Velcade, Thalidomide and Dexamethasone (VTD) Regimen Followed by High-Dose Chemotherapy Plus Autologous Stem Cell Transplant (HDT-ASCT) as Front-Line treatment in Newly Diagnosed Multiple Myeloma (MM) Patients: Preliminary Results of An ongoing Open Label Study

Background and aim: In the last decade HDT-ASCT has significantly improved progression-free and overall survival of patients with MM. Achievement of CR or good partial response and the tumor reduction attained with the induction pretransplant chemotherapy have been shown to be the most relevant prognostic factors for long-term survival. In recent years, novel drugs such as thalidomide and bortezomib have been introduced in the treatment of MM. Bortezomib (B) (Velcade^Ò) as a single agent, gives a response rate ranging from 35% to 50%, including up to a 9% CR rate in relapsed/refractory patients, and of 40%, with a 10% CR rate in the up-front setting. Thalidomide (T) has been identified as the first independently active agent in MM since the introduction of melphalan and prednisone and currently represent the milestone of initial treatment in elderly patients. Since B and T target different molecular pathways, we started a phase II trial in order to assess efficacy, toxicity and rate of PBSC collection after VTD regimen delivered as induction pretransplant chemotherapy in patients with newly diagnosed MM.

Patients and Methods: from June 2007 to July 2008 14 pts (M/F: 11/3) with a median age of 56 years (range: 42–71) were enrolled in the study; six pts (43%) were more than 60 yo and 7 pts had a previous history of M-GUS lasting in median 54 months. At time of treatment there were 71%, 22% and 7% having Durie and Salmon staging III, II and I respectively, while ISS was 1 in 22%, 2 in 50% and 3 in 28% of cases. One pt had renal impairment, extensive bone disease was documented in 78% of cases with 2 pts showing extramedullary disease. Sixty-five percent of pts (9/14) had IgG MM, 14% IgA, 7% light chain, and 14% non secretory myeloma. Unfavourable cytogenetic was recorded in 36% (5/14) of cases. Bortezomib was administered at 1.3 mg/m² on days 1,4, 8, 11 as short IV infusion, thalidomide at daily dose of 100 mg PO and Dexamethasone (40 mg/die PO) the day of bortezomib infusion and the day after (640 mg for each cycle) every 4 weeks for 3–4 courses. All patients received deep venous thrombosis prophylaxis consisting of aspirin 100 mg daily (44%), low molecular weight heparin (28%) and low dose warfarin (28%). Following VTD regimen patients underwent to high-dose cyclophosphamide (4 g/m²) with G-CSF support and peripheral stem cell harvest. MEL 200 was given as conditioning regimen. All patients received standard dose of zoledronic acid monthly.

Results: At present time all patients are evaluable for VTD and PBSC collection while 10 for response after transplant. After 3 courses of VTD 93% of pts achieved more than a partial response including 57% of CR and 36% of VGPR. One pt achieved a PR. VTD regimen resulted well tolerated with main toxicity consisting of WHO grade III peripheral neuropathy recorded in 37 % of pts. There were no pts with relevant hematologic toxicity or other non-hematologic toxicities and there were no chemotherapy reduction or delay because of toxicity. None of pts developed DVT. A sufficient amount of CD34+ cells (median 6.5 × 10⁶/kg; range: 2.7–11.6) was collected in 13 of 14 evaluable pts after a median of 1.4 aphaeresis (range:1–2). One pt failed to collect after CTX and was treated with HD-Ara-C obtaining an adequate number of CD34+ cells for transplant. The median CD 34+ cells infused in the 10 transplanted pts was 3.3 ×10⁶/kg (range: 2.0 – 4.7). Times to platelet (20×10⁹/L) and granulocyte (500×10⁹/L) recovery were 13 and 10 days respectively. After HDC and ASCT 7 of 10 patients presented CR (70%) and 2 (20%) a VGPR with an ORR of 90%. One pt presented progression disease after 6 months from transplant.

Conclusion: these very preliminary data suggest that VTD regimen given as pretransplant chemotherapy is effective and well tolerated regimen; the capacity to give high response rate in a short time without to compromise PBSC collection makes VTD regimen a good option for initial treatment of newly diagnosed MM patients although more pts and longer follow-up are needed to assess the real impact on survival of this regimen.