Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma

Key Inclusion Criteria:

• Relapsed multiple myeloma
• Refractory multiple myeloma defined as meeting 1 or more of the following:

• Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or
• Disease progression within 60 days of discontinuation from most recent therapy
• At least 2 but no more than 3 prior therapies for multiple myeloma
• Prior exposure to an immunomodulatory agent (IMiD)
• Prior exposure to a proteasome inhibitor (PI)
• Documented response of at least partial response (PR) to 1 line of prior therapy
• Measurable disease with at least 1 of the following assessed within the 21 days prior to randomization:

• Serum M-protein ≥ 0.5 g/dL
• Urine M-protein ≥ 200 mg/24 hours
• In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
• Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization
• Adequate organ and bone marrow function within the 21 days prior to randomization defined by:

• Bilirubin < 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN
• Absolute neutrophil count (ANC) ≥ 1000/mm³ (screening ANC should be independent of growth factor support for ≥ 1 week)
• Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell [RBC] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.)
• Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.)
• Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min

Key Exclusion Criteria:

• Waldenström macroglobulinemia
• Multiple myeloma of Immunoglobin M (IgM) subtype
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia (> 2.0 × 10⁹/L circulating plasma cells by standard differential)
• Myelodysplastic syndrome
• Second malignancy within the past 5 years except:

• Adequately treated basal cell or squamous cell skin cancer
• Carcinoma in situ of the cervix
• Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months
• Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
• Treated medullary or papillary thyroid cancer
• Similar condition with an expectation of > 95% five-year disease-free survival
• History of or current amyloidosis
• Cytotoxic chemotherapy within the 28 days prior to randomization
• Immunotherapy within the 21 days prior to randomization
• Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or 1000 mg prednisone
• Radiation therapy:

• Focal therapy within the 7 days prior to randomization
• Extended field therapy within the 21 days prior to randomization
• Prior treatment with either carfilzomib or oprozomib
• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
• Contraindication to dexamethasone or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment
• Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollment
• Active infection within the 14 days prior to randomization requiring systemic antibiotics
• Pleural effusions requiring thoracentesis within the 14 days prior to randomization
• Ascites requiring paracentesis within the 14 days prior to randomization
• Ongoing graft-versus-host disease
• Uncontrolled hypertension or uncontrolled diabetes despite medication
• Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization
• Known cirrhosis