The purpose of this study is to test whether giving high doses of carfilzomib along with the other drugs (lenalidomide and dexamethasone) is safe and which dose is best tolerated by patients. In addition, the study is designed to test the amount of remaining myeloma cells in the body after treatment with higher carfilzomib doses which is known as minimal residual disease (MRD).

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 (> 1 mg/dL) above upper limit of normal or ≥ 2.75 mmol/L (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 >5 mm) in size

• Creatinine Clearance ≥ 60 ml/min. CrCl can be measured or estimated using Cockcroft-Gault method

• Age ≥ 18 years at the time of signing the informed consent documentation

• 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
  • Bisphosphonates are permitted
  • Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted
  • Prior treatment with radiotherapy is permitted
  • Prior treatment for smoldering myeloma is permitted with a washout period of 4 weeks from last dose. Smoldering patients previously treated with carfilzomib are excluded.
  • Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 4 weeks from last dose (on a trial or outside a trial) are eligible

• Plasma cell leukemia

• POEMS syndrome

• Amyloidosis

• 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 or diabetes

• Active hepatitis B or C infection

• Known or suspected HIV or serologically positive

• Has significant cardiovascular disease with NYHA Class III or IV symptoms, EF<40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed during screening evaluation.

• Moderate or severe pulmonary hypertension defined as PASP > 50mm Hg. For those patients were PASP is indeterminate, moderate to severe symptoms of pulmonary hypertension (World Health Organization functional assessment class III or IV) will be used to determine exclusion criteria.

• 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

1 year