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

• ClinicalTrials.gov Identifier: NCT02181413
• Recruitment Status: Active, not recruiting
• First Posted: July 4, 2014
• Results First Posted: May 7, 2019
• Last Update Posted: September 13, 2023
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: June 27, 2014
• First Posted Date: July 4, 2014
• Results First Submitted Date: April 15, 2019
• Results First Posted Date: May 7, 2019
• Last Update Posted Date: September 13, 2023
• Actual Study Start Date: July 1, 2014
• Actual Primary Completion Date: April 16, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 15, 2019)

Progression Free Survival (PFS) [ 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) ]

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.

Original Primary Outcome Measures (submitted: July 1, 2014)

Progression Free Survival (PFS) [ Time Frame: Every 28 days up to 24 months ]

PFS is defined as the time from the date of randomization to the date of first documentation of disease progression, as evaluated by an independent review committee according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first.

Current Secondary Outcome Measures (submitted: April 15, 2019)

• Overall Survival (OS) [ Time Frame: Baseline up to Follow up period (107 months) ]
  OS was measured as the time from the date of randomization to the date of death.
• Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy [ 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) ]
  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 to Progression (TTP) [ Time Frame: Baseline until PD (Month 107) ]
  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.
• Second Progression Free Survival (PFS2) [ 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) ]
  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 to Start of the Next Line of Therapy [ 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) ]
  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 to End of the Next Line of Therapy [ Time Frame: Baseline up to end of next line of therapy (Month 107) ]
  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.
• Duration of the Next Line of Therapy [ Time Frame: From the start of next line therapy after PD to the last dose of next line therapy (up to Month 107) ]
  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.
• Percentage of Participants Who Develop A New Primary Malignancy [ Time Frame: Baseline until death or termination of the study (up to Month 107) ]
• Number of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative, and Maintenance of MRD Negativity [ Time Frame: Baseline up to EOT (24 months) ]
  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.
• Correlation Between MRD Status and Progression Free Survival (PFS) and Overall Survival (OS) [ Time Frame: Baseline up to Month 107 ]
  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.
• OS Benefits in a High-Risk Population [ Time Frame: Randomization up to Month 107 ]
  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.
• PFS Benefits in a High-Risk Population [ Time Frame: Randomization up to Month 107 ]
  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.
• Eastern Cooperative Oncology Group (ECOG) Performance Score [ Time Frame: Baseline up to EOT (24 months), thereafter every 4 weeks until initiation of next line therapy ]
  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.
• Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs) [ Time Frame: First dose of study drug through 30 days after last dose of study drug (up to 24 months) ]
• Number of Participants With Markedly Abnormal Clinical Laboratory Values [ Time Frame: Baseline through 30 days after the last dose of study drug (up to 24 months) ]
• 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 [ Time Frame: Baseline up to PD (up to Month 107) ]
  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).
• Plasma Concentration of Ixazomib [ 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 ]
  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 to Resolution of Peripheral Neuropathy (PN) Events [ Time Frame: From randomization date through 30 days after the last dose of drug (up to 24 months) ]
  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 to Improvement of PN Events [ Time Frame: From randomization date through 30 days after the last dose of drug (up to 24 months) ]
  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.

Original Secondary Outcome Measures (submitted: July 1, 2014)

• Overall Survival (OS) [ Time Frame: Every 28 days from the Randomization date up to 110 months ]
  OS will be measured as the time from the date of randomization to the date of death.
• Percentage of Participants who Achieve or Maintain Any Best Response Category during the Treatment Period [ Time Frame: Up to 24 months ]
  Response was assessed according to IMWG criteria. Best response includes partial response (PR), very good partial response (VGPR) and complete response (CR)
• Time to Progression (TTP) [ Time Frame: From the date randomization to the date of first documented progressive disease (up to 110 months) ]
  TTP is defined as the time from the date of randomization to the date of first documentation of progressive disease, using IMWG criteria.
• Second Progression-Free Survival (PFS2) [ Time Frame: Every 28 days from the randomization to 2nd disease progression or death (up to 110 months) ]
  PFS2 is defined as the time from the date of randomization to the date of second documentation of progressive disease (PD), using IMWG criteria, or death due to any cause, whichever occurs first. The second PD should occur during or after the second line of antineoplastic therapy following study treatment but before the third line of therapy.
• Time to End of the Next Line of Therapy after Study Treatment [ Time Frame: From the randomization to the date of last dose of the next line of therapy (up to 110 months) ]
  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.
• Duration of the Next Line of Therapy after Study Treatment [ Time Frame: From the start of next line therapy to end of study (up to 110 months) ]
  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.
• Percentage of Participants Who Develop A New Primary Malignancy [ Time Frame: From the randomization date till death or termination of the study (up to 110 months) ]
• Percentage of Participants with Conversion from Minimal Residual Disease (MRD) Positive to MRD Negative, or the Maintenance of MRD Negativity [ Time Frame: Screening, Cycle 12 (± 2 cycles)_, and Cycle 24 (± 2 cycles) ]
  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. MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD.
• Correlation between Minimal Residual Disease (MRD) Status and Progression Free Survival (PFS) and Overall Survival (OS) [ Time Frame: Up to 110 months ]
  Correlation will be determined using bone marrow aspirates and blood samples.
• Association between Mutations in Key Signaling Pathways in Multiple Myeloma and response, PFS and OS [ Time Frame: Every 28 days up to 110 months ]
  Key signaling pathways will include RAS/RAF (a pathway necessary for normal cell function) response, progression free survival (PFS), and overall survival (OS) and will be evaluated using archival materials and/or tumor DNA from bone marrow aspirates.
• Relationship between Polymorphisms in Proteasome and Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NFKB)-Related Genes or circulating proteasome levels, and response, PFS, and OS [ Time Frame: Screening ]
  NFKB-related genes will include genes such as proteasome (prosome, macropain) subunit, beta type, 1 (PSMB1) and tumor necrosis factor receptor-associated factor 3 (TRAF-3), or circulating proteasome levels, and response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS), and will be evaluated using blood samples.
• Overall (OS) Survival in a High-Risk Population [ Time Frame: From randomization up to 110 months ]
  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.
• Percentage of Participants with Adverse Events (AEs) [ Time Frame: First dose of study drug through 30 days after last dose of study drug Every 28 days up to 24 months ]
  Adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug.
• Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C30 [ Time Frame: Baseline and every 28 days up to 24 months ]
  The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C30 is completed by the patient. 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 patient answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where1=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).
• EuroQol 5-Dimensional Health Questionnaire (EQ-5D) [ Time Frame: Every 28 days during treatment and PFS follow-up and every 12 weeks during OS follow-up (up to 110 months) ]
  The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). The patient answers 5 questions about their health on that day and checks one of 3 boxes: no problems/pain/anxiety or depression, moderate problems/pain/anxiety or depression, or extreme problems/pain/anxiety or depression, The EQ VAS records the respondent's self-rated health on a 100 mm vertical, visual analogue scale ranging from 0 bottom of the scale (worst imaginable health state) to 100 top of the scale (best imaginable health state).
• Pharmacokinetic Parameter: Plasma Concentration of Ixazomib [ Time Frame: Cycle 1, Day 1 postdose at 1 and 4 hours and Cycle 1 predose on Days 8 and 15; Cycle 2 predose on Days 1 and 8; Cycles 3- through10 on Day 1 predose ]
  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 to Resolution of Peripheral Neuropathy (PN) Events [ Time Frame: From randomization date through 30 days after the last dose of drug (up to 24 Months) ]
  Peripheral neuropathy (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. Time to resolution is defined as the time from the initial onset date (inclusive) to the resolution date for resolved events.
• Time to Improvement of Peripheral Neuropathy (PN) Events [ Time Frame: From randomization date through 30 days after the last dose of drug (up to 25months) ]
  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.
• Progression Free Survival (PFS) in a High-Risk Population [ Time Frame: At the time of screening; day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression (up to 110 months) ]
  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 disease progression.
• Percentage of Participants with Serious Adverse Events (SAEs) [ Time Frame: Will be collected from signing of the informed consent form through 30 days after the last dose of study drug ]
• Assessment of Clinical Laboratory Values [ Time Frame: From First dose date of study drug through 30 days after the last dose of study drug (up to 25 months) ]
• Eastern Cooperative Oncology Group (ECOG) Performance Score [ Time Frame: Up to 24 months ]
  The ECOG performance is a 6-point scale used by doctors to assess how a patient's disease is progressing, how the disease affects the patient's daily life, and to determine appropriate treatment and prognosis. The scale is 0=Normal activity. Fully active, able to carry on all predisease performance without restriction (best) to 5=Dead.
• Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EOTRC) multiple myeloma module QLQ MY-20 [ Time Frame: Baseline and every 28 days during treatment and PFS follow-up and every 12 weeks during OS follow-up (up to 110 months) ]
  The EOTRC multiple myeloma module QLQ MY-20 is a patient-completed, 20-question quality of life questionnaire that has 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). The patient answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Participants With Multiple Myeloma Following Autologous Stem Cell Transplant
• Official Title: A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Patients With Multiple Myeloma Following Autologous Stem Cell Transplant
• Brief 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).

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Multiple Myeloma
• Autologous Stem Cell Transplant

Intervention

• Drug: Ixazomib Citrate
  Ixazomib citrate capsules
  Other Name: MLN9708
• Drug: Placebo
  Ixazomib citrate placebo-matching capsules

Study Arms

• 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 progressive disease (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.
  Intervention: Drug: Ixazomib Citrate
• 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.
  Intervention: Drug: Placebo

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.
• Schjesvold F, Goldschmidt H, Maisnar V, Spicka I, Abildgaard N, Rowlings P, Cain L, Romanus D, Suryanarayan K, Rajkumar V, Odom D, Gnanasakthy A, Dimopoulos M. Quality of life is maintained with ixazomib maintenance in post-transplant newly diagnosed multiple myeloma: The TOURMALINE-MM3 trial. Eur J Haematol. 2020 May;104(5):443-458. doi: 10.1111/ejh.13379. Epub 2020 Feb 22.
• Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, Goldschmidt H, Maisnar V, Moreau P, Min CK, Pluta A, Chng WJ, Kaiser M, Zweegman S, Mateos MV, Spencer A, Iida S, Morgan G, Suryanarayan K, Teng Z, Skacel T, Palumbo A, Dash AB, Gupta N, Labotka R, Rajkumar SV; TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019 Jan 19;393(10168):253-264. doi: 10.1016/S0140-6736(18)33003-4. Epub 2018 Dec 10.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 21, 2018): 656
• Original Estimated Enrollment (submitted: July 1, 2014): 652
• Estimated Study Completion Date: July 31, 2024
• Actual Primary Completion Date: April 16, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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:

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Norway, Poland, Portugal, Singapore, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: 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 )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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 Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda
• Original Responsible Party: Millennium Pharmaceuticals, Inc.
• Current Study Sponsor: Takeda
• Original Study Sponsor: Millennium Pharmaceuticals, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: August 2023