Elotuzumab, Carfilzomib, Lenalidomide, and Low Dose Dexamethasone in Treating Patients with Newly Diagnosed Multiple Myeloma

Inclusion Criteria

• Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy * Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or bortezomib/principal investigator (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; a higher total dose of corticosteroid is allowed for the management of cord compression at the discretion of the PI, as long as the subject does not exhibit any steroid related toxicities at the initiation of study treatment
• Both transplant and non-transplant candidates are eligible
• Diagnosis of symptomatic multiple myeloma as per current International Myeloma Working Group (IMWG) uniform criteria prior to initial treatment
• Monoclonal plasma cells in the bone marrow (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
• White blood cell count (WBC) >= 2000/uL (obtained within 21 days prior to enrollment)
• Platelets >= 75 x 10^3/uL (obtained within 21 days prior to enrollment)
• Absolute neutrophil count (ANC) > 1000/uL (obtained within 21 days prior to enrollment)
• Hemoglobin > 8.0 g/dL (obtained within 21 days prior to enrollment)
• Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min (obtained within 21 days prior to enrollment) * Use the Cockcroft-Gault formula * Alternatively to Cockcroft-Gault formula of CrCl, 24 hour (hr) urine CrCl can be used
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (obtained within 21 days prior to enrollment)
• 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 (obtained within 21 days prior to enrollment)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 25 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)
• 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
• 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
• All study participants in the US must be consented to and registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategies (REMS) program and be willing and able to comply with the requirements of Revlimid REMS
• Voluntary written informed consent

Exclusion Criteria

• 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
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Geriatric assessment score of >= 2
• Known or suspected amyloidosis
• Plasma cell leukemia
• Within 4 weeks since any plasmapheresis
• Within 3 weeks of any corticosteroids except per inclusion criteria above
• Waldenstrom’s macroglobulinemia or IgM myeloma
• 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
• Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone
• Peripheral neuropathy >= grade 2 at screening
• Prior cerebrovascular accident (CVA) with persistent neurological deficit
• Diarrhea > grade 1 in the absence of antidiarrheals
• Central nervous system (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 (e.g., unstable angina, congestive heart failure, New York Heart Association class III-IV) * Uncontrolled cardiac arrhythmia (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4 grade 2:2) or clinically significant electrocardiogram (ECG) abnormalities * Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec
• Uncontrolled hypertension (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
• 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