Testing the Addition of Ixazomib/Placebo to Lenalidomide in Patients With Evidence of Residual Multiple Myeloma, OPTIMUM Trial

Study Overview
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Brief Summary
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This phase III trial studies how well lenalidomide in combination with ixazomib works compared to lenalidomide alone in treating patients with evidence of residual multiple myeloma after stem cell transplantation. Lenalidomide may help shrink or slow the growth of multiple myeloma. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide and ixazomib together may work better than giving lenalidomide alone in treating patients with evidence of residual multiple myeloma after a stem cell transplantation.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate whether escalating maintenance therapy with the addition of ixazomib citrate (ixazomib) to lenalidomide improves overall survival (OS) among patients who are minimal residual disease (MRD) positive after approximately 1 year of lenalidomide maintenance following an early stem cell transplant (=< 12 months from diagnosis). SECONDARY OBJECTIVES: I. To establish whether progression-free survival (PFS) is superior with the addition of ixazomib to lenalidomide maintenance. II. To evaluate best response on treatment and compare response rates between arms. III. To evaluate the safety profile of ixazomib added to lenalidomide and compare toxicity rates between arms. EXPLORATORY OBJECTIVES: I. To measure treatment exposure and adherence. II. To estimate treatment duration, duration of response and time to progression. PATIENT-REPORTED OUTCOMES (PRO) OBJECTIVES: I. To quantify the extent to which the addition of ixazomib to lenalidomide maintenance contributes to neuropathy and associated physical and functional impairments. (Primary) II. To assess the impact of the addition of ixazomib to lenalidomide maintenance on disease control and associated physical and functional well-being. (Primary) III. To evaluate time to worsening and recovery rate related to neuropathy. (Secondary) IV. To evaluate time to improvement and response rate related to disease control. (Secondary) V. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse events (Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events [PRO-CTCAE]) longitudinally and compare responses with provider-reported adverse events. (Exploratory) VI. To measure the likelihood of medication adherence and examine the relationship with treatment exposure. (Exploratory) VII. To assess correlation among patient reported outcome measures and association with clinical outcomes. (Exploratory) VIII. To tabulate PRO compliance and completion rates. (Exploratory) IMAGING OBJECTIVES: I. To evaluate the association between baseline fludeoxyglucose F-18 (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and patient outcomes. II. To compare overall survival (OS) with the addition of ixazomib to lenalidomide among baseline 18F-FDG PET/CT-positive and 18F-FDG PET/CT -negative subgroups. III. To compare the change in quantitative 18F-FDG PET/CT parameters over time with the addition of ixazomib to lenalidomide. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and positron emission tomography (PET) and computed tomography (CT) scan at screening and on study as well as undergo collection of blood samples throughout the trial. ARM B: Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 3 months if < 2 years from study entry, every 6 months if 2-5 years from study entry, then every 12 months for up to 10 years from study entry.

Official Title
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Optimizing Prolonged Treatment In Myeloma Using MRD Assessment (OPTIMUM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspirate
* Procedure: Bone Marrow Biopsy
* Procedure: Computed Tomography
* Drug: Ixazomib Citrate
* Drug: Lenalidomide
* Other: Placebo Administration
* Procedure: Positron Emission Tomography
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: STEP 0: PRE-REGISTRATION Patient must be >= 18 years of age Patient must be previously diagnosed with multiple myeloma (MM) and be on lenalidomide maintenance with >= 5mg daily for at least 6 months and no more than 18 months after an early autologous stem cell transplantation (SCT =< 12 months of diagnosis). Patient must not be off lenalidomide maintenance therapy for more than 30 days prior to start of treatment on Step 1 of this protocol Patient must be able to undergo a diagnostic bone marrow aspirate following pre-registration to Step 0 NOTE: A bone marrow aspirate specimen must be submitted to Mayo Clinic Hematology Laboratory for central assessment of minimal residual disease (MRD) status to confirm patient's eligibility for Step 1 randomization. Mayo Clinic will forward results to the submitting institution within three (3) business days of receipt of the bone marrow specimen Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Patient must have been able to maintain at least 5mg daily dose of lenalidomide without growth factor support Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial STEP 1 RANDOMIZATION Patient must meet Step 0 eligibility criteria at the time of Step 1 randomization Patients must have evidence of residual disease by central MRD testing or by presence of monoclonal protein in serum or urine Patient must have serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) performed =< 28 days prior to randomization NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hour (hr). Please note that if both serum and urine M-components are present, both must be followed in order to evaluate response Hemoglobin >= 8 g/dL (obtained =< 14 days prior to randomization) Untransfused platelet count >= 75,000 cells/mm^3 (obtained =< 14 days prior to randomization) Absolute neutrophil count (ANC) >= 1000 cells/mm^3 (obtained =< 14 days prior to randomization) Calculated creatinine clearance >= 30 mL/min (obtained =< 14 days prior to randomization) Total bilirubin =< 1.5 times the upper limit of normal (ULN) (obtained =< 14 days prior to randomization) Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 times the upper limit of normal (ULN) (obtained =< 14 days prior to randomization) Patient must agree to register into the mandatory Revlimid Risk Evaluation and Mitigation Strategies (REMS) registered trademark program and be willing and able to comply with the requirements of Revlimid REMS registered trademark Patients of childbearing potential must either abstain from sexual intercourse for the duration of their participation in the study or agree to use TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting study treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 90 days after the last dose of protocol treatment. Patients must also agree to not breastfeed during this same time period. Men must agree to either abstain from sexual intercourse for the duration of their participation in the study or use a latex condom during sexual contact with a partner of childbearing potential while participating in the study and for 90 days after the last dose of protocol treatment even if they have had a successful vasectomy. Patients must also agree to abstain from donating sperm while on study treatment and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy. All patients must agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment Exclusion Criteria: Patient must not have primary refractory or progressive disease on a proteasome inhibitor-based regimen during induction therapy prior to stem cell transplant Patient must not be on other concurrent chemotherapy, or any ancillary therapy considered investigational NOTE: Bisphosphonates are considered to be supportive care rather than therapy and are allowed while on protocol treatment Patient must not have uncontrolled psychiatric illness or social situations that would limit compliance with study requirements Patient must not have another malignancy requiring treatment or have received treatment within two years before pre-registration or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection Patients must not have known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or lenalidomide including difficulty swallowing Patient must not have known hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection, but testing specifically for the trial is not required Patient must not be off lenalidomide maintenance therapy for more than 30 days prior to start of treatment on Step 1 of this protocol Patients must not have grade 2 or higher peripheral neuropathy or grade 1 peripheral neuropathy with pain per Common Terminology Criteria for Adverse Events (CTCAE) Patients must not have uncontrolled intercurrent illness Patients must not have grade 2 or higher diarrhea per CTCAE in the absence of antidiarrheals Patients must not have been on systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (such as rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort Patient must not be pregnant due to potential harm to the fetus from ixazomib and lenalidomide. All patients of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to the first dose of lenalidomide and again within 24 hours prior to the first dose of lenalidomide. Patients of childbearing potential must also agree to ongoing pregnancy testing while on treatment. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (lenalidomide, ixazomib citrate)<br>Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspirate<br>* Undergo bone marrow aspirate<br>* Other names: Human Bone Marrow Aspirate;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Ixazomib Citrate<br>* Given PO<br>* Other names: Ninlaro;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Arm B (lenalidomide, placebo)<br>Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspirate<br>* Undergo bone marrow aspirate<br>* Other names: Human Bone Marrow Aspirate;Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Other: Placebo Administration<br>* Given PO<br>Procedure: Positron Emission Tomography<br>* Undergo PET scan<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be estimated using the Kaplan-Meier (KM) method and compared using a stratified log-rank test. Stratified cox proportional hazards regression will produce a treatment hazard ratio estimate (ixazomib-lenalidomide/placebo-lenalidomide. | From randomization to death due to any cause, or censored at date last known alive, assessed up to 15 years | 
| Change in Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group-Neurotoxicity (GOG-Ntx) Trial Outcome Index (TOI) score | Descriptive statistics (mean, standard deviation [SD], median, range) will be used to evaluate the distribution of levels and changes for the set of health-related quality of life (QOL) evaluations. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. | Baseline up to 12 cycles | 
| Change in FACT-Multiple Myeloma (MM) TOI score | Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. | Baseline up to 24 cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Will be estimated using the KM method and compared using the stratified log-rank test. Only deaths that occur within 3 months of the last disease evaluation are considered events. | From randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation, assessed up to 15 years | 
| Best response on treatment | Will be based on standard International Myeloma Working Group (IMWG) criteria and tabulated by category. Response rates (stringent complete response [sCR], complete response [CR], very good partial response [VGPR]) will be compared using the chi-squared test for proportions. | Up to 60 cycles post-randomization | 
| Minimal residual disease (MRD) conversion rate |  | At 12 and 24 cycles post-randomization | 
| Incidence of adverse events | Will be assessed by worst grade and type determined using Common Terminology Criteria for Adverse Events. Will compare the rates of worst grade 3 or higher non-hematologic treatment-related events using the chi-squared test for proportions. Will plan to examine comprehensively adverse events experienced by study participants using the Tox-T method. | Up to 15 years | 
| Change in FACT- General (G) score | Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. The t-test will be used to assess the change in FACT-G score between treatment arms. Also, FACT-G scores after 12 cycles of treatment will be compared between MRD positive and negative groups at that time point. | Baseline up to 12 cycles | 
| Time to worsening of FACT/GOG-Ntx TOI | Will be analyzed with the KM method and compared using the log-rank test. Time to worsening of symptoms with PFS and OS will be assessed with Kendall's Tau adjusted for censored observations. | Baseline to a decrease of 8 points (minimally important differences [MID]), respectively, or censored at the date of last assessment | 
| Change in levels of all instruments | Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. | Baseline up to 1 year after treatment discontinuation | 
| FACT/GOG-Ntx TOI recovery rate | The recovery rate will be estimated in the patients experiencing a MID decrease (the proportion of patients with the FACT/GOG-Ntx TOI score returning to baseline level). Will provide rates on each arm including exact binomial 95% confidence intervals. | Up to 1 year after treatment discontinuation | 
| Time to improvement of the FACT-MM TOI | Will be analyzed with the KM method and compared using the log-rank test. | Baseline to an increase of 10 points (MID), respectively, or censored at the date of last assessment | 
| FACT-MM TOI response rate | Will be defined as the proportion of patients experiencing a MID improvement since baseline at each assessment time point. Will provide rates on each arm including exact binomial 95% confidence intervals. | Up to 1 year after treatment discontinuation |