Inclusion Criteria:

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):

1. Serum M-protein ≥ 0.5 g/dL, or

2. Urine M-protein ≥ 200 mg/24 hours, or

3. 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 are to be 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

Exclusion Criteria:

1. Multiple myeloma of IgM subtype

2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes)

3. Plasma cell leukemia (> 2.0 × 109/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 4 months prior to enrollment

13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral
therapy directed at 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:

1. Adequately treated basal cell or squamous cell skin cancer

2. Carcinoma in situ of the cervix

3. Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA)
over 12 months

4. Breast carcinoma in situ with full surgical resection

5. 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