Bortezomib-associated transient and cyclical thrombocytopenia: evidence for lack of marrow cytotoxicity

Abstract

6610 Introduction: Bortezomib (VELCADE, btz) is a first-in-class proteasome inhibitor with efficacy in multiple myeloma (MM). Btz has been associated with transient, cyclical thrombocytopenia (TP). Preliminary data suggest the mechanism of TP with btz may differ from standard cytotoxic treatment (tx), & clinical data suggest no difficulty in collecting stem cells after btz. Methods: 228 patients (pts) with relapsed &/or refractory MM received IV bolus btz 1.3 mg/m2 on day (d) 1, 4, 8, & 11 of a 21-d cycle in the SUMMIT (N Engl J Med 2003;348:2609) & CREST (Br J Haematol 2004;127:165) trials. Plts were measured on tx d. In a murine study, normal male BALB/c mice received IV btz 2.5 mg/kg or vehicle. Results: Mean plt counts decreased with tx in each cycle & rapidly recovered to baseline by d1 of the subsequent cycle with a mean maximal 60% reduction. Among pts with complete or partial response, the lowest mean plt nadir occurred in cycle 1; among all pts, this nadir occurred later, in cycle 4. For the entire population, plt transfusion requirements decreased from 14–16% in cycles 1–2 to 8% in cycle 4 & 4% in cycle 6. An appropriate increase in serum thrombopoietin was noted with TP as assessed in a pt subset. Response to tx was independent of baseline plt count (table). Mice receiving single dose btz developed TP 2–4d post tx; plt count recovery was rapid (6–14d post tx). Megakaryocyte cellularity & morphology during & following tx showed no significant difference between btz & control. D14 marrow showed increased megakaryocyte numbers with higher ploidy suggesting rebound response to peripheral TP. Conclusions: Bortezomib is associated with transient, reversible TP. Based on murine studies, bortezomib does not affect megakaryocyte content or morphology thus sparing them irreversible cytotoxic injury. Since baseline plt count is not predictive of response to bortezomib & plt nadir occurs early in tx, supporting pts with TP using transfusions may maximize the benefit of tx. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Advisory Board, Celgene, Millennium Celgene, Millennium, Speakers Bureau Millennium