Study of Initial Treatment With Elotuzumab, Carfilzomib, Lenalidomide and Dexamethasone in Multiple Myeloma

Inclusion Criteria

• Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study. No enrollment waivers will be granted.
• Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy

a. Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or bortezomib/PI-based regimens does not disqualify the subject (the corticosteroid treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of lenalidomide and/or PI-based therapy)

• Both transplant and non-transplant candidates are eligible.
• Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment
• Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma
• Measurable disease, prior to initial treatment as indicated by one or more of the following:
• Serum M-protein ≥ 1 g/dL
• Urine M-protein ≥ 200 mg/24 hours
• If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL)
• Involved serum free light chains ≥ 10 mg/dL provided that free light chain ratio is abnormal
• Screening laboratory values must meet the following criteria and should be obtained within 21 days prior to enrollment WBC ≥ 2000/µL Platelets ≥ 75 x103/µL ANC >1000/µL Hemoglobin > 8.0 g/dL Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min
• Use the Cockcroft-Gault formula below):

o Female CrCl = (140 - age in years) x weight in kg x 0.85

• 72 x serum creatinine in mg/dL

o Male CrCl = (140 - age in years) x weight in kg x 1.00

• 72 x serum creatinine in mg/dL
• Alternatively to Cockcroft-Gault formula of CrCl, 24hr urine CrCl can be used AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin Grade 1 in the absence of antidiarrheals
• CNS involvement
• Corrected calcium ≥ 11.5 mg/dL within 2 weeks of randomization
• Pregnant or lactating females
• Radiotherapy within 14 days before randomization. Seven days may be considered if to single area
• Major surgery within 3 weeks prior to first dose
• Subject has clinically significant cardiac disease, including:
• myocardial infarction within 1 year before Cycle 1 Day 1, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV
• uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade 2:2) or clinically significant ECG abnormalities
• screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
• Uncontrolled HTN 14 days prior to enrollment
• Prior or concurrent deep vein thrombosis or pulmonary embolism
• Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
• Uncontrolled hypertension (defined as average systolic blood pressure ≥140 or average diastolic blood pressure ≥90, with blood pressure measured ≥3 times in the two weeks prior to enrollment ) or diabetes
• Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
• Active infection
• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who are seropositive because of hepatitis B virus vaccine are eligible.
• Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
• An