Risk Factors for Thromboembolism (TE) in Multiple Myeloma (MM) Patients (pts) Treated with Immunomodulatory Agents (IMiDs) Plus Dexamethasone (dex)
Authors: Patel Jai N , Jagosky Megan Helena , Robinson Myra M , Slaughter Daniel , Arnall Justin , Matusz-Fisher Ashley , Bhutani Manisha , Voorhees Peter M. , Usmani Saad Z. 
Published: October 2019

Abstract
Introduction: MM pts have one of the highest risks of TE among cancer pts. Use of IMiDs plus dex further increases this risk. Guidelines recommend thromboprophylaxis based on risk assessment; however, limited large-scale studies have attempted to validate previous and identify new patient-specific risk factors associated with TE in MM pts.
Methods: We conducted a retrospective review of 834 new or relapsed MM pts treated at Levine Cancer Institute between January 2012 to December 2017. Eligibility criteria for final analysis included age ≥ 18 years, diagnosis of MM, and treatment with thalidomide, lenalidomide or pomalidomide plus dex. Incidence of TE, including pulmonary embolism, deep vein thrombosis, and myocardial or cerebrovascular infarction, was documented up to 6 months after start of IMiD therapy. Presence of anticoagulation (AC)/antiplatelet therapy and type (aspirin [ASA], clopidogrel, low molecular weight heparin, warfarin, rivaroxaban, apixaban, dabigatran) were documented for each pt. Univariate and multivariable logistic regression models were used to investigate the association between TE incidence and race, gender, age, BMI, cytogenetic risk level, disease burden (bone marrow plasma cell percentage), AC/antiplatelet use, history of TE, and presence or history of comorbidities, including diabetes, kidney disease, atrial fibrillation, coronary artery disease, heart disease, and clotting disorder.
Results: Of 834 pts, 373 were eligible for final analysis; 311 were excluded for not receiving an IMiD, 109 did not receive dex concomitantly with IMiD, and the remainder had other plasma cell dyscrasias and/or insufficient records. Mean age at IMiD start was 65.8 years; 48.5% were female, 58.2% Caucasian, and 35.4% African American. Most pts (96.5%) received lenalidomide as initial IMiD and 24% had high-risk disease. Half of all pts had ≥ 1 comorbidity, 8% had a history of TE, 73.7% received ASA prophylaxis, 14.2% received a stronger AC, and 12.1% did not receive thromboprophylaxis. The overall TE incidence was 31/373 (8.3%), of which 25 (6.7%) were venous and 6 (1.6%) were arterial. Of these, 30 received thromboprophylaxis. TE incidence among patients receiving ASA was 25/275 (21 venous, 4 arterial) and incidence among patients receiving stronger ACs was 5/53 (4 venous, 1 arterial). The univariate and multivariable results are summarized in the table. In univariate analysis, presence of ≥ 1 comorbidity (OR 2.98, 95% CI 1.30-6.84; p=0.01) and history of kidney disease (OR 2.65, 95% CI 1.25-5.62; p=0.01) were significantly associated with TE incidence; a trend was noted for higher TE risk in males (p=0.06). Presence of any comorbidity was the only covariate retained in the multivariable model (OR 2.82, 95% CI 1.22-6.57; p=0.016). TE incidence in pts with any comorbidity was 12% compared to 4.4% in those without any comorbidity (p=0.008). No other clinical factors were associated with TE incidence.
Conclusion: In a large single-institution analysis, we identified that MM pts with ≥ 1 comorbidity had a significantly higher risk of TE. This is consistent with current guidelines that recommend use of at least ASA prophylaxis in this population with escalation to stronger AC in patients with more than one comorbidity. Of the comorbidities studied, kidney disease was the only one significant in univariate analysis. Unique to our study, we evaluated the association between disease burden and cytogenetic risk with TE incidence and identified no significant association. Also, prior studies suggest African Americans are at a higher TE risk, however, this was not the case in our population, which was comprised of at least one-third African Americans. Interestingly, while the goal of thromboprophylaxis is to decrease TE risk, there remained an 8.3% event rate with all but one of the patients prescribed prophylaxis when the event occurred. While compliance with thromboprophylaxis is difficult to quantify, this raises concern that ASA and some ACs may not be sufficient to ameliorate TE risk entirely. Adherence to current prophylaxis guidelines is critical, along with further prospective investigation into which ACs are most efficacious at preventing TE events, particularly in high risk pts.
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Disclosures
Voorhees: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Amgen Inc.: Speakers Bureau; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.