH
    Darmstadt, Hessen 64283, Germany
  • Klinikum Frankfurt Hochst GmbH
    Frankfurt am Main, Hessen 65929, Germany
  • Pius Hospital Oldenburg
    Oldenburg, Niedersachsen 26121, Germany
  • Universitatsklinikum Bonn
    Bonn, Nordrhein-Westfalen 53105, Germany
  • Universitatsklinikum Essen
    Essen, Nordrhein-Westfalen 45122, Germany
  • Evangelisches Krankenhaus Essen Werden gGmbH
    Essen, Nordrhein-Westfalen 45239, Germany
  • Katholisches Krankenhaus Hagen gGmbH
    Hagen, Nordrhein-Westfalen 58095, Germany
  • Uniklinik Koln
    Koln, Nordrhein-Westfalen 50937, Germany
  • Universitatsmedizin der Johannes Gutenberg-Universitat Mainz
    Mainz, Rheinland-Pfalz 55131, Germany
  • Universitatsklinikum Carl Gustav Carus an der TU Dresden
    Dresden, Sachsen 1307, Germany
  • Helios Klinikum Berlin-Buch
    Berlin, 13125, Germany
  • Charite - Universitatsmedizin Berlin
    Berlin, 13353, Germany
  • Asklepios Klinik St. Georg
    Hamburg, 20099, Germany
  • Universitatsklinikum Hamburg Eppendorf
    Hamburg, 20246, Germany
  • Asklepios Klinik Altona
    Hamburg, 22763, Germany
  • KRH Klinikum Siloah-Oststadt-Heidehaus
    Hannover, 30459, Germany
  • Klinikum der Stadt Ludwigshafen gGmbH
    Ludwigshafen, 67063, Germany
  • Universitatsklinikum Tubingen
    Tubingen, 72076, Germany
  • Evangelismos General Hospital of Athens
    Athens, Attiki 10676, Greece
  • Laiko General Hospital of Athens
    Athens, Attiki 11527, Greece
  • Alexandra Hospital
    Athens, 11528, Greece
  • Georgios Papanikolaou General Hospital of Thessaloniki
    Thessaloniki, 57010, Greece
  • Semmelweis Egyetem
    Budapest, 1083, Hungary
  • Del-pesti Centrumkorhaz- Orszagos Hematologiai es Infektologiai Intezet
    Budapest, 1097, Hungary
  • Debreceni Egyetem Klinikai Kozpont
    Debrecen, 4032, Hungary
  • Somogy Megyei Kaposi Mor Oktato Korhaz
    Kaposvar, 7400, Hungary

Showing the first 100 of 227 sites across 33 countries.

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References and documents

Publications

  • 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. doi: 10.1007/s00277-020-04302-0. PubMed 32613281 ↗
  • 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. PubMed 31880006 ↗
  • 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. PubMed 30545780 ↗

Study documents

  • Study protocol · Nov 22, 2021
  • Statistical analysis plan · May 31, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting information: Study protocol, Sap, Icf, Csr

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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Nov 19, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT02181413
Lead sponsor
Takeda
Responsible party
Sponsor
First posted
Jul 4, 2014
Start date
Jul 16, 2014
Primary completion
Apr 16, 2018
Completion
Sep 8, 2023
Results posted
May 7, 2019
Last update
Nov 19, 2024

Study contacts

Study Director
study director · Takeda

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Oct 2024. You cannot join it, but the record below documents what was studied.

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