Bortezomib Does Not Increase Thromboembolic Risk in Multiple Myeloma and May Offer a Protective Effect with Thalidomide/Lenalidomide-Based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens.

Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep-vein thrombosis (DVT) and pulmonary embolism (PE). The VTE risk in MM is increased by various patient- and disease-related factors; however, type of anti-MM therapy represents a key factor, with a substantially elevated risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide (thal) or lenalidomide (len) in combination with dexamethasone (dex) and/or chemotherapy (Palumbo et al, Leukemia 2008); VTE risk with len-dex (RD) is further increased with concomitant erythropoietin (EPO). By contrast, treatment with the proteasome inhibitor bortezomib (btz), either alone or in combination, does not increase VTE risk. In the VISTA phase 3 trial of melphalan-prednisone (MP) vs btz plus MP (VMP) in previously untreated MM patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008), data from an updated safety analysis showed similar rates of DVT (VMP: 5/340 [1%], four grade 3; MP: 6/337 [2%], two grade 3) and PE (VMP: 4/340 [1%], two grade 4; MP: 3/337 [1%], one grade 3, two grade 4) between arms; as reported by Richardson et al (IMW 2009), rates of DVT/PE were not affected by use of erythropoiesis-stimulating agents, including EPO. These findings reflect those from the APEX phase 3 trial of single-agent btz vs high-dose dex in relapsed MM (Lonial et al, Br J Haematol 2008); rates of DVT/PE were low (0.6% vs 2.7%) and unaffected by concomitant EPO use, and VTE risk appeared lower with btz vs dex, controlling for EPO use (odds ratio 0.207, p=0.046). As previously reported, btz shows anti-hemostatic effects in patients with relapsed or refractory MM, resulting in a decrease in platelet count and significant reductions in agonist-induced platelet aggregation (Zangari et al, Haematologica 2008); these findings support btz exerting anti-thrombotic actions and thus potentially providing a protective effect in combination with regimens with elevated VTE risk. A review of data from phase 3 trials of btz- and/or IMiD-based therapy in frontline MM and other studies of novel combination regimens supports this hypothesis. Despite the confounding effect of variable VTE prophylaxis, btz-based regimens are associated with DVT/PE rates of 0–4% (Figure), similar to those seen with MP and dex alone (Palumbo et al, Leukemia 2008), whereas IMiD-based btz-free regimens are generally associated with substantially higher rates. Direct comparisons of regimens of thrombogenic potential with/without btz demonstrate lower VTE risk with btz; as previously reported, DVT rates of 0% vs 10% (p=0.0006) were seen with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) with vs without btz in an analysis of patients enrolled on two University of Arkansas trials (Zangari et al, ASH 2004). Palumbo et al (EHA 2009) also reported lower rates of VTE events with btz, thal, dex (VTD, ∼4.5%) and VMP—thal (VMPT, ∼2.7%) vs TD (7%) in a phase 3 randomized trial of aspirin, low molecular weight heparin, and warfarin as VTE prophylaxis, while in another phase 3 study Rosiñol et al (ASH 2008) showed a lower rate of thrombotic events with VTD vs TD (1.7% vs 13%, p=0.02, no prophylaxis). Indirect, between-study comparisons of VTE risk support these findings; in six phase 3 studies, TD was associated with 5.5–23% DVT/PE, while in two phase 3 studies, the rate with VTD was 1.7–4%. Similarly, rates were 6–12% in five phase 3 studies of MP-thal (MPT) vs 4% with VMPT (Palumbo et al, EHA 2009). Finally, len-low-dose dex (Rd) and RD resulted in DVT/PE rates of 12–27% in two phase 3 studies, whereas a rate of only 4% was reported in a phase 1/2 study of btz-RD (RVD) by Richardson et al (IMW 2009). Taken together, these findings confirm the low VTE risk associated with btz and support a potential protective effect of btz in combination with IMiD-based regimens associated with elevated VTE risk.

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Rates of DVT/PE by median age, according to regimen (studies with N>50; cyclo=cyclophosphamide; dox=doxorubicin; pred=prednisone).

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Rates of DVT/PE by median age, according to regimen (studies with N>50; cyclo=cyclophosphamide; dox=doxorubicin; pred=prednisone).

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Zangari:Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Fink:DOD Radioprotectants: Research Funding.