Multiple factors are likely involved in the resistance to antithrombotic therapy that is frequently observed among patients with multiple myeloma (MM), and additional research is needed to determine what factors are affecting anticoagulation strategies, according to the authors of a review published in Cancer Drug Resistance.
“Despite current thromboprophylaxis strategies, venous thromboembolism (VTE) rates remain disappointingly high,” the authors wrote. VTE is associated with morbidity, anti-MM treatment interruption, or eliminating eligibility for future anti-MM agents.
Anticoagulants such as aspirin, low-dose low molecular weight heparin, warfarin, and potentially the direct oral anticoagulant medications (DOACs) are used to help mitigate the risk of thrombosis. Despite this prophylaxis, it is estimated that 10% of patients with MM will nonetheless develop thrombosis.
Previous studies suggested that the risk of thrombosis is highest within the first 3 months after an MM diagnosis. It is thought that this may be a result of high neoplastic activity or tumor burden, and after treatment initiation, the release of procoagulant factors and cytokines. Furthermore, some classes of anti-MM agents are associated with an increased risk of thrombosis.
“It is also increasingly evident that there are a multitude of factors contributing to the prothrombotic milieu seen in MM,” the authors wrote in their report.
Resistance to heparin may occur, which may be the result of a deficiency of antithrombin and/or high levels of coagulation factor VII. A study that used thrombin generation assays (TGAs) to evaluate the effect of heparin on thrombin production among patients with MM concluded that the dose of heparin used in a subset of patients was either inadequate or clinically-relevant heparin resistance was present.
Several studies suggest that abnormal activated protein C (APC) is not uncommon among patients with MM and can lead to a hypercoagulable state. High levels of circulating M protein may also contribute to thrombosis by injuring the vascular wall and interfering with fibrinolysis, which is required for clot resolution and retraction.
In the review, the authors concluded that “further work is necessitated to elucidate specific pathways and factors contributing to the hypercoagulable phenotype observed in these patients.” They added that “additional clinical studies should focus on identifying novel biomarkers of VTE risk in MM and developing effective screening methods for anticoagulant resistance.”
Comerford C, Glavey S, O’Sullivan JM, Quinn J. Potential mechanisms of resistance to current antithrombotic strategies in multiple myeloma. Cancer Drug Resist. 2022;5:214-228. doi: 10.20517/cdr.2021.115