Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

Inclusion Criteria:

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

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

3. Bone marrow specimen will be required at study entry; available DNA sample will beused 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 creatininebelow 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 firstpregnancy test must be performed within 10-14 days before and the second pregnancytest 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 topractice complete abstinence from heterosexual intercourse during the following timeperiods 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 afterdiscontinuation from the study. UCM IRB CRd vs. R Version 1.0 Page 11

11. Male subjects must agree to use a latex condom during sexual contact with females ofchildbearing potential while participating in the study and for at least 28 daysfollowing discontinuation from the study even if he has undergone a successfulvasectomy.

12. All study participants in the US must be consented to and registered into themandatory Revlimid REMS® program and be willing and able to comply with therequirements 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 thiswindow may be considered for inclusion on a case-by-case basis.

2. Patients who progressed after initial therapy.

3. Subjects whose therapy changed due to suboptimal response, intolerance, etc.,remain eligible, provided they do not meet criteria for progression.

4. No more than two regimens for induction will be allowed excluding dexamethasonealone.

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

6. Patients who have already started or received post-transplant maintenance orconsolidation regimen

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

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

9. Plasma cell leukemia

10. Waldenström's macroglobulinemia or IgM myeloma

11. Peripheral neuropathy ≥ Grade 2 at screening

12. Diarrhea > Grade 1 in the absence of antidiarrheals

13. CNS involvement

14. Pregnant or lactating females

15. Radiotherapy within 14 days before randomization. Seven days may be considered if tosingle area.

16. Major surgery within 3 weeks prior to first dose

17. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IVheart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, orelectrocardiographic evidence of acute ischemia or active conduction systemabnormalities

18. Prior or concurrent deep vein thrombosis or pulmonary embolism

19. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECGduring screening

20. Uncontrolled hypertension or diabetes

21. Acute infection requiring systemic antibiotics, antivirals, or antifungals withintwo weeks prior to first dose

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

23. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3years except a) adequately treated basal cell, squamous cell skin cancer, thyroidcancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 withstable prostate specific antigen levels or cancer considered cured by surgicalresection alone

24. Any clinically significant medical disease or condition that, in the TreatingInvestigator's opinion, may interfere with protocol adherence or a subject's abilityto give informed consent