Bleeding risk in patients with multiple myeloma treated for venous thromboembolism: a MarketScan analysis

Background Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Thromboprophylaxis is thoroughly studied in MM. Contrarily, studies assessing the risk of bleeding in people with MM on anticoagulation are lacking. Objectives To determine the rate of serious bleeding in patients with MM receiving anticoagulation for VTE and the clinical factors associated with bleeding risk. Methods Using the MarketScan commercial database, we identified 1298 people with MM treated with anticoagulation for incident VTE events between 2011 and 2019. Hospitalized bleeding was identified using the Cunningham algorithm. Rates of bleeding were calculated and Cox regression identified risk factors for bleeding. Results Bleeding occurred in 51 (3.9%) cases during median follow-up of 1.13 years. Rate of bleeding among patients with MM on anticoagulation was 24.0 per 1000 person-years. In adjusted regression, factors associated with increased bleeding included age (HR, 1.31 per 10-year increase; 95% CI, 1.03-1.65), Charlson comorbidity index (HR, 1.29 per SD increase; 95% CI, 1.02-1.58), use of antiplatelet agents (HR, 2.4; 95% CI, 1.03-5.68), diabetes (HR, 1.85; 95% CI, 1.06-3.26), and renal disease (HR, 1.80; 95% CI, 1.05-3.16). Cumulative incidence of bleeding was 4.7%, 3.2%, and 3.4% for warfarin, low molecular weight heparin, and direct oral anticoagulants, respectively. Conclusion In this real-world analysis, the rate of bleeding in people with MM on anticoagulation was comparable to those in other subsets of cancer-related VTE. Bleeding rate was lower with low molecular weight heparin and direct oral anticoagulants than warfarin. Higher comorbidity index, diabetes, antiplatelet agent use, and renal disease were risk factors for serious bleeding.


| I N T R O D U C T I O N
Multiple Myeloma (MM) is a plasma cell neoplasm with high risk of venous thromboembolism (VTE). [1] Disease-specific factors promote hypercoagulability, including increased plasma viscosity [2,3] and proinflammatory cytokines mediating plasma cell endothelial interactions. [4,5] The risk is accentuated by treatment-related factors including dexamethasone backbone [6] and use of immunomodulatory drugs (IMiDs), which are associated with thrombosis risk. [7,8] Concomitantly, pathophysiology pathways in MM result in increased bleeding risk. Disease-specific factors include impaired platelet aggregation resulting from nonspecific interactions of monoclonal proteins and platelets' surface, [3] poor coagulation triggered by M-protein interference with fibrin monomer polymerization, [4] and acquired autoantibodies against von Willebrand factor from abnormal plasma cells. [9] These mechanisms result in hemostatic abnormalities, causing altered in vitro platelet aggregation tests and prolonged coagulation and bleeding times. [3,4] MM treatment can also accentuate the bleeding risk, particularly via treatment-related thrombocytopenia. [1] Given an estimated 9-fold increased risk of VTE [10] and an absolute risk over 10% without thromboprophylaxis, [11,12] research efforts focus on preventing VTE in MM, including development of risk assessment scores and consensus guidelines, [13,14] and clinical trials to define thromboprophylaxis.
In contrast, research aimed at determining the risk of bleeding in MM is scarce. This research gap is partly because of the bleeding risk poorly correlating with laboratory abnormalities, and clinically relevant bleeding being relatively rare, [15] mostly occurring in advanced stages as terminal complications. [16] Nevertheless, assessing bleeding in MM is important because management of bleeding complications is often challenging, and underestimation of bleeding risk may result in poorer outcomes. [3,9] The risk of bleeding associated with anticoagulation for incident VTE in MM is not currently defined. As VTE incidence remains high because of poor adherence to prophylaxis [17] and higher IMiD-based therapy, [18] understanding the bleeding risk in this subgroup of cancer-related VTE constitutes a topic requiring further research.
Hemostasis abnormalities inherent to MM suggest higher bleeding burden, [9]

