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/m2 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.

Figure 1.

Incidence of grade 3/4 thrombocytopenia according to baseline platelet counts.

Figure 2.

Mean platelet count with standard error during each treatment cycle.

Figure 3.

Platelet recovery. (A) Platelet recovery over time in patients with less than 50% plasma cell infiltration in the bone marrow (n = 103). (B) Platelet recovery over time in patients with 50% or greater plasma cell infiltration in the bone marrow (n = 116).

Figure 4.

Mean day 1 cycle 1 platelet counts and the percentage of patients treated with bortezomib 1.3 mg/m2 over time.

Figure 5.

Platelet transfusions and erythropoietin. (A) Administration of platelet transfusions or erythropoietin (EPO) in all patients (n = 228) and (B) in responders with complete, partial, or minimal response (n = 80).

Figure 6.

TPO and platelet counts. (A) Relationship of plasma thrombopoietin levels and peripheral platelet counts (× 10⁹/L) during treatment with bortezomib twice weekly every 3 weeks for 8 cycles. The thrombopoietin level was measured in pg/mL and normalized to the day-1 level in order to combine the results from 5 patients. The platelet count represents the median platelet count for the same 5 patients in whom TPO was measured. (B) Similar data from a single patient receiving weekly bortezomib demonstrating less variance in the platelet count (× 10⁹/L) and plasma TPO level (pg/mL).

Figure 7.

Bortezomib-treated mice, platelet counts, and megakaryocytes. (A) Platelet counts from BALB/c mice after intravenous administration of bortezomib 2.5 mg/kg. (B) Absolute numbers of megakaryocytes (1 femur, 2 tibiae) in different ploidy subsets from mice killed 4 or 15 days after receiving bortezomib 2.5 mg/kg. Untreated mice served as baseline controls and there were 4 to 5 mice per group. Error bars represent standard deviation. (C-E) Bone marrow sections showing megakaryocyte cells. (C) Untreated control. (D) Four days after bortezomib 2.5 mg/kg. (E) Fifteen days after bortezomib 2.5 mg/kg. Original magnifications, × 200; inset, × 600.

Figure 8.

Relationship of average plasma thrombopoietin levels (pg/mL) and peripheral platelet counts (× 106/mL) in BALB/c mice during multidose treatment with bortezomib on days 1, 4, 8, 11 (arrows). Four to 6 mice per time point. Error bars represent the standard error of the mean.