Lenalidomide vs Placebo Maintenance Therapy Following Melphalan Prednisone Velcade® Induction Therapy in NDMM

The purpose of this study is to compare the safety and efficacy of Lenalidomide versus Placebo maintenance following melphalan, prednisone and velcade induction therapy in newly diagnosed multiple myeloma.

After the study is unblinded, subjects in treatment Arm A (Len 10 mg) will remain on study therapy at the Investigator's discretion and subjects in treatment Arm B (placebo), will be discontinued from study treatment. Subjects who discontinued from study treatment for any reason will enter the LTFU Phase.

The planned total number of evaluable subjects for PFS was approximately 351 (234 in the lenalidomide treatment arm; 117 in the placebo treatment arm) and the study will be conducted in European countries. However, due to the significant enrollment challenges and the changes in the NDMM treatment practices in subjects who are not eligible for transplant, such as the recent approval of Revlimid in NDMM setting, the DMC recommended to close study enrollment. Study enrollment was closed on 12 October 2015.

Eligibility Criteria:
Inclusion Criteria:

* Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

Related to initial diagnosis and prior Melphalan Prednisone Velcade (MPV) induction therapy

1. Previously untreated and symptomatic multiple myeloma.
2. All 3 criteria (Durie, 2003) and at least one of the Creatinine Renal insufficiency Anemia lytic Bone lesions or osteoporosis criteria must be met.
3. Measurable disease by protein electrophoresis analyses.
4. All subjects must be treated with a minimum of 6 and a maximum of 9 cycles of MPV induction regimen, and must have achieved at least Partial Response as best overall response and maintained at Melphalan Prednisone Velcade discontinuation. If a subject achieves Complete Response prior to at least 6 cycles, the subject will be eligible, but a minimum of 6 cycles must be administered otherwise.
5. Subjects must not have received any prior anti-myeloma chemotherapy or any investigational agent except 6-9 cycles of induction therapy with Melphalan Prednisone Velcade.
6. Subjects must have cytogenetic (17 p deletion, and 4;14 translocation), β-2 microglobulin and serum albumin (International Staging System) results from their initial diagnosis available at the time of screening.

   Related to the subject
7. Must understand and voluntarily sign the informed consent document prior to the conduct of any study related assessments/procedures,
8. Age ≥ 65 years: if \< 65 years of age, the subject must be non eligible for stem cell transplantation,
9. Eastern Cooperative Oncology Group performance status score ≤ 2,
10. Able to adhere to the study visit schedules and other protocol requirements,
11. Females of Childbearing Potential must:

    1. Have two negative pregnancy tests as verified by the study doctor prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after the end of study therapy. This applies even if the subject practices true abstinence2 from heterosexual contact.
    2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting Investigational Product, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
12. Male Subjects must:

    1. Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female or childbearing potential while participating in the study, during dose interruptions and for at least 28 days following Investigational Product discontinuation, even if he has undergone a successful vasectomy.
    2. Agree to not donate semen during Investigational Product therapy and for 28 days after end of study therapy.
13. All subjects must:

    1. Have an understanding that the study medication could have a potential teratogenic risk.
    2. Agree to abstain from donating blood while taking Investigational Product therapy and following discontinuation of Investigational Product therapy.
    3. Agree not to share study medication with another person.
    4. All female of childbearing potential and male subjects must be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

* The presence of any of the following will exclude the subject from the study enrollment:

  1. Previous treatment with anti-myeloma therapy other than the required 6-9 cycles of Melphalan Prednisone Velcade induction therapy (does not include local radiotherapy, bisphosphonates, or a single short course of steroid \[ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of randomization\]).
  2. Subjects who didn't achieve Partial Response or better after getting at least 6 cycles of Melphalan Prednisone Velcade and at the end of Melphalan Prednisone Velcade whatever the overall response are not eligible.
  3. Prior therapy with immunomodulating or immunosuppressive agents, or epigenetic or desoxyribonucleic acid modulating agents. Subjects who received investigational agents are also excluded.
  4. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  5. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
  6. Pregnant or lactating females.
  7. Any of the following laboratory abnormalities:

     Absolute neutrophil count \< 1,000/L (1.0 x 10\*9/L) Untransfused platelet count \< 50,000 cells/L (50 x 10\*9/L) Serum glutamic oxaloacetic transaminase/alanine aminotransferase or serum glutamic pyruvic transaminase/alanine aminotransferase \> 3.0 x upper limit of normal Serum bilirubin levels \> 1.5 x upper limit of normal
  8. Renal insufficiency (creatinine clearance \< 30 mL/min by Cockcroft-Gault method) or actual creatinine clearance result, or renal failure requiring hemodialysis or peritoneal dialysis.
  9. Prior history of malignancies including skin cancer, other than multiple myeloma.
  10. Prior history of deep venous thrombosis or pulmonary embolus within 3 years of randomization.
  11. Subjects who are unable or unwilling to undergo anti-thrombotic therapy.
  12. Peripheral neuropathy of \> Grade 2 severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
  13. Known Human Immunodeficiency Virus positivity or active infectious hepatitis, type A, B, or C.
  14. Primary amyloidosis (immunoglobulin light chain) and myeloma complicated by amyloidosis.
  15. Prior allogeneic or autologous stem cell transplantation.
  16. Significant active cardiac disease within the previous 6 months including:

      New York Heart Association class II-IV congestive heart failure Unstable angina or angina requiring surgical or medical intervention Myocardial infarction
  17. Any condition that confounds the ability to interpret data from the study.