Thalidomide-Dexamethasone (TD) is a standard induction therapy for Multiple Myeloma (MM). The present study is designed to compare TD with VELCADE-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan-based double autologous stem cell transplantation for previously untreated patients aged ≤65 years with symptomatic MM. Primary study endpoint is the rate of complete response (CR) plus near-complete response (nCR) to induction treatment. Secondary endpoints include the rate of CR plus nCR to double transplantation and subsequent consolidation therapy, time to progression (TTP), progression-free survival (PFS),overall survival (OS) and toxicity profile of both VTD and TD.

This prospective phase 3 trial is aimed at evaluating whether, in comparison with standard TD, addition of Velcade to TD increases rate of CR and nCR from 15% to 30%, respectively. For this purpose, symptomatic patients aged 18-65 years with previously untreated MM and quantifiable M-protein in serum or urine are randomized (1:1) to receive induction therapy comprising three 3-week cycles of Velcade 1.3 mg/sqm, days 1, 4, 8, 11, thalidomide 100 mg, days 1-14, cycle 1, then 200 mg daily, and dexamethasone 40 mg, days 1, 2, 4, 5, 8, 9, 11, 12, or thalidomide and dexamethasone (same schedule and dosage as in VTD). Randomization to VTD or TD is stratified according to International Staging System disease stage at diagnosis. Following induction therapy, patients in both arms receive cyclophosphamide (4 g/sqm, day 0 and granulocyte colony-stimulating factor, 10 μcg/kg/day, from day +2) to collect autologous peripheral blood stem cells (minimum threshold CD34+ cells: 4 x 10^6/kg) and two subsequent courses of stem cell-supported high dose melphalan (200 mg/sqm), 3 to 6 months apart. Upon neutrophil (≥1 x 10^9/L) and platelet (≥75 x 10^9/L) recovery following the first autotransplantation, patients receive thalidomide (100 mg daily) and dexamethasone (40 mg, days 1-4 every 4 weeks) as bridge therapy until the day before the second transplantation.

Patients initially randomized to receive VTD or TD induction therapy are planned to receive two 5-week cycles of VTD (Velcade 1.3 mg/sqm, days 1, 8, 15, 22; thalidomide 100 mg daily; dexamethasone 40 mg, days 1, 2, 8, 9, 15, 16, 22, 23) or TD (thalidomide 100 mg daily; dexamethasone 40 mg, days 1-4 and 20-23) as consolidation therapy, starting 3 months after last transplant. Maintenance therapy comprise dexamethasone 40 mg, days 1-4, repeated monthly until relapse or progression.

Inclusion criteria:

• Confirmed diagnosis of symptomatic MM based on standard criteria.
• No prior or current systemic therapy for MM, including steroids.
• At least 18 years and less than 65 years of age.
• Presence of quantifiable M protein in serum (e.g. greater than 1 g/dL for IgG MM, greater than 0.5 g/dL of IgA or IgD MM) or urine (e.g. greater than 200 mg/day for BJ MM).
• Karnofsky performance status (PS) at least 60%.
• Willing and able to comply with the protocol requirements.
• Agreement from both male and female patients to follow the risk management program established for the prevention of pregnancy, including double methods for contraception and beta-HCG tests for women of childbearing potential and contraception for males.
• Adequate organ function, including heart, liver, kidney (serum creatinine less than 2 mg/dL)
• Platelet count at least 70 x 10/mcL and absolute neutrophil count at least 1 x 10/mcl

Exclusion criteria:

• Diagnosis of asymptomatic MM or of MGUS based on standard criteria.
• Diagnosis of non-secretory MM.
• Diagnosis of AL Amyloidosis.
• Prior or current systemic therapy for MM, including steroids (with exception of bisphosphonates).
• Patient has received other investigational drugs within 30 days before enrollment.
• Female subjects pregnant or breastfeeding
• Patient has Grade 2 or higher peripheral neuropathy (NCI criteria).
• Patient has a prior history of thrombosis or venous thromboembolism or pulmonary embolism.
• Patient has a previous diagnosis of antiphospholipid antibodies or lupus anticoagulant, factor V Leiden mutation, prothrombin G21210A mutation, antithrombin, protein C or S deficiency.
• Patient has a clear indication to receive a specific other anti-platelet therapy (e.g. clopidogrel, ticlopidine).
• Patient has a clear indication to receive long-term anticoagulant therapy (e.g. prosthetic heart valve, atrial fibrillation).
• Active bleeding or high risk of bleeding (gastrointestinal bleeding within the past 12 months; endoscopic diagnosis of peptic ulcer disease or ulcerative esophagitis within the past 6 months unless there is documented endoscopic evidence of healing; intracranial bleeding within the past year; amyloidosis; known bleeding diathesis).
• Seropositive for HIV, or active hepatitis A, B or C infection.
• Poorly controlled hypertension or diabetes mellitus (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before the start of therapy) or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study.
• Patient has hypersensitivity to bortezomib, boron or mannitol.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Previous or concurrent malignancies at other sites, with the exception of appropriately treated localized epithelial skin or cervical cancer. Patients with remote histories (>5 years) of other cured tumors may be entered.
• Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 4 weeks before enrolment.