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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Multiple Myeloma, Autologous Stem Cell Transplant

Intervention / Treatment
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* Drug: Ixazomib Citrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic multiple myeloma according to standard criteria. 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. 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. Started screening no earlier than 75 days after transplant, completed screening within 15 days, and randomized no later than 115 days after transplant. Must have not received post-ASCT consolidation therapy. Documented response to ASCT (PR, VGPR, CR/stringent complete response [sCR]) according to IMWG criteria. ECOG performance status of 0 to 2. 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.) 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. Suitable venous access for the study-required blood sampling. Is willing and able to adhere to the study visit schedule and other protocol requirements. 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: 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. Double (tandem) ASCT. Radiotherapy within 14 days before the first dose of study drug. 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. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. Major surgery within 14 days before randomization. Central nervous system involvement. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before randomization. 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. 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. 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. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive. 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). Psychiatric illness/social situation that would limit compliance with study requirements. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 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. Treatment with any investigational products within 60 days before the first dose of the study drug regimen.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ixazomib Citrate<br>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. | Drug: Ixazomib Citrate<br>* Ixazomib citrate capsules<br>* Other names: MLN9708;|
| Placebo Comparator: Placebo<br>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<br>* Ixazomib citrate placebo-matching capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was measured as the time from the date of randomization to the date of death. | Baseline up to Follow up period (107 months) | 
| Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy | 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. | Baseline up to EOT (24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months) | 
| 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. | Baseline until PD (Month 107) | 
| 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 >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. | 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) | 
| 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 occurs first. | 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 End of the Next Line of Therapy | 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. | Baseline up to end of next line of therapy (Month 107) | 
| Duration of the Next Line of Therapy | 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. | From the start of next line therapy after PD to the last dose of next line therapy (up to Month 107) | 
| Percentage of Participants Who Develop A New Primary Malignancy |  | 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 | 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. | Baseline up to EOT (24 months) | 
| Correlation Between MRD Status and Progression Free Survival (PFS) and Overall Survival (OS) | 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. | Baseline up to Month 107 | 
| OS Benefits in a High-Risk Population | 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. | Randomization up to Month 107 | 
| PFS Benefits in a High-Risk Population | 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. | Randomization up to Month 107 | 
| Eastern Cooperative Oncology Group (ECOG) Performance Score | 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. | Baseline up to EOT (24 months), thereafter every 4 weeks until initiation of next line therapy | 
| Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs) |  | 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 |  | 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 | 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). | Baseline up to PD (up to Month 107) | 
| Plasma Concentration of Ixazomib | 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. | 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 | 
| Time to Resolution of Peripheral Neuropathy (PN) Events | 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. | From randomization date through 30 days after the last dose of drug (up to 24 months) | 
| 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. | From randomization date through 30 days after the last dose of drug (up to 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy, Ixazomib citrate