Bortezomib (Velcade™) is an effective treatment for advanced multiple myeloma (MM). The association of Velcade™ to standard MP significantly increased response rate.When combined with Thalidomide, Velcade™ showed additive activity. Based on these observations, a phase II multicenter trial of Velcade™ plus Melphalan, Prednisone and Thalidomide (V-MPT) as salvage treatment was conducted. This is a dose escalation study with three sequential dose levels of Velcade™. The V-MPT regimen included 6 five-week courses of oral Melphalan (6 mg/m2 on days 1–5), Prednisone (60 mg/m2 on days 1–5), Thalidomide (100 mg continuously). In the first cohort Velcade™ at 1 mg/m2 was added on days 1, 4, 15, 22 of each course followed by a 13-day rest period. In the second and in the third cohort, Velcade™ was administered at 1.3 mg/m2 and 1.6 mg/m2, respectively. DLT was defined as the occurrence in the first 2 courses of any grade 3–4 non hematological toxicities, a grade 4 neutropenia ≥ a week, or any grade 4 hematological toxicity except neutropenia. Velcade™ dose increment was implemented whenever at least 3 patients (pts) completed 2 courses without any DLT. As of July 2005, 20 pts have been enrolled in this study, median age 65 years (range 38–73), 65% IgG, 20% IgA, 15% Bence Jones. The median b2 microglobulin was 3.83 mg/L (range 0.5–13.8). Nine pts received V-MPT as second line therapy, 11 as third line. Fourteen patients received prior autologous transplant, 5 conventional chemotherapy and 4 thalidomide-based regimens. In the first 10 pts cohort, 3 DLT were observed in the first 2 courses (grade 3 pneumonia at cycle 1, grade 3 febrile neutropenia at cycle 1 and grade 3 vasculitis at cycle 2). Treatment was discontinued in pts who experienced pneumonia and vasculitis. Velcade™ was reduced to 0.7 mg/m2 in patient who experienced febrile neutropenia. Grade 3 hematological toxicities included thrombocytopenia (3 pts) and neutropenia (5 pts). The most common grade 1–2 toxicities were: constipation, infections, rash. In the second cohort, five of the 10 pts completed at least 2 cycles. Two DLT in the first 2 courses were observed (grade 3 Herpes Zoster infections). Grade 3 hematological toxicities included thrombocytopenia (1 pt) and neutropenia (1 pt). The most common grade 1–2 toxicities were: constipation, infections, fatigue. After introduction of prophylaxis with acyclovir, no new HZV reactivation was observed. Among the 6 pts with baseline peripheral neuropathy before V-MPT treatment, 4 pts remained stable, and 2 worsened (grade 2). Treatment-related (grade 1) neuropathy developed de novo in 2 pts. After a median of 3 courses (range 2–6) and a median follow-up of 5 months, 10 pts (67%) had a response ≥ 50%: 2 complete responses (CR), 1 near CR, 7 partial responses. Two pts (13%) achieved minor response (MR) and one stable disease. One pt experienced progressive disease after a MR and one was refractory to treatment. Initial results showed that V-MPT is a promising regimen for advanced myeloma. Further investigation is ongoing to determine the maximum tolerated dose of this combination. Updated results will be presented at the meeting.

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