Use of direct oral anticoagulants in multiple myeloma patients taking immunomodulators: 615.036.2

Abstract

Summury. Immunomodulatory drugs (IMDs) are used to treat multiple hematologic malignancies. At the same time, their use is associated with an increased risk of venous thromboembolic complications (VTEC), which requires thromboprophylaxis. Increa- singly, direct oral anticoagulants (DOACs) are being used in practical medicine. Currently, the role of these drugs in patients with malignant neoplasms is being studied. The aim of this review was to evaluate the safety and efficacy of DOACs as thromboprophy- laxis in multiple myeloma (MM) patients receiving IMDs. Clinical studies were analyzed, as well as clinical case reports published in the world literature from 2014 to 2021. The paper systematizes information about thrombotic events and bleeding registered in these studies. Analysis results indicate the efficacy and safety of DOACs using in MM patients on IMDs therapy. Thus, DOACs may represent an attractive alternative to warfarin, acetylsalicylic acid, and low molecular weight heparins for VTEC prevention in this group of patients. The paper also discusses the problems associated with DOACs use and possible ways of solutions.

References

1. Silverstein M., Heit J., Mohr D. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585–93. DOI: 10.1001/archinte.158.6.585. 2. Blom J.W., Doggen C.J., Osanto S., Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293(6):715–22 DOI: 10.1001/jama.293.6.71.5. 3. Schoen M.W., Luo S., Gage B. et al. Association of venous thromboembolism with increased mortality in patients with multiple myeloma. J Clin Oncol. 2018;36(15_suppl):8051. DOI: 10.1200/ JCO.2018.36.15_suppl.8051. 4. Федоткина Ю.А., Панченко Е.П. Тромбозы в онкологии. Часть 2. Атеротромбоз. 2017;(2):3–12. DOI: 10.21518/2307–1109–2017–2. Fedotkina Yu.A., Panchenko E.P. Thrombosis in cancer. Part 2. Aterotromboz. 2017;(2):3–12. (In Russ.). DOI: 10.21518/2307–1109– 2017–2. 5. Uzueva S. Sh., Zharkov P.A. Venous thrombosis in pediatric cancer (literature review). Rossijskij zhurnal detskoj gematologii i onko­ logii. 2019;6(4):69–75. (In Russ.). DOI: 10.21682/2311–1267–2019– 6–4–69–75. 6. Kristinsson S.Y., Pfeiffer R.M., Björkholm M. et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood. 2010;115(24):4991–8. DOI: 10.1182/blood-2009–11–252072. 7. Гриценко Т.А., Косякова Ю.А., Давыдкин И.Л. и др. Болезни крови в амбулаторной практике. Под ред. И.Л. Давыдкина. М.: ГЭОТАР­Медиа, 2020. 272 с. 8. Gritsenko T.A., Kosyakova Yu.A., Davydkin I.L. et al. Blood diseases in outpatient practice. Ed. I.L. Davydkin. Moscow: GEOTAR­Media, 2020. 272 pр. (In Russ.). 9. Kristinsson S.Y., Fears T.R., Gridley G. et al. Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma. Blood. 2008;112(9):3582–6. DOI: 10.1182/ blood-2008–04–151076. 10. Man L., Morris A., Brown J. et al. Use of direct oral anticoagulants in patients on immunomodulatory agents. J Thromb Thrombolysis. 2017;44(3):298–302. DOI: 10.1007/s11239–017–1534–9. 11. Rajkumar S.V., Blood E., Vesole D. et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24(3):431–6. DOI: 10.1200/JCO.2005.03.0221. 12. Dimopoulos M.A., Chen C., Spencer A. et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23(11):2147–52. DOI: 10.1038/leu.2009.147. 13. Palumbo A., Rajkumar S.V., Dimopoulos M.A. et al. Prevention of thalidomideand lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. DOI: 10.1038/sj.leu.2405062. Terpos E., Kleber M., Engelhardt M. et al. European Myeloma Network guidelines for the management of multiple myelomarelated complications. Haematologica. 2015;100(10):1254–66. DOI: 10.3324/haematol.2014.117176. 14. Moreau P., San Miguel J., Sonneveld P. et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv52-iv61. DOI: 10.1093/ annonc/mdx096. 15. Anderson K. C., Alsina M., Atanackovic D. et al. Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2015;13(11):1398–435. DOI: 10.6004/ jnccn.2015.0167. 16. Raskob G.E., van Es N., Segers A. et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, doubleblind, double-dummy trial. Lancet Haematol. 2016;3(8):e379-e387. DOI: 10.1016/S2352–3026(16)30057–6. 17. Verso M., Munoz A., Bauersachs R. et al. Effects of concomitant administration of anticancer agents and apixaban or dalteparin on recurrence and bleeding in patients with cancer-associated venous thromboembolism. Eur J Cancer. 2021;148:371–81. DOI: 10.1016/j.ejca.2021.02.026. 18. Wysokinski W.E., Houghton D.E., Casanegra A.I. et al. Comparison of apixaban to rivaroxaban and enoxaparin in acute cancer-associated venous thromboembolism. Am J Hematol. 2019;94(11):1185– 92. DOI: 10.1002/ajh.25604. 19. Young A.M., Marshall A., Thirlwall J. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017–23. DOI: 10.1200/JCO.2018.78.8034. 20. McBane R.D., WysokinskiW.E., Le-Rademacher J. et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018;132(Supplement 1):421. DOI: 10.1182/blood-2018–99–118808. 21. Raskob G.E., Büller H.R., Segers A. Edoxaban for cancer-associated venous thromboembolism. N Engl J Med. 2018;379(1):95–6. DOI: 10.1056/NEJMc1806646. 22. NCCN Clinical practice guidelines in oncology. Multiple myeloma. Version 5.2022. Available at: www.nccn.org. 23. Somonova O.V., Antukh E.A., Dolgushin B.I. Practical recommendations for the prevention and treatment of thromboembolic complications in cancer patients. Malignant tumors. Prak­ ticheskie rekomendacii RUSSCO. 2020;10(3s2):131–40. (In Russ.). DOI: 10.18027/2224-5057-2020-10-3s2-47. Available at: https:// phlebology-sro.ru/upload/iblock/a9e/prakticheskie-rekomendatsii-po-vteo-u-onkologicheskikh-bolnykh-2020.pdf. 24. Cosmi B. An update on the efficacy and safety of novel anticoagulants for cancer associated thrombosis. Expert Opin Pharma­ cother. 2021;22(5):583–94. DOI: 10.1080/14656566.2020.1847273. 25. Li W., Garcia D., Cornell R.F. et al. Cardiovascular and thrombotic complications of novel multiple myeloma therapies: a review. JAMA Oncol. 2017;3(7):980–8. DOI: 10.1001/jamaoncol.2016.3350. 26. Dimopoulos M.A., Zervas K., Kouvatseas G. et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12(7):991–5. DOI: 10.1023/a:1011132808904. 27. Baz R., Li L., Kottke-Marchant K. et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc. 2005;80(12):1568–74. DOI: 10.4065/80.12.1568. 28. Schütt P., Ebeling P., Buttkereit U. et al. Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma. Eur J Hae­ matol. 2005;74(1):40–6. DOI: 10.1111/j.1600–0609.2004.00349.x. 29. Richardson P., Jagannath S., Hussein M. et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114(4):772–8. DOI: 10.1182/ blood-2008–12–196238. 30. Rajkumar S.V., Jacobus S., Callander N.S. et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29–37. DOI: 10.1016/S1470–2045(09)70284–0. 31. Morgan G.J., Schey S.A., Wu P. et al. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br J Hae­ matol. 2007;137(3):268–9. DOI: 10.1111/j.1365–2141.2007.06538.x. 32. Baz R., Walker E., Karam M.A. et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol. 2006;17(12):1766–71. DOI: 10.1093/annonc/mdl313. 33. Schey S.A., Fields P., Bartlett J.B. et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269–76. DOI: 10.1200/JCO.2004.10.052. 34. Lacy M.Q., Hayman S.R., Gertz M.A. et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008–14. DOI: 10.1200/ JCO.2009.23.6802. 35. Paludo J., Mikhael J.R., LaPlant B.R. et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomiderefractory multiple myeloma. Blood. 2017;130(10):1198–204. DOI: 10.1182/blood-2017–05–782961. 36. Kamat A. Rivaroxaban is an effective and well tolerated anti thrombotic agent in patients on lenalidomide therapy and in multiple myeloma. Blood. 2014;124(21):5095. DOI: 10.1182/blood. V124.21.5095.5095. 37. Kawaguchi M., Uchimura N., Okuda Y. et al. Successful treatment of venous thromboembolism with a Factor Xa inhibitor, edoxaban, in patients with lenalidomide-treated multiple myeloma. Rinsho Ketsueki. 2015;56(8):1096–9. [In Japanese]. DOI: 10.11406/ rinketsu.56.1096. 38. Campos-Cabrera G., Mendez-Garcia E., Campos-Cabrera S. et al. Rivaroxaban or aspirin as thromboprophylaxis in multiple myeloma. Blood. 2018;132(Supplement 1):5068. DOI: 10.1182/ blood-2018–99–111579. 39. Stawiarski K.M., Patil G., Witt D., Pollack A. Pulmonary vein thrombosis in a patient with multiple myeloma on treatment with lenalidomide. World J Oncol. 2021;12(2–3):73–6. DOI: 10.14740/ wjon1384. 40. Piedra K.M., Hassoun H., Buie L.W. et al. VTE rates and safety analysis of newly diagnosed multiple myeloma patients receiving carfilzomib-lenalidomide-dexamethasone (KRD) with or without rivaroxaban prophylaxis. Blood. 2019;134 (Supplement 1):1835. DOI: 10.1182/blood-2019–124403. 41. Aguilar C., DueñasA.B., Sevil F., Domínguez C.Use of direct oral anticoagulants (DOACs) as primary or secondary prophylaxis of venous thromboembolism in patients with multiple myeloma on immunomodulatory drugs. Res Pract Thromb Hae­ most. 2020;4(Suppl 1):PD2098. 42. Cornell R.F., Goldhaber S.Z., Engelhardt B.G. et al. Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents. Br J Hae­ matol. 2020;190(4):555–61. DOI: 10.1111/bjh.16653. 43. Oka S., Takeuchi S., Shiragami H. et al. Successful management of venous thromboembolism with apixaban in a multiple myeloma patient on lenalidomide therapy. Rinsho Ketsueki. 2017;58(1):37– 41. (In Japanese). DOI: 10.11406/rinketsu.58.37. 44. SayarZ.,CzuprynskaJ.,PatelJ.P.etal.Whatarethedifficulties in conducting randomised controlled trials of thromboprophylaxis in myeloma patients and how can we address these? Lessons from apixaban versus LMWH or aspirin as thromboprophylaxis in newly diagnosed multiple myeloma (TiMM) feasibility clinical trial. J Thromb Thrombolysis. 2019;48(2):315–22. DOI: 10.1007/ s11239–019–01891–0. 45. Pegourie B., Karlin L., Benboubker L. et al. Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study. Am J Hematol.2019;94(6):635–40. DOI: 10.1002/ajh.25459. 46. StorrarN.P.F.,MathurA.,JohnsonP.R.E.,RoddieP.H.Safetyand efficacy of apixaban for routine thromboprophylaxis in myeloma patients treated with thalidomideand lenalidomide-containing regimens. Br J Haematol. 2019;185(1):142–4. DOI: 10.1111/bjh.15392. 47. Leblebjian H., Hamilton J., Smith S. et al. Improving rates of venous thromboembolism prophylaxis in multiple myeloma patients on immunomodulatory drugs. Blood. 2018;132(Suppl_1):235. DOI: 10.1182/blood-2018–99–115436. 48. Parnes A., Leblebjian H., Hamilton J. et al. Improving rates of venous thromboembolism prophylaxis in multiple myeloma patients on immunomodulatory drugs through a pharmacy-based system. J Oncol Pharm Pract. 2021;28(2):1078155221995885. DOI: 10.1177/1078155221995885. 49. Sanfilippo K.M., Luo S., Carson K.R., Gage B.F. Aspirin may be inadequate thromboprophylaxis in multiple myeloma. Blood. 2017;130(Suppl_1):3419. DOI: https://doi.org/10.1182/blood.V130. Suppl_1.3419.3419. 50. Frere C., Benzidia I., Marjanovic Z., Farge D. Recent advances in the management of cancer-associated thrombosis: new hopes but new challenges. Cancers (Basel). 2019;11(1):71. DOI: 10.3390/cancers11010071. 51. Gribkova I.V., Lipets E.N., Rekhtina I.G. et al. The modification of the thrombin generation test for the clinical assessment of dabigatran etexilate efficiency. Sci Rep. 2016;6:29242. DOI: 10.1038/ srep29242. 52. Capodanno D., Angiolillo D.J. Antithrombotic therapy in patients with chronic kidney disease. Circulation. 2012;125(21):2649–61. DOI: 10.1161/CIRCULATIONAHA.111.084996. 53. Derebail V.K., Rheault M.N., Kerlin BA. Role of direct oral anticoagulants in patients with kidney disease. Kidney Int. 2020;97(4):664– 75. DOI: 10.1016/j.kint.2019.11.027. 54. Lipets E.N.,Ataullakhanov F.I.,Panteleev M.A. Integratedlaboratory coagulation tests in hypercoagulation diagnosis and thrombosis risk assessment. Onkogematologiya. 2015;10(3):73–91. (In Russ.). DOI: 10.17650/1818–8346–2015–10–3–78–91.