This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for subjects with multiple myeloma who have received all available approved treatment options and may therefore be considered candidates for palliative care.

Inclusion Criteria:

1. Multiple myeloma

2. Measurable disease based on central laboratory values, as defined by one or both of the following criteria (assessed within 21 days prior to randomization):

   • Serum M-protein

     • Serum protein electrophoresis (SPEP): ≥ 0.5 g/dL
     • For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA): > 750 mg/dL (0.75 g/dL)

   • Urine Bence Jones protein: ≥ 200 mg/24 h

3. Responsive (defined as a 25% or greater decrease in M-protein or total protein) to at least one line of prior therapy

4. Relapsed multiple myeloma, defined as disease progression while on or after at least 1 prior treatment regimen

5. Refractory multiple myeloma, defined as meeting one or more of the following:

   • Nonresponsive to most recent therapy (eg, stable disease only, or progressive disease while on treatment)
   • Disease progression within 60 days of discontinuation from most recent therapy

6. Received 3 or more prior therapeutic regimens for multiple myeloma

7. Adequate prior treatment with bortezomib (if less than 4 complete cycles, the reason for discontinuation must be reviewed by the Medical Monitor and the reason documented)

8. Prior treatment with an immunomodulatory agent (lenalidomide, if available, and/or thalidomide)

9. Prior treatment with an alkylating agent (standard or high-dose)

10. Prior treatment with a corticosteroid

11. Criterion no longer applicable (with Amendment 2, Criterion 11, the requirement of "prior treatment with an anthracycline unless not clinically indicated" is removed.)

12. Age ≥ 18 years

13. Life expectancy of at least 1 month

14. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

15. Adequate hepatic function, with serum alanine aminotransferase (ALT) < 4 times the upper limit of normal and serum bilirubin < 2.5 mg/dL (42.5 µmol/L). Patients with total bilirubin ≥ 2.5 mg/dL may enrol if their serum direct bilirubin is < 2.5 mg/dL.

16. Total white blood cell (WBC) count ≥ 1.5 × 10^9/L and absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L (use of colony-stimulating factors to achieve these counts is allowed)

17. Hemoglobin ≥ 7.5 g/dL (75 g/L)

    -Use of erythropoietic stimulating factors is allowed:

    • For all patients who receive a red blood cell (RBC) transfusion within 28 days of obtaining the Screening hemoglobin value. The following information must be provided for the Medical Monitor's review for assessment for eligibility:

      • Pre-transfusion hemoglobin (Hb)
      • Number of RBC units administered
      • Use of erythropoietic stimulating factors

18. Platelet count ≥ 30 × 10^9/L

    -There is no restriction on platelet transfusions or thrombopoietic growth factor before or during the screening period

    • For all patients who receive a platelet transfusion within 7 days of obtaining the Screening platelet value, the following information must be provided for the Medical Monitor's review for assessment of eligibility

      • Pre-transfusion platelet count
      • Number of platelet units administered
      • Use of thrombopoietic growth factors

19. Creatinine clearance (CrCl) ≥ 15 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) and dialysis-independent

20. Written informed consent in accordance with regulatory guidelines

21. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of the first dose of study treatment and agree to use an effective method of contraception during the study and for 3 months following the last dose of study treatment. Post-menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.

Exclusion Criteria:

1. Waldenström's macroglobulinemia or IgM myeloma
2. Refractory to all prior therapies
3. Disease measurable only by serum free light chain assay (SFLC)
4. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
5. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
6. Prior carfilzomib treatment
7. Chemotherapy (approved or investigational) within 14 days prior to randomization
8. Immunotherapy or antibody therapy within 28 days prior to randomization
9. Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 14 days prior to randomization
10. Radiotherapy within 7 days prior to randomization
11. Major surgery within 21 days prior to randomization
12. Congestive heart failure (NYHA Class III or IV) or symptomatic cardiac ischemia, conduction system abnormalities uncontrolled by conventional intervention (conduction abnormalities not clinically warranting intervention are allowed)
13. Myocardial infarction in the previous 3 months
14. Acute active infection requiring systemic treatment (antibiotics, antivirals, or antifungals) within 14 days prior to randomization
15. Known human immunodeficiency virus seropositivity
16. Active hepatitis A, B, or C infection
17. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix, vulva, or breast; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, carcinoma in situ of the breast, or benign tumors of the adrenal or pancreas
18. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of randomization
19. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent
20. Pregnant or lactating females
21. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity or known history of allergy to carfilzomib, Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) all anticoagulation and antiplatelet options, antiviral drugs; or intolerance to hydration due to preexisting pulmonary or cardiac impairment