Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients

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 immunoglobulin (Ig) A patients whose disease can only be reliably measured by ≥ 750 mg/dL (0.75 g/dL).

3. Patients must have documented at least partial response (PR) to at least 1 line ofprior therapy. PR documentation can be based on Investigator assessment.
4. Received 1, but no more than 3 prior treatment regimens or lines of therapy formultiple myeloma. (Induction therapy followed by stem cell transplant andconsolidation/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 toprior Velcade therapy, was not removed from Velcade therapy due to toxicity, and willhave at least a 6 month Velcade treatment-free interval from last dose received untilfirst study treatment. (Patients may receive maintenance therapy with drugs that arenot in the proteasome inhibitor class during this 6 month Velcade treatment-freeinterval).
6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR toprior 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 receiveduntil first study treatment. (Patients may receive maintenance therapy with drugs thatare not in the proteasome inhibitor class during this 6 month carfilzomibtreatment-free interval). The exception to this is patients randomized or previouslyrandomized 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 < 1.5times the upper limit of normal (ULN), and aspartate aminotransferase (AST) andalanine aminotransferase (ALT) < 3 times the ULN.
10. Left ventricular ejection fraction (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 erythropoieticstimulating factors and red blood cell (RBC) transfusions per institutional guidelinesis allowed, however most recent RBC transfusion may not have been done within 7 daysprior 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 receivedplatelet transfusions for at least 1 week prior to obtaining the screening plateletcount.
14. Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min within 21 days priorto randomization. Calculation should be based on standard formula such as theCockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 iffemale.
15. Written informed consent in accordance with federal, local, and institutionalguidelines.
16. Female patients of child-bearing potential (FCBP) must have a negative serum pregnancytest within 21 days prior to randomization and agree to use an effective method ofcontraception during and for 3 months following last dose of drug (more frequentpregnancy tests may be conducted if required per local regulations). FCBP is definedas a sexually mature woman who: 1) has not undergone a hysterectomy or bilateraloophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancertherapy 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 andfor 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 torandomization.
3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, andskin changes).
4. Plasma cell leukemia or circulating plasma cells ≥ 2 × 10^9/L.
5. Waldenstrom's Macroglobulinemia.
6. Patients with known amyloidosis.
7. Chemotherapy with approved or investigational anticancer therapeutics within 21 daysprior to randomization.
8. Patients randomized or previously randomized in any other Onyx-Sponsored Phase 3trial.
9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to anextended field involving a significant volume of bone marrow within 21 days prior torandomization (i.e., prior radiation must have been to less than 30% of the bonemarrow).
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 conventionalintervention. Myocardial infarction within four months prior to randomization.
13. Acute active infection requiring systemic antibiotics, antiviral (except antiviraltherapy directed at hepatitis B) or antifungal agents within 14 days prior torandomization.
14. Known human immunodeficiency (HIV) seropositive, hepatitis C infection, and/orhepatitis B (except for patients with hepatitis B surface antigen [SAg] or coreantibody receiving and responding to antiviral therapy directed at hepatitis B: thesepatients 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 torandomization.
19. Female patients who are pregnant or lactating.
20. Known history of allergy to Captisol(a cyclodextrin derivative used to solubilizecarfilzomib).
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 topreexisting pulmonary or cardiac impairment.
24. Ongoing graft-vs-host disease.
25. Patients with pleural effusions requiring thoracentesis or ascites requiringparacentesis within 14 days prior to randomization.