A Study to Compare MPR With MP in Newly Diagnosed Multiple Myeloma Subjects 65 Years Old or Older.

A Phase III, Multicentre, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Parallel Group Study To Determine The Efficacy And Safety Of Lenalidomde (Revlimid®) In Combination With Melphalan And Prednisone Versus Placebo Plus Melphalan And Prednisone In Subjects With Newly Diagnosed Multiple Myeloma Who Are 65 Years Of Age Or Older

The purpose of this study is to determine whether lenalidomide is safe and effective in the treatment of patients with newly diagnosed Multiple Myeloma who are 65 years of age or older.

The three phases for the study as originally defined and as represented in the results of 11 May 2010 are:

Double-blind Treatment Phase: Induction Melphalan/prednisone and lenalidomide 10 mg (MPR) (2 treatment arms), or melphalan/prednisone and placebo (MPp) (1 treatment arm) for up to 9 cycles. If disease progression, subjects have the option to enter into the Open-Label Extension Phase. There is also an option to enter into the Follow-Up Phase. If the disease has not progressed, subject can continue on blinded therapy into Maintenance.

Double-blind Treatment Phase: Maintenance One MPR treatment arm (MPR+R) will continue taking lenalidomide 10 mg in Maintenance. The other MPR treatment arm (MPR+p) will take placebo in Maintenance. The MP p treatment arm will take placebo in Maintenance (MPp+p). If disease progression, subjects have the option to enter the Open-Label Extension Phase to obtain treatment with lenalidomide, or to enter into the Follow-up Phase.

Open-label Extension Phase:

Treatment consists of oral lenalidomide (up to 25 mg) with or without dexamethasone until disease progression or treatment is discontinued for any reason until all study subjects are followed for at least 5 years from the date of randomization or have died. Subjects who discontinue from the Open-Label Extension Phase prior to completing a total of 5 years in the study will enter the Follow-up Phase.

Follow-up Phase:

Subjects are followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects in this study are followed for at least 5 years from randomization or have died.

The pre-planned interim analysis for the Independent Data Monitoring Committee (IDMC) showed that the difference in progression-free survival (PFS) between treatment arms MPR+R and MPp+p (the defined primary comparative analysis for this study) surpassed the pre-specified O'Brien-Fleming boundary for superiority. The IDMC recommended the release of this information to the sponsor and also recommended that all patient and physician study participants receive information concerning the full findings of the MM-015 interim analysis. Therefore, due to these recommendations from the IDMC, treatment-arm codes were sent to the clinical trial centers to unblind the treatment arms of their study subjects once the amended protocol was reviewed and approved by the respective country Health Authorities and Ethics Committees. Subject participation in the MM-015 study continued after unblinding to obtain long-term data for all study endpoints, including overall survival.

When the study was unblinded, subjects still on protocol therapy had completed the Double-Blind Induction, and were on monotherapy in Double-Blind Maintenance. Subjects in arm MPR+R continued their monotherapy on lenalidomide. Subjects in arms MPR+p and MPp+p discontinued their placebo monotherapy and went into an observation period in which no antimyeloma therapy was taken. If disease progressed for any subject, the investigator had the option of entering the subject in Open Label Extension Phase to receive lenalidomide therapy (up to 25 mg daily) or the Follow-up Phase. All subjects were to be followed for at least 5 years from the start of the study.

Inclusion Criteria

1. Must understand and voluntarily sign an informed consent form
2. Age greater than or equal to 65 years at the time of signing the informed consent
3. Newly diagnosed with symptomatic multiple myeloma as defined by the 3 criteria below:

MM diagnostic criteria (all of next 3 required)

1. Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma

2. Monoclonal protein present in the serum and/or urine

3. Myeloma-related organ dysfunction (at least one of the following) [C] Calcium elevation in the blood (serum calcium >10.5mg/dl or upper limit of normal) [R] Renal insufficiency (serum creatinine >2mg/dl) [A] Anemia (hemoglobin <10g/dl or 2g < normal) [B] Lytic bone lesions or osteoporosis AND have measurable disease as defined by the following; IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgA multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgD multiple myeloma: Serum M-protein level greater than or equal to 0.05 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours Light chain multiple myeloma: Serum M-protein level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level greater than or equal to 1.0g/dL or urine M-protein level greater than or equal to 200mg/24hours

4. Karnofsky performance status greater than or equal to 60%.

5. Able to adhere to the study visit schedule and other protocol requirements.

6. Women of Childbearing potential (WCBP) must:

   a. Have a negative medically supervised pregnancy test prior to the start of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices and continues sexual abstinence.

   b Either commit to continued abstinence from heterosexual intercourse (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 study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.

7. Males Subjects must:

   1. Agree to use a condom during sexual contact with a WCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after the cessation of study therapy.
   2. Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.

8. All subjects must

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

Female Subjects:

Females of childbearing potential (FCBP) with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at days 14 and 28 following discontinuation from the study.

In addition to the required pregnancy testing, the Investigator must confirm with FCBP that she is continuing to use two reliable methods of birth control at each visit. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood.

Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be discontinued during this evaluation.

Females must agree to abstain from breastfeeding during study participation and for at least 28 days after the discontinuation from the study.

Male Subjects:

Counseling about the requirement for latex condom use during sexual contact with females of childbearing potential and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood, sperm, or semen.

If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a study subject during study participation, study drug must be immediately discontinued.

Exclusion Criteria

1. Previous treatment with antimyeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [i.e., 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 28 days [4 weeks] of randomization]).

2. Any serious medical condition, including the presence of laboratory abnormalities, which places the subject at an unacceptable risk if he or she participates in this study or confounds experimental the ability to interpret data from the study.

3. Pregnant or lactating females.

4. Radiotherapy within 14 days (2 weeks) of randomization.

5. Plasmapheresis within 28 days (4 weeks) of randomization.

6. Any of the following laboratory abnormalities:

   Absolute neutrophil count (ANC) < 1,500 cells/mL (1.5*10^9/L) Platelet count < 75,000 cells/uL (75*10^9/L) for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; but platelet count <30,000/uL for subjects in whom >= 50% of bone marrow nucleated cells are plasma cells Haemoglobin < 8.0 g/dL (80 g/L) Serum creatinine > 2.5 mg/dL (221 µmol/L) Serum aspartate aminotransferase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) > 3.0 times upper limit of normal (ULN)

7. Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for greater than or equal to 3 years.

   Exceptions include the following:

   Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (TNM Classification of Malignant Tumours (TNM) stage of T1a or T1b)

8. Neuropathy of >= grade 2 severity.

9. Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis, type A, B or C.