A Study of Weekly Carfilzomib in Combination with Dexamethasone for Progressive Multiple MyelomaCHAMPION 1

1. Multiple myeloma with relapsing or progressive disease at study entry 2. Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to enrollment): a. Serum M-protein ≥ 0.5 g/dL, or b. Urine M-protein ≥ 200 mg/24 hours, or c. Only in patients who do not meet a or b, then use serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa/lambda ratio 3. Prior treatment with 1 to 3 prior regimens for multiple myeloma for Phase 1 and Phase 2 (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy 4. Age ≥ 18 years 5. Life expectancy ≥ 6 months 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 7. Adequate hepatic function within 21 days prior to enrollment, with bilirubin < 1.5 × the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN 8. Left ventricular ejection fraction (LVEF) ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated acquisition scan (MUGA) is acceptable if ECHO is not available 9. Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to enrollment. Screening ANC is to be independent of growth factor support for ≥ 1 week 10. Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed; however, most recent RBC transfusion must have been at least 7 days prior to obtaining screening hemoglobin 11. Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%) within 21 days prior to enrollment. Patients must not have received platelet transfusions for at least 7 days prior to obtaining the screening platelet count 12. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min within 21 days prior to enrollment. Calculation based on standard formula, such as the Cockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female 13. Written informed consent in accordance with federal, local, and institutional guidelines 14. Female patients of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use an effective method of contraception during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). Postmenopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test 15. Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with an FCBP

1. Multiple myeloma of Immunoglobulin M (IgM) subtype 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 3. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential) 4. Waldenström's macroglobulinemia 5. Amyloidosis 6. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to enrollment 7. Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment 8. Treatment with bortezomib (Velcade®), thalidomide (Thalomid®) or lenalidomide (Revlimid®) within 21 days prior to enrollment 9. Focal radiation therapy within 7 days prior to enrollment. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (ie, prior radiation must have been to < 30% of the bone marrow) 10. Immunotherapy within 21 days prior to enrollment 11. Major surgery within 21 days prior to enrollment 12. Active congestive heart failure (New York Heart Association [NYHA] Classes III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment 13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B virus [HBV]), or antifungal agents within 14 days prior to enrollment 14. Known human immunodeficiency virus (HIV) seropositivity 15. Known hepatitis B or C virus infection (except for patients with HBV who are receiving and responding to HBV antiviral therapy: these patients are allowed) 16. Patients with known cirrhosis 17. Second malignancy within the past 3 years, except: a. Adequately treated basal cell or squamous cell skin cancer b. Carcinoma in situ of the cervix c. Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months d. Breast carcinoma in situ with full surgical resection e. Treated medullary or papillary thyroid cancer 18. Patients with myelodysplastic syndrome 19. Significant neuropathy (Grades 3 to 4) within 14 days prior to enrollment 20. Female patients who are pregnant or lactating 21. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) 22. Prior carfilzomib treatment 23. Prior participation in any Onyx-sponsored Phase 3 trial 24. Patients with contraindication to dexamethasone 25. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment 26. Ongoing graft-versus-host disease 27. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment 28. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment 29. Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent