This is a Phase 3 randomized trial of carfilzomib, lenalidomide, dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma, eligible to subjects who completed autologous stem cell transplant for symptomatic myeloma who are considered for lenalidomide maintenance.

Primary Objective:

• To compare progression free survival between Kyprolis (Carfilzomib), Revlimid (lenalidomide), Dexamethasone (KRd) arm and lenalidomide arm

Secondary Objectives

• To determine the rate of minimal residual negative disease (MRD) at 6 and 12 months after randomization
• To compare the efficacy (rate of partial response, very good partial response, complete response, and stringent complete response) of KRd vs. Lenalidomide alone after randomization

Inclusion Criteria:

1. Patients who completed single autologous stem cell transplant after completion of at most 2 induction regimens (excluding dexamethasone alone) and are in at least stable disease in the first 100 days after stem cell transplantation.

2. Patients must be within 12 months of initiation of induction therapy and must have had not more than 2 prior induction regimens.

3. Bone marrow specimen will be required at study entry; available DNA sample will be used for calibration step for MRD evaluation by gene sequencing.

4. Males and females ≥ 18 years of age

5. ECOG performance status of 0-1

6. Adequate hepatic function, with bilirubin ≤ 1.5 x ULN and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN

7. ANC ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L.

8. Calculated creatinine clearance (by Cockcroft-Gault) ≥ 50 ml/min or serum creatinine below 2 mg/dL

9. Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days).

10. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study.

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11. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.

12. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.

13. Voluntary written informed consent

Exclusion Criteria:

1. Patients who have had more than 12 months of prior therapy. Patients outside of this window may be considered for inclusion on a case-by-case basis.

2. Patients who progressed after initial therapy.

   1. Subjects whose therapy changed due to suboptimal response, intolerance, etc., remain eligible, provided they do not meet criteria for progression.
   2. No more than two regimens for induction will be allowed excluding dexamethasone alone.

3. Evidence of progressive disease as per International Myeloma Working Group (IMWG) criteria

4. Patients who have already started or received post-transplant maintenance or consolidation regimen

5. Patients not able to tolerate lenalidomide or carfilzomib or dexamethasone

6. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

7. Plasma cell leukemia

8. Waldenström's macroglobulinemia or IgM myeloma

9. Peripheral neuropathy ≥ Grade 2 at screening

10. Diarrhea > Grade 1 in the absence of antidiarrheals

11. CNS involvement

12. Pregnant or lactating females

13. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area.

14. Major surgery within 3 weeks prior to first dose

15. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

16. Prior or concurrent deep vein thrombosis or pulmonary embolism

17. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening

18. Uncontrolled hypertension or diabetes

19. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose

20. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.

21. Non-hematologic malignancy or non-myeloma 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

22. Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent