Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma

This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for adults with relapsed multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive either the control Rd or CRd. Randomization will be stratified by β2 microglobulin levels (< vs ≥ 2.5 mg/L), prior bortezomib (no vs yes), and prior lenalidomide (no vs yes). Participants will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity (whichever occurs first).

Inclusion criteria

• Symptomatic multiple myeloma
• Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):

• Serum M-protein ≥ 0.5 g/dL
• Urine Bence-Jones protein ≥ 200 mg/24 hours
• For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)
• Prior treatment with at least one, but no more than three, regimens for multiple myeloma
• Documented relapse or progressive disease on or after any regimen
• Achieved a response to at least one prior regimen
• Age ≥ 18 years
• Life expectancy ≥ 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate hepatic function, with serum alanine aminotransferase (ALT) ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to randomization
• Absolute neutrophil count ≥ 1.0 × 10^9/L within 21 days prior to randomization
• Hemoglobin ≥ 8 g/dL (80 g/L) within 21 days prior to randomization
• Platelet count ≥ 50 × 10^9/L (≥ 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization
• Creatinine clearance (CrCl) ≥ 50 mL/minute within 21 days prior to randomization
• Written informed consent in accordance with federal, local, and institutional guidelines
• Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception
• Male subjects must agree to practice contraception

Exclusion criteria

• If previously treated with bortezomib (alone or in combination), progression during treatment
• If previously treated with a lenalidomide and dexamethasone (len/dex) combination:

• Progression during the first 3 months of initiating treatment
• Any progression during treatment if the len/dex combination was the subject's most recent line of therapy
• Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
• Prior carfilzomib treatment
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Waldenström's macroglobulinemia or IgM myeloma
• Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
• Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization
• Radiotherapy to multiple sites or immunotherapy/antibody therapy within 28 days prior to randomization; localized radiotherapy to a single site within 7 days prior to randomization
• Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 21 days prior to randomization
• Pregnant or lactating females
• Major surgery within 21 days prior to randomization
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
• Known human immunodeficiency virus infection
• Active hepatitis B or C infection
• Myocardial infarction within 4 months prior to randomization, New York Hear Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
• Other malignancy, including myelodysplastic syndromes (MDS), within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
• Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
• Ongoing graft-vs-host disease
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization
• Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent