Carfilzomib and Lenalidomide With Dexamethasone Combination in Newly Diagnosed, Previously Untreated Multiple Myeloma

Inclusion Criteria

1. Newly diagnosed, histologically confirmed, previously untreated Stage I, II, or III multiple myeloma requiring systemic chemotherapy
2. Diagnosis of symptomatic multiple myeloma per IMWG uniform criteria within the past 90 days
3. Measurable disease, per IMWG (International Myeloma Working Group) criteria (\>= one of the following) within the past 4 weeks:

   * Monoclonal protein \>= 0.5 g/dL by serum protein electrophoresis
   * Monoclonal light chain \>= 200 mg by 24-hour urine protein electrophoresis
   * If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
4. Life expectancy \> 3 months
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
6. Adequate hepatic function, with bilirubin \< 1.5 x the ULN, and AST (Aspartate Aminotransferase) and ALT (Alanine Transaminase) \< 2.5 x ULN
7. Absolute neutrophil count (ANC) \>=1.0 x 109/L, hemoglobin \>= 8 g/dL, platelet count \>= 75 x 109/L
8. Calculated creatinine clearance (by Cockroft-Gault) \>= 60 ml/min
9. Written informed consent in accordance with federal, local, and institutional guidelines.
10. Subjects must agree to adhere to all study requirements, including birth control measures and pregnancy testing, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring.
11. Must be able to take either 81 mg or 325 mg aspirin daily as prophylactic anticoagulation.

Exclusion Criteria

1. Non-secretory or hyposecretory multiple myeloma, defined as \<0.5 g/dL M-protein in serum, \<200 mg/24 hr urine M-protein, or disease only measured by serum free light chain
2. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes) syndrome
3. Plasma cell leukemia
4. Waldenström's macroglobulinemia or IgM myeloma
5. Radiotherapy to multiple sites or immunotherapy within 2 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
6. Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma

   * Prior treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 160 mg of dexamethasone in a 2 week period)
   * Bisphosphonates are permitted
7. Participation in an investigational therapeutic study within 3 weeks or within 5 drug halflives (t1/2) prior to first dose, whichever time is greater
8. Pregnant or lactating females
9. History of allergy to mannitol
10. Major surgery within 3 weeks prior to first dose
11. Myocardial infarction within 3 months prior to enrollment, NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
12. Uncontrolled hypertension or diabetes
13. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
14. Known or suspected HIV infection, known HIV seropositivity
15. Active hepatitis infection
16. Non-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
17. Any 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
18. Significant neuropathy (Grade \>2) at the time of the first dose and/or within 14 days before enrollment
19. Contraindication to any of the required concomitant drugs
20. Subjects in whom the required program of PO and IV fluid hydration is contraindicated
21. Subjects with known or suspected amyloidosis of any organ
22. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis