Prospective Study of Apixaban for Primary Prevention of Venous Thromboembolism in Patients with Multiple Myeloma Receiving Immunomodulatory Therapy, a 3-month Interim Analysis

R. Frank Cornell1; Samuel Z Goldhaber2; Brian G Engelhardt1; Javid Moslehi3; Madan Jagasia1; Daryl Patton4; Shelton Harrell1; Robert Hall1; Houston Wyatt1; Gregory Piazza2

1 Division of Hematology and Oncology, Department of Medicine, Vanderbilt University, Nashville, TN, USA; 2 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 3 Cardio-Oncology Program, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN; 4 Vanderbilt Institute for Clinical and Translational Research

Background

ObjectivesEfficacy:

Assess the rate of symptomatic VTE over 6 months in patients withMM receiving IMIDs who are prescribed apixaban 2.5mg orally twicedaily for primary prevention of VTE

Safety:Assess the 6-month rate of major and clinically-relevant, non-major

bleeding

References

• Immunomodulatory drugs/cereblon-binding agents (IMiDs), includingthalidomide, lenalidomide, and pomalidomide, have improved survivalof patients with multiple myeloma (MM)

• MM has been associated with an increased risk of venousthromboembolism (VTE)1

• Risk of VTE is further increased in the setting of IMiDs2

• Apixaban directly blocks Factor Xa, which inhibits coagulation byinterfering with conversion of prothrombin to thrombin

• Apixaban has been approved for treatment of acute VTE and for riskreduction of recurrent VTE following initial therapy

• We conducted a prospective, single-arm, open-label, phase IV clinicaltrial (NCT02958969) to investigate the safety and efficacy of apixabanfor VTE prophylaxis for patients with MM

• Here we report a 3-month planned interim analysis

1. Li W, Cornell RF, Lenihan D, Slosky D, Jagasia M, Piazza G, et al. Cardiovascular Complications of Novel MultipleMyeloma Treatments. Circulation (2016) 133(9):908-12.

2. Fradley MG, Groarke JD, Laubach J, Alsina M, Lenihan DJ, Cornell RF, et al. Recurrent cardiotoxicity potentiated bythe interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.British journal of haematology (2018) 180(2):271-5.

3. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of theInternational Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostaticmedicinal products in non-surgical patients. J Thromb Haemost (2005) 3(4):692-4

Methods• Fifty patients were identified and enrolled at Vanderbilt University

Medical Center and received apixaban 2.5 mg orally twice daily forprimary prevention of VTE for a planned 6 months.

Key Eligibility:• Eastern Cooperative Oncology Group functional status ≤ 2.• No contraindication to anticoagulant therapy• No prior VTE• No current serious bleeding or within 6 months prior to enrollment• Requirement for dual antiplatelet therapy or for aspirin >165mg daily• Creatinine clearance > 25 mg/min

• Aspirin prophylaxis stopped at time of enrollment

Definitions:

Major bleeding: overt bleeding that is associated with a decrease in hemoglobin of 2g/dL or more, requiring the transfusion of 2 or more units of blood, occurring in a critical site, or contributing to death3

Clinically relevant non-major bleeding: overt bleeding that does not meeting the criteria for major bleeding, but is associated with medical intervention, surgical intervention, or interruption of the study drug3

Table 1 – Baseline Characteristics

N=50

Age, Median (range) 63 (51-74)

Male 25 (50%)

RaceCaucasianBlackAsian

41 (82%)8 (16%)1 (2%)

Myeloma SubtypeIgGIgALight chainOther

30 (60%)10 (20%)7 (14%)3 (6%)

R-ISS stageIIIIIIUnknown

23 (46%)18 (36%)8 (16%)1 (2%)

Platelet count, median (range), x109/LCreatinine clearance, median (range), ml/min

175 (121-353)92 (32-185)

Prior Lines of Therapy, Median (range) 2 (0-8)

Prior AutoSCT 41 (82%)

IMiD TreatmentLenalidomide Pomalidomide

29 (58%)21 (42%)

Treatment SettingNewly DiagnosedRelapsed DiseasePost-transplant Consolidation/Maintenance

2 (4%)15 (30%)33 (66%)

Traditional Cardiovascular Risk FactorsHypertensionObesityHyperlipidemiaDiabetesHistory of Smoking

40 (80%)25 (50%)23 (46%)16 (32%)8 (16%)

17 (34%)

Results

Table 2 – Clinical Events at 3-month Interim Analysis

N=50

Major bleeding 0 (0%)

Venous thromboembolism 0 (0%)

Clinically relevant non-major bleeding*1. Unprovoked epistaxis lasting more than 5 minutes2. Mechanical trauma3. Arm ecchymoses

3 (6%)

Superficial vein thrombosis 0 (0%)

Myocardial infarction (MI) 0 (0%)

Stroke or transient ischemic attack 0 (0%)

Other event: Stopped apixaban early due to allergic reaction manifesting as generalized edema

1 (2%)

Median follow-up, days (range) 84 (23-149)

Results

*All 3 patients were able to resume study drug after brief discontinuation

• Immunomodulator/cereblon-binding agents comprise the therapeutic foundation of therapy for MM at all phases of therapy

• While these agents are generally well tolerated, their increased risk of VTE presents a clinical challenge

• In this pilot study of 50 patients at 3-month interim analysis, low-dose apixaban was safe and well tolerated as thromboprophylaxis for patients with MM receiving IMiDs

• No patients experienced VTE, major hemorrhage, stroke, or MI• Further randomized studies are needed to validate apixaban as a standard primary

prevention anti-thrombotic strategy for patients with MM receiving IMiDs• This regimen has the potential to greatly improve VTE prophylaxis options for patients

with MM

Conclusions