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

Key Inclusion Criteria:

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

• Nonresponsive to most recent therapy (stable disease only or PD while ontreatment), or
• Disease progression within 60 days of discontinuation from most recent therapy

3. At least 2 but no more than 3 prior therapies for multiple myeloma
4. Prior exposure to an immunomodulatory agent (IMiD)
5. Prior exposure to a proteasome inhibitor (PI)
6. Documented response of at least partial response (PR) to 1 line of prior therapy
7. Measurable disease with at least 1 of the following assessed within the 21 days priorto 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

8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
9. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior torandomization
10. Adequate organ and bone marrow function within the 21 days prior to randomizationdefined by:

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

Key Exclusion Criteria:

1. Waldenström macroglobulinemia
2. Multiple myeloma of Immunoglobin M (IgM) subtype
3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, andskin changes)
4. Plasma cell leukemia (> 2.0 × 10⁹/L circulating plasma cells by standard differential)
5. Myelodysplastic syndrome
6. 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., negativemargins)
• Treated medullary or papillary thyroid cancer
• Similar condition with an expectation of > 95% five-year disease-free survival

7. History of or current amyloidosis
8. Cytotoxic chemotherapy within the 28 days prior to randomization
9. Immunotherapy within the 21 days prior to randomization
10. Glucocorticoid therapy within the 14 days prior to randomization that exceeds acumulative dose of 160 mg of dexamethasone or 1000 mg prednisone
11. Radiation therapy:

• Focal therapy within the 7 days prior to randomization
• Extended field therapy within the 21 days prior to randomization

12. Prior treatment with either carfilzomib or oprozomib
13. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilizecarfilzomib)
14. Contraindication to dexamethasone or any of the required concomitant drugs orsupportive treatments, including hypersensitivity to antiviral drugs, or intoleranceto hydration due to pre-existing pulmonary or cardiac impairment
15. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV),symptomatic ischemia, conduction abnormalities uncontrolled by conventionalintervention, acute diffuse infiltrative pulmonary disease, pericardial disease, ormyocardial infarction within 6 months prior to enrollment
16. Active infection within the 14 days prior to randomization requiring systemicantibiotics
17. Pleural effusions requiring thoracentesis within the 14 days prior to randomization
18. Ascites requiring paracentesis within the 14 days prior to randomization
19. Ongoing graft-versus-host disease
20. Uncontrolled hypertension or uncontrolled diabetes despite medication
21. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization
22. Known cirrhosis