To explore the potential role of bortezomib (VELCADE®) in the frontline treatment of multiple myeloma, we conducted a study of bortezomib administered prior to autologous transplant. The primary objective was to determine the effects of bortezomib on cytokine based mobilization and engraftment. Given the critical role NF-κB in lymphocyte development and survival, we also sought to determine the effects of bortezomib on markers of immune function. Following induction, two cycles of bortezomib 1.3 mg/m2 were administered on days 1, 4, 8, and 11 of a 21-day treatment cycle. Peripheral blood stem cells were mobilized with G-CSF 10 mcg/kg/day for 5 days and harvested by large volume apheresis (20 L/day) until a minimum of 2.5 × 106 CD34+ cells/kg were collected. High-dose melphalan 200 mg/m2 was administered followed by autologous stem cell transplant with GM-CSF 250 mcg/m2/day support until neutrophil engraftment. Peripheral blood was collected at baseline (cycle 1, day 1) and after treatment with bortezomib (cycle 2, day 18) for analysis of lymphocyte subsets and serum cytokines. Forty patients were enrolled with 37 continuing on to autologous transplant. Prior to receiving bortezomib, 20 patients had been previously treated with an anthracycline, 22 with thalidomide, and two patients had no induction therapy. Stem cell collection was successful in 37 of 38 patients (97%) with the median first collection of 4.24 × 106 CD34+cells/kg. Following transplant, all patients engrafted with a median time to neutrophil engraftment (ANC ⩾ 500/mm3) of 11 days (range 9-14 days) and platelet engraftment (platelet count ⩾ 20,000/mm3) of 11 days (range 9-31 days). In an intention-to-treat analysis at 100 days post-transplant, we observed a CR in 6 patients (15%), a near CR in 10 patients (25%) and a PR in an additional 19 patients (48%) for an overall response rate of 88%. Following treatment with bortezomib, we observed a 38% decrease in CD56+ NK cells (P = .02) and a 26% increase in CD4/CD8 ratio (P = .0006) with a 18% decrease in CD8+ cytotoxic T-cells (P = .054). No significant changes were detected in either Th1 or Th2 serum cytokine levels: IL-2 (P = .116), TNF-alpha (P = .854), IFN-γ (P = .070), IL-4 (P = .240), IL-6 (0.236), IL-10 (0.151). We conclude that pretransplant bortezomib does not adversely impair stem cell mobilization or engraftment. Bortezomib also decreases NK and cytotoxic T cell subsets without measurable change in serum Th1 and Th2 cytokines.
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Uy et al. (2006) studied this question.