Venous thromboembolism in multiple myeloma – choice of prophylaxis, role of direct oral anticoagulants and special considerations

Abstract

Summary Multiple myeloma is associated with a significant risk of venous thromboembolism (VTE), causing substantial levels of morbidity and mortality. The thrombogenicity of myeloma is multifactorial, with disease‐ and treatment‐related factors playing important roles. Immunomodulatory drugs (IMiDs) and high‐dose dexamethasone, in particular, are known to enhance the thrombotic potential of myeloma. For this reason, assessment of the VTE risk has long been advocated prior to treatment initiation in patients with myeloma requiring IMiD‐based regimens. However, despite routine use of thromboprophylaxis, these patients can still develop VTE and its sequelae. The optimum choice and dose of thromboprophylactic drug is not entirely clear, and with this, there is growing interest regarding use of the direct oral anticoagulants in this setting. In this review we discuss the pathogenesis of thrombosis in multiple myeloma, its relation to some of the commonly used chemotherapeutic regimens, current risk stratification and the evidence supporting the different anticoagulants used as thromboprophylaxis. We propose an amended risk stratification, and consider management of challenging patients, including those with renal impairment and recurrent thrombosis.

Venous thromboembolism risk with contemporary lenalidomide‐based regimens despite thromboprophylaxis in multiple myeloma: A systematic review and meta‐analysis

“…Conversely, the risk is substantially higher with Rd in combination with proteasome inhibitors at 1.3 events per 100 patient‐cycles. Third, the rate of VTE was comparable in trials of ND and R/R MM, in contrast to results from prior studies, mostly before routine thromboprophylaxis, which had shown a higher incidence in ND patients …”

“…First, while computing the event rate per 100 patient‐cycles, there is an implicit assumption that the risk of VTE remains stable over time. However, studies have shown that, in ND MM, majority of VTE events happen in the first 6 months of therapy . To address this, we have reported both the cumulative incidence and the event rate per 100 patient‐cycles.…”

“…Third, the rate of VTE was comparable in trials of ND and R/R MM, in contrast to results from prior studies, mostly before routine thromboprophylaxis, which had shown a higher incidence in ND patients. 12,71 Proposed mechanisms for thrombosis with IMiDs include increased platelet aggregation, 72 single-nucleotide sequence variants, 73,74 and altered balance between procoagulant and anticoagulant proteins on the surface of endothelial cells. 75 Literature on the effect of combining novel antimyeloma agents like proteasome inhibitors and monoclonal antibodies with IMiDs on the risk of VTE is limited.…”

“…However, studies have shown that, in ND MM, majority of VTE events happen in the first 6 months of therapy. 11,71 To address this, we have reported both the cumulative incidence and the event rate per 100 patient-cycles. Second, because MM is associated with a high risk of VTE, especially in the first year after diagnosis, 3,4 the magnitude of the additional contribution of Len-based regimens cannot be identified in this study.…”

Apixaban for the prevention of thromboembolism in immunomodulatory‐treated myeloma patients: Myelaxat, a phase 2 pilot study

“…The incidence of thromboembolic events observed in myeloma treated with thalidomide/lenalidomide (thal/len) combined with dexamethasone or chemotherapy is identical to that observed in populations at high risk of venous thromboembolism, that is, orthopedic surgery, for which anticoagulant prophylaxis is systematically recommended. Although thromboprophylaxis is largely used in treated‐myeloma patients, the type and duration of treatment are debatable . A VTE primary prophylaxis strategy using low molecular weight heparin (LMWH) or aspirin according to a risk assessment model based on treatment received and level of risk was proposed by the International Myeloma Working Group …”