Inclusion Criteria:

• Newly diagnosed patients with histologically confirmed MM based on the following criteria:
  • Clonal plasma cells in the bone marrow
  • Measurable disease within the past 4 weeks defined by any one of the following:
  • Serum monoclonal protein >/= 1.0 g/dL
  • Urine monoclonal protein >/= 200 mg/24 hour
  • Involved serum immunoglobulin free light chain >/= 10 mg/dL AND abnormal kappa/lambda ratio
• Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following:
  • Hypercalcemia: serum calcium ?0.25 mmol/L (> mg/dL) above upper limit of normal or >/= 2.75 mmoL (11 mg/dL)
  • Anemia: hemoglobin value <10 g/dL or >2 g/dL below lower limit of normal
  • Bone disease >/= 1 lytic lesions on skeletal X-ray, CT, or PET-CT. For patients with 1 lytic lesion, bone marrow should demonstrate >/=10% clonal plasma cells
  • Clonal bone marrow plasma cell percentage >/=60%
  • Involved/un-involved serum free light chain ratio >/=100 and involved free light chain >/=100 mg/L
  • > 1 focal lesion on magnetic resonance imaging study (lesion must be >5mm) in size
  • For patients with 1 lytic lesion, bone marrow should demonstrate ≥10% clonal plasma cells
• Creatinine clearance >/=60 ml/min. CrCl can be measured or estimated using Cockcroft-Gault method, MDRD, or CKD-EPI formulae
• Age >/= 18 years at the time of signing the informed consent documentation. Age limit of </= 75 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >/= 1.0 K/uL, hemoglobin >/= 8 g/dL, and platelet count >/= 75 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible.
• Adequate hepatic function, with bilirubin < 1.5 x the ULN, and AST and ALT < 3.0 x ULN
• All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (Coumadin) or alternative anti-coagulant
• All study participants must be registered into the mandatory eREMS program and be willing and able to comply with the requirements of REMS
• 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. 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.
  • A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Exclusion Criteria:

• Patients receiving >1 cycle of prior treatment or concurrent systemic treatment for multiple myeloma:
  • Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted
  • Bone targeting agents are permitted
  • Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted
  • Prior treatment with radiotherapy is permitted
  • Prior MM treatment, such as IMIDs or nonn-MM drugs in clinical trials for smoldering myeloma is permitted with a washout period of 2 weeks from last dose. Smoldering patients previously treated carfilzomib are excluded
  • Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 2 weeks from last dose (on a trial or outside a trial) are eligible (Note: Measurable disease is defined as one or more of the following: Serum monoclonal protein ≥ 1.0 g/dL, Urine monoclonal protein ≥ 200 mg/24 hour and/ or Involved serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal kappa/lambda ratio)
• Plasma cell leukemia
• POEMS syndrome
• Amyloidosis
• Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal (note that FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded ifFEV1 <50% of predicted normal).
• Pregnant or lactating females. Because there is a potential risk for adverse events nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide. These potential risks may also apply to other agents used in this study.
• Uncontrolled hypertension (i.e. systolic BP >160 mmHg, diastolic BP > 100 mmHg) or or diabetes
• Active hepatitis B or C infection
• Subject is:
  • Seropositive for human immunodeficiency virus (HIV)
  • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
  • Seropositive for hepatitis C (except in the setting of a sustained virologic response[SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
• Significant cardiovascular disease with NYHA class III or IV symptoms, symptomatic ischemia, current uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization and Left ventricular ejection fraction < 40% assessed by transthoracic echocardiogram (ECHO),Current unstable angina as determined by history and physical exam, hypertrophic cardiomyopathy or restrictive cardiomyopathy
• Pulmonary hypertension
• Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption of oral agents
• Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
• Significant neuropathy >/= Grade 3 or Grade 2 neuropathy with pain at baseline
• Contraindication to any concomitant medication, including antivirals or anticoagulation.
• Major surgery within 3 weeks prior to first dose