TT 3 represents a further development of the Total Therapy concept after completion of accrual to TT 2 with 668 patients. Based on the high salvage potential of the Velcade + Thal + Dex (VTD) regimen for endstage MM, VTD had been added to PACE (4 day continuous infusions of cisplatin 10 mg/m2, adriamycin 10 mg/m2, cyclophosphamide 400 mg/m2 and etoposide 40 mg/m2) x 2 cycles for induction with PBSC collection with first or second cycle; followed by MEL 200 mg/m2-based autotransplant 2–3 months apart and subsequent consolidation therapy with further VTD PACE and VTD maintenance. As of July 1, 2004, allowing for a 1-month time to evaluate initial response and toxicity, 57 patients have been accrued to TT 3. M protein responses by level demonstrated ≥ near-CR in 16% prior to cycle 2; 26% after cycle 2 prior to first transplant and nearly 40% after first transplant (patients not yet evaluable for response for a particular step were considered non-responders; intent-to-treat analysis). The PBSC collection target of 20 million CD 34 cells/kg was accomplished within 2 days of collection in all 10 patients mobilized on the first cycle; among 29 patients collected on the second cycle, 17 collected at least 20 million CD 34 cells/kg during 2–3 days, especially when only 2 or 3 doses of Vel 1.0 mg/m2 were applied, whereas in case of 4 doses (day −2, +1, +5, +8) 5 of 23 patients failed to collect on this cycle and 13 reached ≥ 20 x 106/kg procurement goal. There was only 1 treatment-related death in a setting of renal failure at diagnosis. Other toxicities were mainly myelosuppression whereas non-hematologic toxicities appeared to be similar to those seen with DT PACE previously. Laboratory correlates such as gene expression profiling, after a test dose of Velcade and after VTD PACE along with early suppression of FDG uptake on PET will also be presented. These preliminary data indicate remarkable activity and safety of a regimen that incorporates all available drugs with single agent activity in a multi-combination strategy, aimed at maximizing and accelerating tumor mass reduction in an effort to overcome the negative consequences especially of metaphase cytogenetic abnormalities.

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