Velcade, Melphalan, Prednisone And Thalidomide Versus Velcade, Melphalan, Prednisone in Multiple Myeloma Patients

A PHASE III, MULTI-CENTER, RANDOMIZED OPEN LABEL STUDY OF VELCADE, MELPHALAN, PREDNISONE AND THALIDOMIDE (V-MPT) Versus VELCADE, MELPHALAN, PREDNISONE (V-MP) IN ELDERLY UNTREATED MULTIPLE MYELOMA PATIENTS

The proposed study will evaluate whether the combination of VELCADE, Thalidomide , Melphalan and Prednisone (V-MPT), as induction treatment for newly diagnosed elderly MM patients, improves outcomes compared to the combination VELCADE-MP.

This phase III study represents a prospective randomized open label multicenter trial to evaluate whether the combination of VELCADE, Melphalan, Prednisone and Thalidomide (V-MPT), as induction treatment for newly diagnosed elderly MM patients, improves outcomes compared to the combination VELCADE-MP.

Subjects will be randomized in a 1:1 allocation between:

Arm A: 250 patients: V-MPT treatment Arm B: 250 patients: V-MP treatment Patients excluded from randomization are to be registered in Arm C. Patients randomized in arm A (Thalidomide based) will be further enrolled in the sub-study about the DVT prophylaxis.

Patients will be evaluated at scheduled visits in up to 3 study periods: pre-treatment, treatment and long-term follow-up (LTFU).

1. Pre-treatment period:

   Screening visits, performed at study entry. After providing written informed consent to participate in the study, patients will be evaluated for study eligibility After registration subjects will be randomized.

2. Treatment period:

   Subjects in Arm A will receive:

   1. Induction therapy:

      nine 5-week courses of VELCADE/Melphalan/Prednisone/Thalidomide (V-MPT)

   2. Maintenance therapy:

   Thalidomide in combination with VELCADE

   Subjects in Arm B will receive:

   1. Induction therapy:

      nine 5-week courses of VELCADE/Melphalan/Prednisone (V-MP)

   2. No maintenance therapy is scheduled At the end of induction treatment or at the time of discontinuation of all study drugs, all patients are to attend study center visits on an every 6 to 8-week basis, until development of confirmed Progressive Disease (PD)

3. LTFU period:

After development of confirmed PD all patients are to be followed for survival every 3 months via telephone or office visit.

Inclusion Criteria:

• Age > 65 year old and not a candidate for stem cell transplant, or younger who refuses or is not eligible for high-dose therapy
• Symptomatic multiple myeloma or asymptomatic multiple myeloma with related organ or tissue damage
• Presence of measurable disease
• Karnofsky performance status (PS) > 60%
• Able to read and complete the HRQOL instruments
• Agrees to use an acceptable barrier method for contraception for the duration of the study
• Pretreatment clinical laboratory values within 14 days of randomization:

platelet count ≥ 100x109/L

• hemoglobin ≥ 8 g/dL
• absolute neutrophil count (ANC) ≥ 1.0x109/L
• AST ≤ 2.5 times the upper limit of normal
• ALT ≤ 2.5 times the upper limit of normal
• total bilirubin ≤ 1.5 times the upper limit of normal
• serum creatinine ≤ 2.5mg/dL
• corrected serum calcium <14 mg/dL (<3.5 mmol/L)
• Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• Women of child-bearing potential must agree to use 2 methods of contraception: 1 effective (for example hormonal or tubal ligation) and 1 barrier (for example latex condom, diaphragm) for at least 4 weeks before starting the therapy, during the Treatment Period, and for 4 weeks after the last dose;
• Males must agree to use barrier contraception (latex condoms) when engaging in reproductive activity during the Treatment Period and for 4 weeks after the last dose.

Exclusion Criteria:

• Diagnosis of smoldering multiple myeloma or MGUS.
• Diagnosis of Waldenstrom's disease
• Prior or current systemic therapy for multiple myeloma including steroids (with exception of emergency use of a short course [maximum 4 days] of steroids before randomization or prior or current use of biphosphonates)
• Radiation therapy within 30 days before randomization
• Plasmapheresis within 30 days before randomization
• Major surgery within 30 days before randomization (Kyphoplasty is not considered major surgery)
• History of allergic reaction attributable to compounds containing boron or mannitol, or to Thalidomide
• Peripheral neuropathy Grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 3.0
• Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
• Other malignancy within the past 5 years. Exceptions: basal cell or non metastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or FIGO Stage 1 carcinoma of the cervix
• Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes, pulmonary disease) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study
• Use of any investigational drugs within 30 days before randomization.
• Pregnant or lactating women. A serum β-hCG pregnancy test must be performed at the Screening visit, for female patients of child-bearing potential. If the test is positive, the patient must be excluded from the study. Confirmation that the patient is not pregnant must be established by a negative serum or urinary pregnancy test with the result obtained 1 day prior to the Baseline visit (or the day of the visit if results are available before drug delivery).