The following criteria is provided for health care professionals.

Inclusion Criteria:

1. Has a diagnosis of MM based on standard criteria1 as follows:

   Major criteria:

   • Plasmacytomas on tissue biopsy.
   • Bone marrow plasmacytosis (greater than 30% plasma cells).
   • Monoclonal immunoglobulin (Ig) spike on serum electrophoresis IgG greater than 3.5 g/dL or IgA greater than 2.0 g/dL; kappa or lambda light chain excretion greater than 1 g/day on 24-hour urine protein electrophoresis.

   Minor criteria:

   • bone marrow plasmacytosis (10% to 30% plasma cells)
   • monoclonal immunoglobulin present but of lesser magnitude than given under major criteria
   • lytic bone lesions
   • normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600 mg/dL

   Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:

   • any 2 of the major criteria
   • major criterion 1 plus minor criterion 2, 3, or 4
   • major criterion 3 plus minor criterion 1 or 3
   • minor criteria 1, 2, and 3, or 1, 2, and 4
2. Currently has progressive MM that has progressed while receiving or within 8 weeks of receiving carfilzomib 27mg/m2 alone or as part of their last carfilzomib-containing combination regimens.
3. Patient must have received at least one full cycle of carfilzomib at a dose of 27mg/m2 prior to showing evidence of PD from their last carfilzomib-containing regimen.
4. Patient must have previously received treatment with an immunomodulatory agent to be eligible for the study.
5. There is no limit to the number of prior lines of therapy that a patient may have received.
6. Measurable disease, as defined by one or more of the following (assessed within 14 days prior to first dose):
   • Serum M-protein ≥ 0.5 g/dL, or
   • Urine M-protein ≥ 200 mg/24 hours, or
   • 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 κ/λ ratio
7. Age ≥ 18 years.
8. Life expectancy ≥ 6 months.
9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
10. Adequate hepatic function within 14 days prior to first dose, with bilirubin < 1.5 × the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN.
11. LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
12. Absolute neutrophil count (ANC) ≥ 1000/mm3 within 14 days prior to first dose. Screening ANC is to be independent of granulocyte colony stimulating factor support for ≥ 1 week and pegylated granulocyte colony stimulating factor for ≥ 2 weeks.
13. Hemoglobin ≥ 8.0 g/dL within 14 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.
14. Platelet count ≥ 75,000/mm3 (≥ 50,000/mm3 if myeloma involvement in the bone marrow is > 50%) within 14 days prior to first dose. Patients must not have received platelet transfusions for at least 7 days prior to obtaining the screening platelet count.
15. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min within 14 days prior to first dose. Calculations are based on a standard formula, such as the Cockcroft and Gault: [(140 - Age) × Mass (kg) / (72 × Creatinine mg/ dL)]; multiply result by 0.85 if female.
16. Written informed consent in accordance with federal, local, and institutional guidelines.
17. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within the 7 days prior to study drug administration and a negative urine pregnancy test within the 3 days prior to the first study drug administration
18. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 highly effective methods of contraception during the study and for 30 days following the last dose of study treatment including a male condom.

Exclusion Criteria:

• Multiple myeloma of IgM subtype
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
• Waldenström's macroglobulinemia
• Amyloidosis 6. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to first dose
• Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to first dose
• Treatment with bortezomib (Velcade®), thalidomide, pomalidomide (Pomalyst®) or lenalidomide (Revlimid®) within 21 days prior to first dose
• Focal radiation therapy within 7 days prior to first dose. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (i.e., prior radiation must have been to < 30% of the bone marrow)
• Immunotherapy within 21 days prior to first dose
• Major surgery within 21 days prior to first dose
• 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 first dose. Echocardiogram or MUGA evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment
• Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at HBV), or antifungal agents within 14 days prior to first dose
• Known human immunodeficiency virus (HIV) seropositivity
• Known active hepatitis B or C virus infection (except for patients with HBV receiving and responding to HBV antiviral therapy: these patients are allowed)
• Patients with known cirrhosis
• 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
• Patients with myelodysplastic syndrome
• Significant neuropathy (Grades 3 to 4) within 14 days prior to first dose
• Peripheral neuropathy with pain ≥ G2 within 14 days prior to first dose
• Women who are pregnant and/or breast feeding
• Known hypersensitivity to dexamethasone
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
• Hypersensitivity to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs.
• Prior participation in any Onyx-sponsored Phase 3 trial
• Ongoing graft-versus-host disease
• Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
• 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.