Study of Carfilzomib in Relapsed Multiple Myeloma

Disease Related o Multiple myeloma o Subjects must have measurable disease, defined as one or more of the following: • Serum M-protein ≥ 1 g/dL • Urine M-protein ≥ 200 mg/24 hours o Subjects must have been responsive (i.e., achieve a minimal response [MR] or better) to standard, first line therapy o Relapsed and/or refractory or progressive disease after at least one, but no more than three, prior therapeutic treatments or regimens for multiple myeloma. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Induction therapy and stem cell transplant will be considered as one regimen 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 < 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of < 3.0 times the upper limit of normal o Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing o Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count > 1,000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count > 50,000/mm³ o Subjects should be platelet transfusion independent o Screening absolute neutrophil count (ANC) should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks o Subjects may receive red blood cell (RBC) transfusion or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines o Calculated or 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. o Serum creatinine ≤ 2 mg/dL 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. o Subjects must be able to receive outpatient treatment and laboratory monitoring at the institute that administers agent.

Disease Related o Multiple Myeloma Immunoglobulin M (IgM) o Subjects previously treated with any proteasome inhibitor (for Part 2 Proteasome Inhibitor – Naïve only, criteria added at Amendment 2) o Subjects must not be primary refractory to standard first-line therapy o Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum, < 200 mg/24 hour M-protein in urine o Subjects with disease measurable only by serum free light chain (SFLC) analysis 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 first dose, 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 ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months o Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose o Known or suspected human immunodeficiency (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 < Gleason Grade 6 with stable prostate-specific antigen (PSA) o Subjects with treatment related myelodysplastic syndrome o Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation o Subjects with known contraindication to receiving allopurinol o Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment o Subjects with known or suspected amyloidosis Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis o Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent Ethical / Other o Female subjects who are pregnant or lactating o Serious psychiatric or medical conditions that could interfere with treatment