A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Participants With Relapsed and/or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the addition of oral ixazomib to the background therapy of lenalidomide and dexamethasone improves progression free survival (PFS) in participants with relapsed and/or refractory multiple myeloma (RRMM).

Detailed Description
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The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will look at progression free survival (PFS), overall survival (OS) and safety in participants who take ixazomib in addition to lenalidomide and dexamethasone compared to placebo in addition to lenalidomide and dexamethasone. The study enrolled 722 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): Ixazomib 4 mg + lenalidomide + dexamethasone Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient + lenalidomide + dexamethasone All participants will receive treatment in 28 day cycles until disease progression or unacceptable toxicity. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 80 months. Participants will make multiple visits to the clinic, and will be contacted every 4 weeks for PFS and every 12 weeks for OS.

Official Title
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A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral Ixazomib (MLN9708) Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

Conditions
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Relapsed Multiple Myeloma, Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Ixazomib
* Drug: Lenalidomide
* Drug: Dexamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants 18 years of age or older. Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis. NOTE: The initial diagnosis must have been symptomatic multiple myeloma, although the relapsed disease did not need to be symptomatic. Must have had measurable disease, defined by at least 1 of the following 3 measurements: Serum M-protein ≥ 1 g/dL (≥ 10 g/L). Urine M-protein ≥ 200 mg/24 hours. Serum free light chain (FLC) assay: involved FLC level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum FLC ratio was abnormal. Participants with relapsed and/or refractory multiple myeloma (RRMM) who had received 1 to 3 prior therapies. NOTE: population included the following 3 categories of participants: Participants who relapsed from their previous treatment(s) but were not refractory to any previous treatment. Participants who were refractory to all lines of previous treatment(s) (ie, participants who had never responded to any therapies received). Participants who relapsed from at least 1 previous treatment AND additionally were refractory to at least 1 previous treatment. For the purposes of this study, refractory disease was defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy. A line of therapy was defined as 1 or more cycles of a planned treatment program. This may have consisted of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance was considered 1 line of therapy. Autologous and allogenic transplants were permitted. Must have met the following clinical laboratory criteria: Absolute neutrophil count (ANC) ≥ 1000/mm^3 and platelet count ≥ 75,000/mm^3. Platelet transfusions to help participants meet eligibility criteria were not allowed within 3 days prior to randomization. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. Calculated creatinine clearance ≥ 30 mL/min NOTE: Participants with a low creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min, according to lenalidomide prescribing information/local practice) were to receive a reduced lenalidomide dose of 10 mg once daily (QD) on Days 1 through 21 of a 28-day cycle. The lenalidomide dose may have been escalated to 15 mg QD after 2 cycles if the participant was not responding to treatment and was tolerating the treatment. If renal function normalized (ie, creatinine clearance >60 mL/min or >50 mL/min, according to lenalidomide prescribing information/local practice) and the participant continued to tolerate this treatment, lenalidomide may then have been escalated to 25 mg QD. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Participants who received prior allogenic transplant must have had no active graft-versus-host disease. Female participants who: Were postmenopausal for at least 24 months before the screening visit, OR Were surgically sterile, OR If they were of childbearing potential must have: had a negative pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide; either agreed to practice true abstinence, when this was in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal were not acceptable methods of contraception.) OR begun 2 reliable methods of birth control (1 highly effective method and 1 additional effective method) at the same time, at least 28 days before starting study treatment through 90 days after the last dose of study treatment; and agreed to ongoing pregnancy testing AND must have also adhered to the guidelines of the RevAssist program (US participants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMate program (Japanese participants) or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual (all other participants who were not using commercial supplies). Male patients, even if surgically sterilized (ie, status postvasectomy), who: Agreed to practice true abstinence, when this was in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal were not acceptable methods of contraception.) OR Agreed to practice effective barrier contraception during the entire study treatment period and 90 days after the last dose of study treatment if their partner was of childbearing potential, even if they had a successful vasectomy, AND Must have also adhered to the guidelines of the RevAssist program (US participants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMate program (Japanese participants) or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the study Manual (all other participants who were not using commercial supplies) Must have been able to take concurrent aspirin 81 to 325 mg daily (or enoxaparin 40 mg subcutaneously daily [or its equivalent] if allergic to aspirin), per published standard or institutional standard of care, as prophylactic anticoagulation. NOTE: For participants with prior history of deep vein thrombosis (DVT), low-molecular-weight heparin (LMWH) was mandatory. Voluntary written consent must have been given before performance of any study related procedure not part of standard medical care, with the understanding that consent may have been withdrawn by the participant at any time without prejudice to future medical care. Was willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: Was refractory to lenalidomide or proteasome inhibitor-based therapy at any line. NOTE: Refractory disease was defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy. Participants who progressed after 60 days from the last dose of a given therapy were considered relapsed and were eligible for inclusion in the study. Participants who were refractory to thalidomide-based therapy were eligible. Female participants who were breast feeding or pregnant. Failure to have fully recovered (ie, Grade 1 toxicity) from the effects of prior chemotherapy (except for alopecia) regardless of the interval since last treatment. Major surgery within 14 days before randomization. Radiotherapy within 14 days before randomization. Central nervous system involvement. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before randomization. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) 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 6 months before randomization in the study. Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong 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. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus 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 condition that could interfere with the oral absorption or tolerance of treatment. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type were not excluded if they had undergone complete resection.

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 + Lenalidomide + Dexamethasone<br>Ixazomib 4 mg, capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until progressive disease (PD) or unacceptable toxicity, whichever occurred first up to end of treatment (EOT) up to approximately 42.9 months. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: NINLARO®;Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>|
| Placebo Comparator: Placebo + Lenalidomide + Dexamethasone<br>Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15; plus lenalidomide 25 mg, orally, once, on Days 1 through 21; and dexamethasone 40 mg, orally, once, on Days 1, 8, 15 and 22 of a 28-day cycle for multiple cycles until PD or unacceptable toxicity, whichever occurred first up to approximately 41 months. | Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>Drug: Placebo<br>* Ixazomib 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) as Assessed by the Independent Review Committee (IRC) | Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurs first. Response including PD was assessed by independent review committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. PD requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl); Urine M-component (absolute increase ≥ 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 10 mg/dl); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease. Status evaluated every 4 weeks until disease progression (PD) was confirmed. | From date of randomization until disease progression or death up to approximately 27 months (approximate median follow-up 15 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. | From date of randomization until death (up to approximately 97 months) | 
| Overall Survival in High-Risk Participants Carrying Deletion 17 [Del(17)] | Overall survival is defined as the time from the date of randomization to the date of death. The high-risk participants whose myeloma carried del(17) subgroup was defined as the cases reported as positive for del(17) by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17) by local laboratory. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. Data is only reported high-risk participants with Del(17). | From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months) | 
| Overall Response Rate (ORR) as Assessed by the IRC | ORR was defined as the percentage of participants with Complete Response (CR) including stringent complete response (sCR), very good partial response (VGPR) and Partial Response (PR) assessed by the IRC using IMWG criteria. Percentages are rounded off to single decimal. | Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months(approximate median follow-up 15 months) | 
| Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) as Assessed by the IRC | Response was assessed by the IRC using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR is defined as Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours. Percentages are rounded off to single decimal. | Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months) | 
| Duration of Response (DOR) | DOR was measured as the time in months from the date of first documentation of a confirmed response of PR or better (CR [including sCR] + PR+ VGPR) to the date of the first documented disease progression (PD) among participants who responded to the treatment. Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. | Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 38 months | 
| Time to Progression (TTP) as Assessed by the IRC | TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD) as assessed by the IRC using IMWG criteria. | Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Eastern Cooperative Oncology Group (ECOG) performance score, laboratory values, vital sign measurements and reported adverse events (AEs) were collected and assessed to evaluate the safety of therapy throughout the study. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. | From the date of signing of the informed consent form through 30 days after the last dose of study drug up to approximately 115 months | 
| Number of Participants With Change From Baseline in Pain Response | Pain response was defined as 30% reduction from Baseline in Brief Pain Inventory-Short Form (BPI-SF) worst pain score over the last 24 hours without an increase in analgesic (oral morphine equivalents) use at 2 consecutive evaluations. The BPI-SF contains 15 items designed to capture the pain severity (worst, least, average, and now [current pain]), pain location, medication to relieve the pain, and the interference of pain with various daily activities including general activity, mood, walking activity, normal work, relations with other people, sleep, and enjoyment of life. The pain severity items are rated on a 0 to 10 scale where: 0=no pain and 10=pain as bad as you can imagine and averaged for a total score of 0 (best) to 10 (Worst). | Baseline and end of treatment (EOT) (up to approximately 38 months) | 
| Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) Questionnaire (EORTC-QLQ-C30) | The EORTC-QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer participants. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact).The EORTC-QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement. Scores are linearly transformed to a 0-100 scale. High scores for the global and functional domains indicate higher quality of life or functioning. Higher scores on the symptom scales represent higher levels of symptomatology or problems. | Baseline, EOT and follow-up (up to approximately 97 months) | 
| Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY-20) | The EORTC-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 participant answers questions about their health during the past week using a 4-point scale where 1=Not at All to 4=Very Much. A negative change from Baseline indicates improvement. Scores are linearly transformed to a 0-100 scale. Higher scores on the symptom scales (e.g. Disease Symptoms, Side Effects of Treatment) represent higher levels of symptomatology or problems. High scores for Body Image and Future Perspective represent better quality of life or functioning. | Baseline, EOT and follow-up (up to approximately 97 months) | 
| OS in High-Risk Participants | Overall survival (OS) is defined as the time from the date of randomization to the date of death. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are not included in the analysis. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive. Data is only reported for high-risk participants. | From the time of screening until disease progression and thereafter every 12 weeks until death or study termination (up to approximately 97 months) | 
| PFS in High-Risk Participants | Progression Free Survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first. Response was assessed by independent review committee (IRC) using IMWG response criteria. High-risk participants are defined as participants carrying cytogenic abnormalities: del(17), translocation t(4;14), or t(14;16) as reported by the central laboratory combined with those cases that lacked a central laboratory result but with known del (17), t(4;14), or t(14;16) by local laboratory. Cytogenetic abnormalities of del(13) and +1q are not included in the analysis. | From date of randomization until disease progression or death up to approximately 38 months (approximate median follow-up 15 months) | 
| Plasma Concentration Over Time for Ixazomib |  | Pre-dose and post-dose at multiple timepoints up to Cycle 10 Day 1 (each cycle length = 28 days) | 
| Overall Response Rate in Participants Defined by Polymorphism | Data is reported for percentage of participants defined by polymorphism defined by polymorphisms in proteasome genes, such as polymorphism P11A in PSMB1 gene. Percentages are rounded off to single decimal. | Day 1 of each cycle (every 4 weeks) until disease progression up to approximately 27 months (approximate median follow-up 15 months) | 

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