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 on
treatment), 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 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

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 to
randomization

10. 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:

1. Waldenström macroglobulinemia

2. Multiple myeloma of Immunoglobin M (IgM) subtype

3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin 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., negative
margins)

- 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 a
cumulative 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 solubilize
carfilzomib)

14. 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

15. 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

16. Active infection within the 14 days prior to randomization requiring systemic
antibiotics

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