Updates on thrombotic events associated with multiple myeloma

ABSTRACT

Introduction: Despite the implementation of thromboprophylaxis guidelines, the risk of venous thromboembolism (VTE) in patients with Multiple Myeloma (MM) remains significant. There is, therefore, a need for more sensitive risk stratification tools and optimization of our thromboprophylaxis approach.

Areas covered: Since 2015 there have been no breakthrough data in this field. This review aims to cover recent data that have evaluated the effectiveness and extent to which IMWG 2014 guidelines are being applied. In addition, new data on the identification of potential biomarkers of coagulation that reflect the procoagulant processes that take place in these patients and are associated with increased VTE risk will be presented. Recent developments of clinical scores that aim to effectively risk stratify MM patients and guide thromboprophylaxis will be discussed. Finally, new data on the use of direct oral anticoagulants (DOACs) in the context of thrombosis prevention in MM patients will be covered.

Expert opinion: There is an ever-increasing need for a Risk assessment model that combines weighted clinical factors with biomarkers of coagulation that can sensitively risk stratify MM patients and guide management of VTE prevention which will also include Direct oral anticoagulants as data from ongoing clinical trials are much anticipated.

KEYWORDS:

• Venous thromboembolism
• multiple myeloma
• risk assessment models
• coagulation biomarkers
• direct oral anticoagulants

Article highlights

• Venous thromboembolism (VTE) remains one of the most common complications in patients with Multiple myeloma (MM) particularly in patients that receive immunomodulatory drug-containing regimens combined with high-dose dexamethasone or multi-agent chemotherapy.

• VTE risk is higher in newly diagnosed MM patients and during the first few months following diagnosis and treatment initiation. The most common localization is deep vein thrombosis.

• The increased risk of thrombosis is multifactorial. Risk assessment included patient-related risk factors, disease-related risk factors, and treatment-related risk factors.

• There is emerging data on the mechanisms that lead to the procoagulant environment seen in patients with MM. The rate of VTE is higher in pre-symptomatic stages of the disease (MGUS) pointing to a role for the monoclonal plasma cell and the monoclonal immunoglobulin in the induction of a prothrombotic environment.

• Many groups have published data on the role of the monoclonal component which causes hyperviscosity, interferes with fibrin fiber formation and acts like an autoantibody (Lupus anticoagulant like activity, inhibition of protein S and C) or the presence of hypercoagulability (increased TF-MP, vWF, VIII, fibrinogen, impaired fibrinolysis, APCR, PAI-1 increase, decrease of PS, t-PA and APC).

• The IWMG and EMN have published in 2014 and 2015 recommendations on the management of MM patients on IMiDs: LMWH or therapeutic dose warfarin is recommended for patients stratified as high risk (more than one VTE risk factor) and aspirin is the agent of choice for patients with none or one risk factor for VTE. Recommendations are based on limited data from RCTs and also on expert opinion.

• Direct oral anticoagulants (DOACs) are increasingly gaining ground as alternative options to the management of thrombosis due to the convenience of the oral route and lack of need for monitoring together with emerging data on comparative efficacy and improved safety. None is currently licensed for prophylaxis of cancer-associated VTE. There is an ongoing RCT assessing apixaban 2.5 mg bd versus placebo as thromboprophylaxis in patients on IMiDs and data from the interim analysis of the pilot study are promising.

• Despite application of the recommendations VTE risk remains high and makes the development of more effective risk assessment tools and optimal risk-stratification more than imperative.

• In ASH 2018 some groups presented the clinical scores they developed to assess VTE risk in patients with MM and these include the Myeloma Clot Score, the IMPEDE VTE risk score and the HAS-RISC score. These require of course prospective validation before they become incorporated in clinical practice.

• The incorporation of biomarkers of coagulation into RAMs in combination with clinical risk factors could potentially increase sensitivity of risk stratification. Many groups are trying to identify coagulation biomarkers are directly reflect increased VTE risk in MM patients. Potential candidates based on the limited data so far include P-selectin, D-dimers, procoagulant-phospholipid dependent clotting time and markers of thrombin generation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.