Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients

* INCLUSION CRITERIA: * Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria: 1. Clonal plasma cells in the bone marrow 2. Measurable disease within the past 4 weeks defined by any one of the following: 1. Serum monoclonal protein greater than or equal to 1.0 g/dL 2. Urine monoclonal protein greater than 200 mg/24 hour 3. Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal kappa/lambda ratio 3. Evidence of underlying end organ damage attributed to underlying plasma cell proliferative disorder meeting at least one of the following: 1. Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L 2. Renal Insufficiency: serum creatinine greater than 2.0 mg/dL 3. Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal reference 4. Bone disease: lytic lesions, severe osteopenia or pathological fractures * Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) x Mass (in kilograms) x \[0.85 if Female\] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is \<60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must be also greater than or equal to 60 ml/min. * Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of carfilzomib in combination with lenalidomide in patients less than18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL (transfusions are permissible), and platelet count greater than or equal to 75 K/uL * Adequate hepatic function, with bilirubin less than 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 times ULN. * All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (coumadin). * All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist . * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10-14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. Females of child bearing potential (FCBP) must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. * Subjects must be able to give informed consent EXCLUSION CRITERIA: * Prior or concurrent systemic treatment for MM. * Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids is permitted. * Bisphosphonates are permitted. * Treatment with corticosteroids for indications other than MM is permitted. * Radiotherapy is permitted. * Treatment for smoldering myeloma is permitted. * Plasma cell leukemia * Pregnant or lactating females. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide, breastfeeding should be discontinued if the mother is treated with carfilzomib and lenalidomide. These potential risks may also apply to other agents used in this study. * Uncontrolled hypertension or diabetes * Active hepatitis B or C infection * Has significant cardiovascular disease with New York Heart Association (NYHA) Class III or IV symptoms, or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed if clinically warranted. * Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption * Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements * Significant neuropathy greater than or equal to Grade 3 at baseline * Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy * Major surgery within 1 month prior to enrollment * Recruitment Strategies: * Patients that progress from the smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) Natural History Study (NCI Protocol: 10-C-0096) will be potential candidates. * Other participant sources will be from outside physician referrals. * Our ongoing natural history study and outside physician referral network has a high representation of minorities.