Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

Study Overview
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Brief Summary
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This is a Phase 3 randomized trial of carfilzomib, lenalidomide, dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma, eligible to subjects who completed autologous stem cell transplant for symptomatic myeloma who are considered for lenalidomide maintenance.

Detailed Description
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Primary Objective: To compare progression free survival between Kyprolis (Carfilzomib), Revlimid (lenalidomide), Dexamethasone (KRd) arm and lenalidomide arm Secondary Objectives To determine the rate of minimal residual negative disease (MRD) at 6 and 12 months after randomization To compare the efficacy (rate of partial response, very good partial response, complete response, and stringent complete response) of KRd vs. Lenalidomide alone after randomization

Official Title
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Phase 3 Randomized Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Carfilzomib
* Drug: Dexamethasone
* Drug: Lenalidomide (Control)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who completed single autologous stem cell transplant after completion of at most 2 induction regimens (excluding dexamethasone alone) and are in at least stable disease in the first 100 days after stem cell transplantation. Patients must be within 12 months of initiation of induction therapy and must have had not more than 2 prior induction regimens. Bone marrow specimen will be required at study entry; available DNA sample will be used for calibration step for MRD evaluation by gene sequencing. Males and females ≥ 18 years of age ECOG performance status of 0-1 Adequate hepatic function, with bilirubin ≤ 1.5 x ULN and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN ANC ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L. Calculated creatinine clearance (by Cockcroft-Gault) ≥ 50 ml/min or serum creatinine below 2 mg/dL Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days). FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. UCM IRB CRd vs. R Version 1.0 Page 11 Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®. Voluntary written informed consent Exclusion Criteria: Patients who have had more than 12 months of prior therapy. Patients outside of this window may be considered for inclusion on a case-by-case basis. Patients who progressed after initial therapy. Subjects whose therapy changed due to suboptimal response, intolerance, etc., remain eligible, provided they do not meet criteria for progression. No more than two regimens for induction will be allowed excluding dexamethasone alone. Evidence of progressive disease as per International Myeloma Working Group (IMWG) criteria Patients who have already started or received post-transplant maintenance or consolidation regimen Patients not able to tolerate lenalidomide or carfilzomib or dexamethasone POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Plasma cell leukemia Waldenström's macroglobulinemia or IgM myeloma Peripheral neuropathy ≥ Grade 2 at screening Diarrhea > Grade 1 in the absence of antidiarrheals CNS involvement Pregnant or lactating females Radiotherapy within 14 days before randomization. Seven days may be considered if to single area. Major surgery within 3 weeks prior to first dose Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities Prior or concurrent deep vein thrombosis or pulmonary embolism Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening Uncontrolled hypertension or diabetes Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lenalidomide (Control)<br>Treatment with lenalidomide only | Drug: Lenalidomide (Control)<br>* Cycles 1-4: Days 1-28. Lenalidomide will begin at a dose of 10 mg PO daily (2 capsules per day). After three months, the dose will be increased, provided ANC ≥ 1,000/µL, platelet count ≥ 75,000/µL, and all nonhematologic toxicity is ≤ grade 1, to 15 mg PO daily (3 capsules per day). Cycles 5 and beyond: best tolerated dose days 1-28<br>* Other names: Revlimid;|
| Experimental: Experimental Combination Regimen<br>Experimental arm using a combination of Carfilzomib, Lenalidomide and Dexamethasone | Drug: Lenalidomide<br>* Cycle 1: 15 mg days 1-21 Cycles 2-4: 25 mg days 1-21 if tolerated, otherwise continue at lower dose Cycles 5 and beyond: best tolerated dose days 1-21<br>* Other names: Revlimid;Drug: Carfilzomib<br>* Cycle 1: 20 mg/m2 Days 1, 2; 36 mg/m2 Days 8, 9, 15, 16. Alternatively, intermediate dose escalation (to 27mg/m2 on days 8,9 of cycle 1) will be al12,lowed at the treating physician's discretion. Cycle 2-4: 36 mg/m2 if tolerated Days 1, 2, 8, 9, 15, 16 Cycles 5-8 (patients that are MRD- and have no risk factors at the end of cycle 6) and Cycle 5 - 36 (for MRD+ patients and high risk patients at the end of cycle 6): best tolerated dose Days 1, 2, 15, 16<br>* Other names: Kyprolis;Drug: Dexamethasone<br>* Cycles 1 - 4: 20 mg PO or IV per dose Days 1, 8, 15, 22 Cycles 5+: 20 mg or best tolerated dose PO or IV per dose Days 1, 8, 15, 22<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival rates in participants receiving drug combination | Measurement of time to disease worsening as measured by International Myeloma Working Group (IMWG) response criteria. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of minimal residual negative disease (MRD) in participants receiving drug combination | Calculation of number of participants with MRD-negative disease. | 3 years | 
| Response rate in participants receiving drug combination | Number of participants with disease response (e.g. improvement) as measured by International Myeloma Working Group (IMWG) response criteria. | 3 years | 
| Treatment-related side effects | Number of participants with grade 2 or greater treatment-related side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | From date of screening until end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, stem-cell transplant, Symptomatic myeloma, lenalidomide, carfilzomib, dexamethasone