Inclusion Criteria

- INCLUSION CRITERIA:

- Newly diagnosed patients with histologically confirmed MM based on the following
criteria:

1. Clonal plasma cells in the bone marrow

2. Measurable disease within the past 4 weeks defined by any one of the following:

1. Serum monoclonal protein greater than or equal to 1.0 g/dL

2. Urine monoclonal protein greater than200 mg/24 hour

3. Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal
kappa/lambda ratio

3. Evidence of underlying end organ damage attributed to underlying plasma cell
proliferative disorder meeting at least one of the following:

1. Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L

2. Renal Insufficiency: serum creatinine greater than 2.0 mg/dL

3. Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal
reference

4. Bone disease: lytic lesions, severe osteopenia or pathological fractures

- Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by
Cockcroft-Gault method. CrCl (calculated) = (140 - Age) x Mass (in kilograms) x [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 msut be also greater than or equal to 60 ml/min.

- 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 less than18 years of age, children are excluded from this study, but will be
eligible for future pediatric trials.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater
than or equal to 8 g/dL (transfusions are permissible), and platelet count greater
than or equal to 75 K/uL

- Adequate hepatic function, with bilirubin less than 1.5 times the ULN, and AST and
ALT less than 3.0 times ULN.

- All study participants must be able to tolerate one of the following
thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin
(coumadin).

- All study participants must be registered into the mandatory RevAssist(Registered
Trademark) program, and be willing and able to comply with the requirements of
RevAssist(Registered Trademark).

- 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.

- Subjects must be able to give informed consent

EXCLUSION CRITERIA:

- Prior or concurrent systemic treatment for MM.

- Treatment of hypercalcemia or spinal cord compression or aggressively
progressing myeloma with corticosteroids is permitted.

- Bisphosphonates are permitted.

- Treatment with corticosteroids for indications other than MM is permitted.

- Radiotherapy is permitted.

- Treatment for smoldering myeloma is permitted.

- Plasma cell leukemia

- Pregnant or lactating females. Because there is a potential risk for adverse events
in nursing infants secondary to treatment of the mother with carfilzomib in
combination with lenalidomide, breastfeeding should be discontinued if the mother is
treated with carfilzomib and lenalidomide. These potential risks may also apply to
other agents used in this study.

- Uncontrolled hypertension or diabetes

- Active hepatitis B or C infection

- Has significant cardiovascular disease with NYHA Class III or IV symptoms, or
hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction
within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as
determined by history and physical examination. Echocardiogram will be performed if
clinically warranted.

- Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel
disease, or bowel resection that would prevent absorption

- Uncontrolled intercurrent illness including but not limited to active infection or
psychiatric illness/social situations that would compromise compliance with study
requirements

- Significant neuropathy greater than or equal to Grade 3 at baseline

- Contraindication to any concomitant medication, including antivirals, anticoagulation
prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy

- Major surgery within 1 month prior to enrollment

- Recruitment Strategies:

- Patients that progress from the SMM and MGUS Natural History Study (NCI
Protocol: 10-C-0096) will be potential candidates.

- Other participant sources will be from outside physician referrals.

- Our ongoing natural history study and outside physician referral network has a
high representation of minorities.