Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma

- Disease Related o Multiple myeloma o Subjects must have measurable disease defined as one of the following: • Serum M-protein ≥ 1 g/dL • Urine M-protein ≥ 200 mg/24 hours • Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only) • Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only) o Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy o Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. o Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only) o Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide o Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only) o Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only) - Demographic o Males and females > 18 years of age o Life expectancy of more than three months o Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 - Laboratory o Adequate hepatic function, with bilirubin less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal o Uric acid within normal range (A0 Only) o Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only) o Absolute neutrophil count > 1,000/mm3, hemoglobin > 8.0 g/dL, and platelet count > 50,000/mm3 (A1 Only) • Subjects should be platelet transfusion independent • Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks • Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines o Calculated and measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female. - Ethical / Other o Written informed consent in accordance with federal, local, and institutional guidelines o Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.

- Disease Related o Multiple Myeloma IgM (A1 Only) o Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only) o Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum and < 200 mg/24 hr M-protein in urine o Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only) o Glucocorticoid therapy (prednisone > 10 mg/day orally or equivalent) within the last three weeks o POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) o Plasma cell leukemia o Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose o Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose o Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to Day 1, whichever time is greater o Prior treatment with carfilzomib - Concurrent Conditions o Major surgery within three weeks before Day 1 o Congestive heart failure (New York Heart Association class III to IV), symptomatic cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF < 40 o Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose o Known or suspected HIV infection or subjects who are HIV seropositive o Active hepatitis A,B,or C infection o Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer