Total Therapy 3 (TT3) Incorporating VelcadeR (V) Intro Upfront Management of Multiple Myeloma (MM): Comparison with TT2 + Thalidomide (T).

Abstract

Abstract Background: V effects partial responses in 1/3 of patients with advanced and refractory MM and was more effective when combined with T/dexamethasone (D) in our VTD regimen (Barlogie et al. Blood2004; 103: 20). TT3 was designed to build on the success of TT2 by providing T to all patients and incorporating V in induction, consolidation and maintenance therapies to increase CR to 60% and 2-yr EFS for patients with normal/abnormal metaphase cytogenetics to 95% /75%. Patients and Methods: TT3 consists of 2 induction cycles with VDT-PACE (PBSC collection after the first cycle), followed by melphalan 200mg/sqm-based tandem transplants with peri-transplant T+D, 2 consolidation cycles with VDT-PACE, 1 year maintenance with VTD and 2 years with T+D. Of the 162 patients enrolled prior to 4/20/2005, 156 completed induction therapy, 147 the first and 113 the second transplant. Response rates, toxicities during induction, and stem cell collection results were compared with 314 TT2+T patients. Results: First and second transplant on TT3 were completed faster, at medians of 3 and 5 mo, compared to 5 and 10 mo, respectively, on TT2+T (p<0.001/p<0.001); 92%/78% (TT3) vs 89%/68% (TT-2+T) completed first and second transplant, respectively, (p0.24/p=0.028). The probability of achieving near-CR (n-CR: only immunofixation positive) at 12 mo was 81% with TT3 and 64% with TT2+T (p=.001). The median number of CD34/kg (x106) was 27 with TT3 vs 20 with TT2+T (p<.001). Treatment-related mortality (TRM) at 12 mo was 4% with TT3 and 6% TT2+T (p=.3). With a median follow-up of 9 mo, 18 patients have experienced an event and 14 have died (disease-related 7; treatment-related 6, other 1). Compared to event-free TT3 patients, these 18 patients were older (≥ 65 years: 50% vs 27%; p=0.04), more frequently had metaphase abnormalities (50% vs 24%; p=0.02) and had elevated LDH (50% vs 19%; p=0.003). With respect to grade 3–4 toxicities during induction, TT3 patients had fewer thrombo-embolic events, (p<.001), less febrile neutropenia (p=.03), somnolence (p=.007), sensory neuropathy (.005) and dizziness (< .001), but more anorexia (p< .001) and renal insufficiency (p=.004). Conclusion: TT3 appears to be more effective in inducing ≥ n-CR, compared to TT-2+T, partly due to a higher percentage of patients completing the intended 2 transplants. TRM is not different. It is too early to assess the true CR rate and the 2-y EFS according to cytogenetics.