Validation of Risk-Adapted Venous Thromboembolism Prediction in Multiple Myeloma Patients

Barrett, Aisling; Quinn, John; Lavin, Michelle; Thornton, Patrick; O’Donnell, James S.; Murphy, Philip; Glavey, Siobhán

doi:10.3390/jcm10163536

Cited by 5 publications

(8 citation statements)

References 17 publications

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“…Nonetheless, studies have shown that risk of thrombosis is not completely abrogated by any of these thromboprophylaxis strategies. In fact, high rates of both venous and arterial thrombosis have been reported in patients with MM receiving therapy with immunomodulatory agents despite thromboprophylaxis 24–26 . Bradbury et al reported on the thrombosis rates observed in the Myeloma IX and Myeloma XI phase 3 trials and disappointingly, thrombosis incidence rates at 6 months remained >10% in the later trial despite much higher rates of thromboprophylaxis (80.5% vs. 22.3%) 25 .…”

Section: Thrombosis In Multiple Myelomamentioning

confidence: 99%

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

Comerford

Glavey

Quinn

et al. 2022

Journal of Thrombosis and Haemostasis

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Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti‐myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS‐13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS‐13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.

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Section: Thrombosis In Multiple Myelomamentioning

confidence: 99%

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

Comerford

Glavey

Quinn

et al. 2022

Journal of Thrombosis and Haemostasis

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“…When individual variables from the Khorana score were subjected to univariate and multivariate analysis, the white blood cell count was the only variable that retained predictive significance. 43 .…”

Section: Thrombo-hemorrhagic Risk Factors and Risk Stratificationmentioning

confidence: 99%

Thrombosis in multiple myeloma: risk stratification, antithrombotic prophylaxis, and management of acute events. A consensus-based position paper from an <i>ad hoc</i> expert panel

et al. 2022

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The introduction of new therapeutic agents in multiple myeloma (MM), including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, has improved the outcomes of patients but, in parallel, has changed the frequency and epidemiology of thrombotic events. Now, thrombosis is a significant cause of morbidity and mortality in MM patients, and optimal thromboprophylaxis is far from being reached. Moving from the recognition that the above issue represents an unmet clinical need, an Expert Panel assessed the scientific literature and composed a framework of recommendations for improving thrombosis control in patients candidates for active treatment for MM. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process. It explored four domains, i.e., thrombotic risk factors and risk stratification, primary thromboprophylaxis, management of acute thrombotic events, and secondary thromboprophylaxis. The issued recommendations may assist hematologists in minimizing the risk of thrombosis and guarantee adherence to treatment in patients with MM candidates to active treatment.

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“…The rate of VTE occurrence remains unacceptably high in MM patients with approximately 10% of patients developing a thrombosis during the course of their disease [21,22] . It has been demonstrated that thrombosis rates in patients with malignancy are highest in the first year following diagnosis and in particular, in MM, thrombosis rates appear to be highest in the first 3 months following diagnosis [1,13,22,23] . It is hypothesised that these initial high rates are due to both accelerated neoplastic activity, increased tumour burden and, with treatment initiation, there may be overwhelming release of procoagulant factors and cytokines once apoptosis ensues.…”

Section: Vte Rates Despite Thromboprophylaxis: Immunomodulatory Agentsmentioning

confidence: 99%

“…It has long been acknowledged that there is a strong association between cancer and thrombosis but the risk of these events varies widely across the spectrum of cancer subgroups. VTE rates remain high in patients with MM with almost 10% of patients suffering from thrombosis during their disease course [ 1 , 2 ] .…”

Section: Introductionmentioning

confidence: 99%

“…It is comprised of five clinical and laboratory indices, including type of cancer, platelet count, haemoglobin level and white cell count (WCC) as well as BMI [ 10 ] . However, given that it is largely based on solid organ tumour data, it has been recognised that this score likely has limitations in the MM population with several studies observing that it does not accurately predict VTE risk within this cohort [ 2 , 11 , 12 ] . In fact, in a study of over 300 patients with MM, Barrett et al [ 2 ] noted that WCC was the only single variable from the Khorana score that retained predictive significance for VTE in their cohort.…”

Section: Introductionmentioning

confidence: 99%

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Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma

Comerford¹,

Glavey²,

O’Sullivan³

et al. 2022

CDR

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Multiple Myeloma (MM) is a common haematological malignancy that is associated with a high rate of venous thromboembolism (VTE) with almost 10% of patients suffering thrombosis during their disease course. Recent studies have shown that, despite current thromboprophylaxis strategies, VTE rates in MM remain disappointingly high. The pathophysiology behind this consistently high rate of VTE is likely multifactorial. A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients, however, the optimal method of clinically evaluating this is unclear at present, though some groups have attempted its characterisation with thrombin generation testing (TGT). In addition to testing for heparin resistance, TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels. Apart from these thrombin-mediated processes, other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance, endothelial toxicity secondary to chemotherapy agents, tissue factor abnormalities and the effect of immunoglobulins/“M-proteins” on both the endothelium and on fibrin fibre polymerisation. It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.

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Validation of Risk-Adapted Venous Thromboembolism Prediction in Multiple Myeloma Patients

Cited by 5 publications

References 17 publications

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

Thrombosis in multiple myeloma: risk stratification, antithrombotic prophylaxis, and management of acute events. A consensus-based position paper from an <i>ad hoc</i> expert panel

Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma

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