Study of the Safety and Pharmacokinetics of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma and Varying Degrees of Renal Function

Inclusion criteria

• Written informed consent in accordance with federal, local, and institutional guidelines
• Males and females ≥ 18 years of age
• Multiple Myeloma
• Documented relapsed or progressive disease (PD) after receiving at least two prior treatment regimens (induction therapy with autologous stem cell transplant and maintenance is considered a single regimen), and must have achieved a minimal response or better to at least one of the regimens
• Current measurable disease, as indicated by one or more of the following:

• Serum M-protein ≥ 0.5 g/dL
• Urine M-protein ≥ 200 mg/24 hours
• Serum Free Light Chain (FLC) assay: Involved FLC level ≥ 10 mg/dL provided serum FLC ratio is abnormal
• Life expectancy of more than three months
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) < 3 times ULN
• Total white blood cell (WBC) count ≥ 2,000/mm³
• Absolute neutrophil count (ANC) ≥ 1,000/mm³
• Hemoglobin ≥ 7 gm/dL

• Subjects may receive red blood cell (RBC) transfusions or supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines
• Platelet count ≥ 30,000/ mm³
• 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 three months following the last dose if sexually active with a female of child-bearing potential

Exclusion criteria

• Glucocorticoid therapy in a dose equivalent to prednisone ≥ 20 mg/day within 14 days prior to first dose of study drug
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia
• Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy dose as defined above, within 14 days prior to first dose of study drug or antibody therapy within 6 weeks prior to first dose of study drug
• Radiation therapy or immunotherapy within 3 weeks prior to first dose; localized radiation therapy within 1 week prior to first dose
• Participation in an investigational therapeutic study within 14 days prior to first dose of study drug
• Prior carfilzomib treatment
• Pregnant or lactating females
• Major surgery within 3 weeks prior to first dose of study drug
• Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities or myocardial infarction in the three months prior to first dose of study drug
• Uncontrolled hypertension
• Recent history of acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose of study drug
• Known or suspected human immunodeficiency virus (HIV) infection, known HIV seropositivity
• Active hepatitis A, B, or C infection
• Other malignancy within the past 3 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 7 with stable prostate specific antigen (PSA) levels
• Any clinically significant medical or psychiatric disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
• Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days prior to enrollment
• Subjects in whom the required program of oral hydration and intravenous fluid hydration is contraindicated, e.g., due to preexisting pulmonary or cardiac impairment
• Subjects with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis
• Subjects with a known contraindication to receiving dexamethasone or allopurinol
• Receipt of granulocyte- and granulocyte/ macrophage- colony stimulating factor (G-CSF and GM-CSF) within 1 week prior to first dose of study drug
• Receipt of pegylated G-CSF within 2 weeks prior to first dose of study drug
• RBC and platelet transfusions within 7 days prior to first dose of study drug
• Subjects with known or suspected cardiac amyloidosis
• Subjects with myelodysplastic syndrome
• Subjects undergoing peritoneal dialysis