BORTEZOMIB IN COMBINATION WITH CYTOTOXIC AGENT THERAPY FOR MULTIPLE MYELOMA

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Abstract

Bortezomib and cytotoxic agents have synergistic activity against myeloma cells. We underwent a phase I/II study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) combination therapy in patients with relapsed or refractory myeloma. In a phase I study, the maximally tolerated dose of bortezomib was determined. Bortezomib was administered iv on days 1, 4, 8 and 11 at a dose of 1.0 mg/m2 in cohort 1 and 1.3 mg/m2 in cohort 2, in combination with a fixed dose of doxorubicin, 9 mg/m2 given iv on days 1–4, and dexamethasone, 20 mg po on days 1–2, 4–5, 8–9 and 11–12. A phase II study was undertaken by using a recommended dose of bortezomib and overall response rate, survival time and toxicity profiles were examined. The dose-limiting toxicity (DLT), defined as grade 4 hematological toxicity lasting more than 5 days and/or grade 3 or higher non-hematological toxicity, was observed in two of six patients in cohort 1, indicating that this dose was considered tolerable. In cohort 2, three of five patients developed DLTs, indicating that this dose was intolerable, and 1.0 mg/m2 of bortezomib was recommended for iPAD therapy. In a phase II study, 27 patients, aged 40 to 78 (median 63), were enrolled. Overall response (CR + PR) was achieved in 89% (95% CI, 76–100%), and complete response (CR + nCR) in 30% (95% CI, 11–48%). The median overall survival time was not reached and progression-free survival time was 12.3 months (95% CI, 6.1–18.5 months). One patient died of pneumonia. Grade 3/4 thrombocytopenia, neutropenia and anemia developed in 67%, 41% and 19%, respectively, and febrile neutropenia in 11%. Sensory neuropathy was observed in 78% with grade 3/4 in 22% of the patients.It suggests that higher response rate and longer response duration can be achieved by the addition of doxorubicin to bortezomib. However, the incidence of peripheral neuropathy is high. To decrease neurologic toxic effects, bortezomib is given in once-weekly schedule by subcutaneous injection in the current study.

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