| Study population
We identified patients with MM 18 to 99 years of age with incident VTE treated with anticoagulation. MM was defined as at least 1 inpatient or 2 outpatient claims at least 7 days apart based on International Classification of Diseases (ICD)-9 or ICD-10 codes, a strategy with 88% sensitivity and 86% positive predictive value (PPV). [19] At least 90 days of continuous enrollment before VTE were required, to acquire comorbidity information. VTE was defined as at least 1 inpatient or 2 outpatient claims 7 to 184 days apart, using ICD-9 or ICD-10 codes, and initiation of anticoagulation within 30 days of diagnosis. This method has 72% sensitivity 72% and 91% PPV to identify VTE. [20] ICD codes used are summarized in Supplementary   Table S1. Subjects with prior VTE during the 90-day run-in period before the incident event were excluded.

| Outcome ascertainment
Primary outcome was severe bleeding complications, defined as any bleeding event causing hospitalization using the Cunningham algorithm. [21] This strategy has 89% to 99% PPV to identify bleeding (intracranial, gastrointestinal, and others) and can successfully identify bleeding complications from VTE anticoagulation. [22] Enrollees with hospitalized bleeding during the 90-day run-in period before VTE were excluded.

Essentials
• Bleeding occurred in 3.9% patients with anticoagulated myeloma during median follow-up of 1.1 years.
• Rate of hospitalized bleeding in anticoagulated patients with myeloma was 24 per 1000 person-years.
• Bleeding rates in myeloma are comparable to other subsets of cancer-related thromboembolism.
• Clinical factors including diabetes and renal disease can identify individual bleeding risk.

| Prespecified covariates
Comorbidities and use of IMiDs or prescription antiplatelets (excluding aspirin) were ascertained during the time period before VTE. History of major bleeding was based on validated algorithms using ICD-9 or ICD-10 codes applied to inpatient and outpatient claims. [21,23] Charlson comorbidity index (CCI) was calculated based on comorbidity covariates. IMiD-based therapy was defined using outpatient pharmacy claims, including the National Drug Code, prescription fill date, and number of days supplied. Outpatient prescriptions were used to identify the first anticoagulant prescribed for VTE: warfarin, direct oral anticoagulants (DOACs), or low molecular weight heparin (LMWH). The validity of warfarin identification from administrative claims has 94% sensitivity and 99% PPV [24]; validity studies for DOACs and LMWH are lacking. For analysis, patients remained in the anticoagulation category initially prescribed to mimic an intention-to-treat design. [25]

| Statistical analysis
Follow-up began at date of first anticoagulant prescription filled.
Person-time at risk accumulated until incident hospitalized bleeding, death, or end of study (December 31st, 2019). Cox proportional hazard regression models estimated the hazard ratios (HRs) and 95% CIs for risk of hospitalized bleeding, adjusted for age and sex. The model comparing DOACs and LMWH to warfarin was adjusted for age, sex, CCI, and IMiD-based therapy. To identify clinical risk factors associated with bleeding, each comorbidity covariate was modeled individually, adjusted for age, sex, renal disease, and antiplatelet agent use. Proportional hazards assumption was checked with an interaction term between exposure and time. Statistical significance was determined at α < 0.05, without adjusting for multiple comparisons. Statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc.).

| R E S U L T S A N D D I S C U S S I O N
The study population included 1298 people with established MM diagnosis and incident VTE event for which they were treated with anticoagulation. Mean age (SD) was 65.6 (12) years and 43% were female. People treated with IMiD-based regimens accounted for 54.8% and average CCI was 5.
Patient characteristics, according to anticoagulation strategy, are presented in Table 1 Of the bleeding events, 28 occurred among warfarin users, 12 among LMWH users, and 11 among DOACs users. The cumulative incidence of hospitalized bleeding was 4.7% for patients treated with warfarin, 3.2% for those treated with LMWH, and 3.4% for those treated with DOACs. However, these differences were not statistically significant, and estimated incidence rates were similar across