Dexamethasone is an important drug in the treatment of myeloma and is widely used in novel combinations, however, resistance can develop and clinical intolerance is frequent. Novel regimens that are effective and dexamethasone sparing are therefore required. Bortezomib (Velcade), the first-in-class proteasome inhibitor, has shown to be effective for the treatment of relapsed refractory myeloma, and has been shown to enhance the antitumor efficacy of both Melphalan and Anthracyclines. Early clinical results have demonstrated the efficacy and tolerability of combinations of Velcade with either of these agents. We have carried out a dose-escalating phase 1 study is to assess the safety, tolerability and response rate of the Velcade/Idarubicin/Melphalan (VIM) combination. Patients with relapsed/refractory myeloma who were either resistant or intolerant to dexamethasone were recruited. The study aimed to recruit 6 cohorts of 3 patients with standard dose Velcade and increasing doses of Melphalan and Idarubicin. Velcade (1.3 mg/m2) was administered on days 1, 4, 8 and 11 on a 28-day cycle with total number of 3 cycles, with the single dose of Melphalan (10, 15 or 20 mg/m2, i.v.) on day 4 and Idarubicin (5 or 10mg/m2) on days 4,5,(6 and 7). NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade 3 or 4 non-haem toxicity (excluding neuropathy) or any grade 4 haem toxicity (excluding neutropenia) which does not resolve to a grade 2 within 2 weeks of completing a course. As of July 2007, 14 patients were enrolled in cohorts 1–3 with a median age of 59 (range 36–68). The median number of prior therapies was 2.5 (range 1–5), including 10 pts with prior high dose therapy, 11 with Anthracyclines, and 13 with Thalidomide. In patients assessable for response 9/13 achieved a response with 2 CR, 5 PR and 2 MR according to EBMT criteria. The side effect profile was manageable and no unexpected toxicities were seen. Grade 3 toxicities were mostly related to myelosuppression with 79% thrombocytopenia and 71% neutropenia. 12 patients received GCSF to maintain their neutrophil count and 10 pts received platelet transfusions. Despite the myelosuppression no increase in infections or serious bleeding was observed. 5 patients required a dose reduction of Velcade and/or course delay due to low counts and 1 patient also required Melphalan dose reduction. Other side effects included upper respiratory tract infection (36%), peripheral neuropathy (29%) and shingles (14%), resulting in a recommendation of aciclovir prophylaxis for all patients. New/worsening neuropathy led to dose reduction of Velcade in 2 patients and discontinuation of treatment in 1 patient. One DLT of G3 respiratory tract infection was observed in cohort 3 (Mel 15 mg/m2, Idarubicin 5 mg/m2 on day 4–7), therefore another 3 patients will be enrolled to this cohort. The study indicates that VIM had a manageable toxicity profile with significant clinical activity in this dexamethasone refractory group of patients.
Disclosure: Employment: GT - Works for J&J Pharmaceutical Research and Development, MA Holder of VELCADE® in Europe. Honoraria Information: FED and GJM have recieved Honoraria from Ortho Biotech (parent company J&J).