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

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