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