Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

Abstract

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m 2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production. (Blood. 2005; 106:3777-3784)

Bortezomib plus intermediate‐dose dexamethasone and thalidomide in elderly untreated patients with multiple myeloma: A Chinese experience

“…The types and relative incidence of hematological toxicities reported here are consistent with those seen in previous studies [21,22]. The occurrence of thrombocytopenia with bortezomib is transient and cyclical [23], with recovery within the rest period suggesting a possible different pathogenesis than that seen with conventional chemotherapeutic agents. The 5% incidence of Grade 3/4 peripheral neuropathy seen in this study was similar to that seen in prior studies; it was the most common AE leading to discontinuation of bortezomib therapy.…”

Approach to the Diagnosis and Management of Drug-Induced Immune Thrombocytopenia

“…It is commonly associated with the development of transient thrombocytopenia [11]. Although the precise mechanism remains uncertain, bortezomib may interfere with platelet release from megakaryocytes, rather than causing a general cytotoxic effect on hematopoietic progenitor cells [12]. Thiazide diuretics, tolbutamide, and antivirals have also been associated thrombocytopenia which may be due to suppression of megakaryocytes.…”

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

“…Three proteasome inhibitors (PIs), bortezomib (BTZ: Kane et al , 2003; Richardson et al , 2003, 2005), carfilzomib (CFZ) and ixazomib (IXZ) are currently approved for the treatment of MM, with several others in development. Although important therapeutic advances, these PIs are associated with significant and dose‐limiting off‐target toxicities (Lonial et al , 2005; Richardson et al , 2006; Cai et al , 2014; Harvey, 2014; Atrash et al , 2015; Wanchoo et al , 2015) and the development of acquired resistance (Fall et al , 2014; Huber et al , 2015; Niewerth et al , 2015). Despite consistently high response rates with PI‐based combinations, almost all MM patients eventually relapse, with progressively lower rates and durations of response with each subsequent line of therapy and poor prognosis as resistance emerges (Kumar et al , 2012).…”