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. 1. 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) 2. Both transplant and non-transplant candidates are eligible. 3. Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment 4. Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma 5. Measurable disease, prior to initial treatment as indicated by one or more of the following: 1. Serum M-protein ≥ 1 g/dL 2. Urine M-protein ≥ 200 mg/24 hours 3. If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL) 4. Involved serum free light chains ≥ 10 mg/dL provided that free light chain ratio is abnormal 6. 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 1. 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 2. 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 \< 3.0 mg/dL) or ≤ 2 x ULN if lenalidomide is being prescribed. 7. Males and females ≥ 18 years of age 8. ECOG performance status of 0-1 9. Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days). 10. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. 11. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy. 12. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of Revlimid REMS. 13. Voluntary written informed consent Exclusion Criteria: * Subjects meeting any of the following exclusion criteria are not eligible to enroll in this study. No enrollment waivers will be granted. 1. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as \<1.0 g/dL M-protein in serum, \<200 mg/24 hr urine M-protein, and no measurable disease as per IMWG by Freelite. 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 3. Geriatric assessment score of ≥2 as defined by Palumbo et al. 4. Known or suspected Amyloidosis 5. Plasma cell leukemia 6. Within 4 weeks since any plasmapheresis 7. Within 3 weeks of any corticosteroids except per inclusion criteria #2 8. Waldenström's macroglobulinemia or IgM myeloma 9. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater 10. Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone 11. Peripheral neuropathy ≥ Grade 2 at screening 12. Prior CVA with persistent neurological deficit 13. Diarrhea \> Grade 1 in the absence of antidiarrheals 14. CNS involvement 15. Corrected calcium ≥ 11.5 mg/dL within 2 weeks of randomization 16. Pregnant or lactating females 17. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area 18. Major surgery within 3 weeks prior to first dose 19. 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 20. Uncontrolled HTN 14 days prior to enrollment 21. Prior or concurrent deep vein thrombosis or pulmonary embolism 22. Rate-corrected QT interval of electrocardiograph (QTc) \> 470 msec on a 12-lead ECG during screening 23. 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 24. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose 25. Active infection 26. 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. 27. 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 28. Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent