The following criteria is provided for health care professionals.

• Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma confirmed by the Laboratory of Pathology, NCI or the Department of Laboratory Medicine, CC based on the International Myeloma Working Group Criteria:
  • Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells greater than or equal 10% and <60%
  • Absence of anemia: Hemoglobin >10 g/dl
  • Absence of renal failure: serum creatinine < 2.0 mg/dL Absence of hypercalcemia: Ca <10.5 mg/dl
  • Absence of lytic bone lesion on X-ray, CT, or PET/CT and not more than 1 lesion on spinal MRI
  • Involved-un-involved light chain ratio must be <100
• Measurable disease within the past 4 weeks defined by any one of the following:
  • Serum monoclonal protein greater than or equal to 1.0 g/dl
  • Urine monoclonal protein >200 mg/24 hour
  • Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio
• 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 <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
• ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
• Patients must have normal organ and marrow function as defined below:
  • absolute neutrophil count greater than or equal to1.0 K/uL
  • platelets greater than or equal to75 K/uL
  • hemoglobin greater than or equal to 8 g/dL(transfusions are permissible)
  • total bilirubin less than or equal to 1.5 times institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) less than or equal to 3.0 times institutional upper limit of normal
  • Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms) times [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 also be greater than or equal to 60 ml/min.
• In addition to having SMM, patients must also be classified as high-risk SMM per Mayo Clinic or Spanish PETHEMA criteria
  • Criteria set forward by Rajkumar, Landgren, Mateos may also be used to define high risk disease, namely clonal bone marrow plasma cells greater than or equal to 10% and any one or more of the following:
    • Serum M protein greater than or equal to 30g/L
    • IgA SMM
    • Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes
    • Serum involved/uninvolved FLC ratio greater than or equal to 8 (but less than 100)
    • Progressive increase in M protein level (evolving type of SMM; increase in serum M protein by greater than or equal to 25% on 2 successive evaluations within a 6-month period)
    • Clonal BMPCs 50%-60%
    • Abnormal PC immunophenotype (greater than or equal to 95% of BMPCs are clonal) and reduction of greater than or equal to 1 uninvolved immunoglobulin isotypes
    • t(4;14) or del(17p) or 1q gain
    • Increased circulating PCs
    • MRI with diffuse abnormalities or 1 focal lesion
    • PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction
• All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist.
  • The effects of carfilzomib and lenalidomide on the developing human fetus are unknown. For this reason and because immunomodulatory agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception. 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. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

• Patients who are receiving any other investigational agents.
• Concurrent systemic treatment or prior therapy within 4 weeks for SMM
  • Treatment with corticosteroids for other indications is permitted
• Patients with a diagnosis of MM as defined by the 2014 IMWH diagnostic criteria.
• Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or lenalidomide agents used in study, such as bortezomib or thalidomide.
• Uncontrolled hypertension or diabetes
• Pregnant or lactating females. Pregnant women are excluded from this study because Carfilzomib/Lenalidomide are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Carfilzomib/Lenalidomide, breastfeeding should be discontinued if the mother is treated with Carfilzomib/Lenalidomide. These potential risks may also apply to other agents used in this study
• Significant cardiovascular disease with NYHA Class II, III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia
• Active hepatitis B or C infection
• Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption
• Significant neuropathy >Grade 2 at the time of first dose or within 14 days of enrollment

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations within 2 weeks that would limit compliance with study requirements.

History of other malignancy (apart from basal cell carcinoma of the skin, or in situ cervix carcinoma) except if the patient has been free of symptoms and without active therapy during at least 5years

Major surgery within 1 month prior to enrollment