Bortezomib in Combination with High-Dose Dexamethasone (HD dex) and Erythropoietin (EPO) Does Not Result in an Increased Risk of Thromboembolic Complications.

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Introduction: There is an increasing awareness of the risk of thromboembolic complications (TE) associated with multiple myeloma (MM) due to underlying patient- and disease-related factors as well as choice of therapy. Notably, prior TE, and use of HD dex, doxorubicin, concomitant EPO in combination with lenalidomide or thalidomide, have all been suggested to increase TE risk in MM patients (pts) and require more complex management strategies (Niesvizky et al., J Clin Oncol2006;24(Suppl):423s; Hussein, Thromb Haemost2006;95:924–30; Rajkumar et al, J Clin Oncol2006;24:431–6; Zangari et al, Blood2002;100:1168–71). Based on these reports, experience with another novel agent, bortezomib (btz), recently approved for second line MM, was studied. Methods: Adverse event data were examined from the phase 2 SUMMIT and CREST studies of btz ± dex in relapsed and/or refractory MM, and the phase 3 APEX study of btz vs dex in relapsed MM (1–3 prior lines of therapy). Rates of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were calculated for pts receiving btz ± dex ± EPO in the phase 2 studies, and for pts receiving btz or dex ± EPO in the APEX study. Results: Data were analyzed for all 256 pts enrolled in SUMMIT and CREST, of whom 106 received added dex, and for 331 btz-treated and 332 dex-treated pts in APEX. Rates of DVT and/or PE were very low, with no notable differences when dex and/or EPO were given with btz (Table 1). In the APEX trial, overall odds ratio for the risk of DVT/PE according to EPO use = 1.670 (95% CI: 0.500, 5.580); P = 0.4051. Furthermore, there appeared to be a decrease in TE risk with btz vs dex, controlling for EPO use; odds ratio = 0.207 (95% CI: 0.044, 0.971), P = 0.0459. Summary: Btz plus dex and/or concomitant EPO does not appear to be associated with an elevated TE risk in this analysis. This observation is supported by two phase 2 studies of btz plus dex in 97 frontline MM pts, in which no TE was reported despite some concomitant EPO use (Jagannath et al, Blood2005;106(Suppl):231a; Harousseau et al, J Clin Oncol2005;23(Suppl):598s). Furthermore, btz appears to lower the risk of TE when used in combination with agents of known thrombogenic potential (Palumbo et al, Haematologica2006;91(s1):729; Ciolli et al, Haematologica2006;91(s1):764; Terpos et al, Haematologica2006;91(s1):223; Richardson et al, Blood2005;106(Suppl):365a; Zangari et al, Blood2004;104(Suppl):4914a). Table 1. Rates of DVT and PE with btz ± dex ± EPO in phase 2 and 3 trials of btz. Combined incidence in SUMMIT and CREST phase 2 trials Btz alone Plus dex EPO No EPO Total EPO No EPO Total *1 pt had both DVT and PE †2 pts had both DVT and PE (N=158) (N=98) (N=256) (N=74) (N=32) (N=106) DVT 3 (1.9%) – 3 (1.2%) – – – PE 1 (0.6%) 1 (1.0%) 2 (0.8%) – 1 (3.1%) 1 (0.9%) DVT/PE 3* (1.9%) 1 (1.0%) 4* (1.6%) – 1 (3.1%) 1 (0.9%) Incidence in APEX phase 3 trial Btz Dex EPO (N=137) No EPO (N=194) EPO (N=106) No EPO (N=226) DVT 1 (0.7%) – 2 (1.9%) 4 (1.8%) PE 1 (0.7%) – 1 (0.9%) 4 (1.8%) DVT/PE 2 (1.5%) – 3 (2.8%) 6† (2.7%)