Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma

Inclusion Criteria: * Age \>18 years with no upper age limit * Diagnosis of newly diagnosed multiple myeloma with indication for initiation of therapy. * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * No prior MM-directed therapy except for dexamethasone (up to 160 mg) and/or bortezomib (up to 5.2 mg/m2) and/or cyclophosphamide up to 1000 mg/m2 administered for management of acute manifestations of MM (hypercalcemia, renal impairment, pain) for no longer than 4 weeks prior to enrollment. If subject received any prior therapy, pretreatment parameters necessary for disease characterization and response assessment must be available. * Measurable disease meeting at least one of the following criteria: 1. Serum monoclonal (M) protein ≥1.0 g/dl 2. ≥ 200 mg of M protein/24h in the urine 3. Serum-free light chain ≥10 mg/dL and abnormal kappa to lambda ratio. * Life expectancy ≥12 months. * Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) within 21 days prior to initiation of therapy. * Creatinine clearance (CrCl) ≥ 40 mL/minute within 21 days prior to start of therapy either measured or calculated using a standard formula (eg. Cockcroft and Gault). * Written informed consent in accordance with federal, local, and institutional guidelines. * Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception. Male subjects must agree to practice contraception. * All subjects must agree to comply with and be enrolled in Revlimid REMS program. Exclusion Criteria: * Diagnosis of amyloidosis, Crow-Fukase syndrome, Waldenstrom's macroglobulinemia, smoldering MM. * Major surgery, radiotherapy or infection requiring therapy within 14 days of starting treatment. * Known FEV1 or cDLCO \< 50% of predicted. * Pregnant or lactating females. * Known human immunodeficiency virus infection. * Active hepatitis B (Hepatitis B core antibody positive and subsequent Hepatitis B surface antigen positive or Hepatitis B DNA positive) or C infection (Hepatitis C antibody positive and subsequent detectable viral load). * Unstable angina or myocardial infarction within 4 months prior to registration, New York Heart Association Class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker. * Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months prior to initiation of therapy * Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas. * Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 21 days prior to registration. * Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 21 days prior to registration. * Contraindication or intolerance to required supportive care medications (Aspirin and Acyclovir). * Any other clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.