Inclusion Criteria:

1. Multiple myeloma with relapsing or progressing disease at study entry.

2. Patients must have evaluable multiple myeloma with, at least one of the following
(assessed within 21 days prior to randomization):

- Serum M-protein ≥ 0.5 g/dL, or

- Urine M-protein ≥ 200 mg/24 hour, or

- In patients without detectable serum or urine M-protein, serum free light chain
(SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa/lamda
ratio, or

- For IgA patients whose disease can only be reliably measured by serum
quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL).

3. Patients must have documented at least PR to at least 1 line of prior therapy. PR
documentation can be based on Investigator assessment.

4. Received 1, but no more than 3 prior treatment regimens or lines of therapy for
multiple myeloma. (Induction therapy followed by stem cell transplant and
consolidation/maintenance therapy will be considered as one line of therapy).

5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to
prior Velcade therapy, was not removed from Velcade therapy due to toxicity, and will
have at least a 6 month Velcade treatment-free interval from last dose received until
first study treatment. (Patients may receive maintenance therapy with drugs that are
not in the proteasome inhibitor class during this 6 month Velcade treatment-free
interval).

6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to
prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity,
and had at least a 6-month carfilzomib treatment-free interval from last dose
received until first study treatment. (Patients may receive maintenance therapy with
drugs that are not in the proteasome inhibitor class during this 6 month carfilzomib
treatment-free interval). The exception to this is patients randomized or previously
randomized in any other Onyx-Sponsored Phase 3 trial.

7. Males and females ≥ 18 years of age.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.

9. Adequate hepatic function within 21 days prior to randomization, with bilirubin < 1.5
times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) < 3 times the ULN.

10. LVEF ≥ 40%.

11. Absolute neutrophil count (ANC) ≥ 1000/mm3 within 21 days prior to randomization.
Screening ANC should be independent of growth factor support for ≥ 1 week.

12. Hemoglobin ≥ 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic
stimulating factors and red blood cell (RBC) transfusions per institutional
guidelines is allowed, however most recent RBC transfusion may not have been done
within 7 days prior to obtaining screening hemoglobin.

13. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow
is > 50%) within 21 days prior to randomization. Patients should not have received
platelet transfusions for at least 1 week prior to obtaining the screening platelet
count.

14. Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min within 21 days
prior to randomization. Calculation should 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.

15. Written informed consent in accordance with federal, local, and institutional
guidelines.

16. Female patients of child-bearing potential (FCBP) must have a negative serum
pregnancy test within 21 days prior to randomization 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). FCBP
is defined as a sexually mature woman who: 1) has not undergone a hysterectomy or
bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea
following cancer therapy does not rule out childbearing potential) for at least 12
consecutive months (i.e., has had menses at any time in the preceding 12 consecutive
months).

17. Male patients must use an effective barrier method of contraception during study and
for 3 months following the last dose if sexually active with a FCBP.

Exclusion Criteria:

1. Multiple Myeloma of IgM subtype.

2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to
randomization.

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

4. Plasma cell leukemia or circulating plasma cells ≥ 2 × 109/L.

5. Waldenstrom's Macroglobulinemia.

6. Patients with known amyloidosis.

7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days
prior to randomization.

8. Patients randomized or previously randomized in any other Onyx-Sponsored Phase 3
trial.

9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to
an extended field involving a significant volume of bone marrow within 21 days prior
to randomization (i.e., prior radiation must have been to less than 30% of the bone
marrow).

10. Immunotherapy within 21 days prior to randomization.

11. Major surgery (excluding kyphoplasty) within 28 days prior to randomization.

12. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV),
symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
intervention. Myocardial infarction within four months prior to randomization.

13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral
therapy directed at hepatitis B) or antifungal agents within 14 days prior to
randomization.

14. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for
patients with hepatitis B surface antigen [SAg] or core antibody receiving and
responding to antiviral therapy directed at hepatitis B: these patients are allowed).

15. Patients with known cirrhosis.

16. Second malignancy within the past 3 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

- breast carcinoma in situ with full surgical resection

- treated medullary or papillary thyroid cancer

17. Patients with myelodysplastic syndrome.

18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to
randomization.

19. Female patients who are pregnant or lactating.

20. Known history of allergy to Captisol(a cyclodextrin derivative used to solubilize
carfilzomib).

21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.

22. Patients with contraindication to dexamethasone.

23. 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.

24. Ongoing graft-vs-host disease.

25. Patients with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to randomization.