THROMBOPROPHYLAXIS IN MULTIPLE MYELOMA PATIENTS RECEIVING IMMUNOMODULATORY DRUGS
Multiple myeloma (MM) has been associated with an increase in the risk of venous thromboembolism (VTE) and death. Several risk factors of VTE include patients, diseases, and treatments such as patients receiving immunomodulatory drugs (IMiDs) in combination with high doses of dexamethasone or chemotherapy. The thromboprophylaxis protocols depend on risk stratifications. Patients with a standard risk of VTE are given 81-325 mg of aspirin daily. However, patients who are at higher risk are given a daily dose of low-molecular-weight heparins/LMWH (enoxaparin 40 mg), subcutaneously or dose-adjusted warfarin that has a target INR of 2.0-3.0. Medication is given for a minimum of 4-6 months or it can be given in combination with IMiDs during treatment for MM. Importantly, risk assessment for VTE and bleeding should be regularly monitored.
2. National comprehensive cancer network. NCCN guidelines: multiple myeloma. Version 1.2020 [Internet]. Plymouth Meeting (PA): NCCN; 2019 [cited 2019 Oct 10]. Available from: http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf [Subscription required to view].
3. Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, et al. Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018;4(9):1221-7.
4. National Cancer Institute. Surveillance, epidemiology, and end results (SEER) Program [Internet]. Bethesda (MD): SEER; 2019. Cancer stat facts: Myeloma [Internet]. 2018 [cited 2019 Mar 20]. Available from: http://www.seer.cancer.gov
5. Tariman JD. Changes in cancer treatment: Mabs, Mibs, Mids, Nabs, and Nibs. Nurs Clin North Am. 2017;52:65-81.
6. Durie BGM. Current FDA-approved medications [Internet]. North Hollywood (CA): International Myeloma Foundation; 2019 [cited 2019 Oct 10]. Available from: https://www.myeloma.org/multiple-myeloma-drugs
7. Ludwig H, Delforge M, Facon T, Einsele H, Gay F, Moreau P, et al. Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network. Leukemia. 2018;32(7):1542-60.
8. Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24(1):22-32.
9. Holstein SA, McCarthy PL. Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience. Drugs. 2017;77:505-20.
10. Thai Gynecologic Cancer Society. Venous thromboembolism in gynecologic cancer: recommendation and management [Internet]. Bangkok: The Society; 2014 [cited 2019 Oct 12]. Available from: http://www.tgcsthai.com/file/2359044553.pdf (in Thai)
11. National comprehensive cancer network. NCCN guidelines: cancer-associated venous thromboembolic disease. Version 1.2019 [Internet]. Plymouth Meeting (PA): NCCN; 2019 [cited 2019 Oct 10]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf [Subscription required to view].
12. Farge D, Frere C, Connors JM, Ay C, Khorana AA, Munoz A, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2019;20:e566-81.
13. Swan D, Rocci A, Bradbury C, Thachil J. Venous thromboembolism in multiple myeloma - choice of prophylaxis, role of direct oral anticoagulants and special considerations. Br J Haematol. 2018;183:538-56.
14. Schoen MW, Luo S, Gage B, Carson KR, Sanﬁlippo KM. Association of venous thromboembolism with increased mortality in patients with multiple myeloma. J Clin Oncol. 2018;36(15 Suppl.):A8051.
15. Piazza G. Venous thromboembolism and cancer. Circulation. 2013;128(24):2614-8.
16. Li W, Cornell RF, Lenihan D, Slosky D, Jagasia M, Piazza G, et al. Cardiovascular complications of novel multiple myeloma treatments. Circulation. 2016;133(9):908-12.
17. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al.; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-23.
18. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32(6):587-600.
19. Anaissie EJ, Coleman EA, Goodwin JA, Kennedy RL, Lockhart KD, Stewart CB, et al. Prophylactic recombinant erythropoietin therapy and thalidomide are predictors of venous thromboembolism in patients with multiple myeloma: limited effectiveness of thromboprophylaxis. Cancer. 2012;118:549-57.
20. Martino M, Oliva E, Console G, Stelitano C, Fujo M, Messina G, et al. Administration of recombinant human erythropoietin alpha before autologous stem cell transplantation reduces transfusion requirement in multiple myeloma patients. Support Care Cancer. 2005;13:182-7.
21. National comprehensive cancer network. NCCN guidelines: hematopoietic growth factors. Version 2.2019 [Internet]. Plymouth Meeting (PA): NCCN; 2019 [cited 2019 Oct 10]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf [Subscription required to view].
22. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299(8):914-24.
23. Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med. 2006;354(19):2079-80.
24. Rajkumar SV. Multiple myeloma: Treatment of complications [Internet]. Waltham (MA): UpToDate; c2019 [cited 2019 Oct 10]. Available from: https://www.uptodate.com/contents/multiple-myeloma-treatment-of-complications [Subscription required to view].
25. Zangari M, Fink L, Zhan F, Tricot G. Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. Clin Lymphoma Myeloma Leuk. 2011;11(2):228-36.
26. Nayak L, Shi H, Atkins GB, Lin Z, Schmaier AH, Jain MK. The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2). Blood. 2014;123(24):3828-31.
27. Siegel D, Martin T, Nooka A, Harvey RD, Vij R, Niesvizky R, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-61.
28. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-52.
29. Scarabelli T, Gavazzoni M, Chen-Scarabelli C, Sahni G, Saravolatz L, Narula J, et al. Cardiovascular toxicity of carfilzomib on vascular tone, vascular reactivity and endothelial function. Circulation. 2014;130 suppl 2:A12193.
30. Scarabelli TM, Chen-Scarabelli C, Gavazzoni M, Sahni G, Saravolatz L, Raddino R, et al. Cardiovascular effects of carfilzomib, a new proteasome inhibitor, on coronary resistencies, vascular tone and vascular reactivity. J Am Coll Cardiol. 2015;65(10 Suppl.):A2143
31. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293(6):715-22.
32. Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med. 2001;344(25):1951-2.
33. El Accaoui RN, Shamseddeen WA, Taher AT. Thalidomide and thrombosis: a meta-analysis. Thromb Haemost. 2007;97(6):1031-6.
34. Li W, Garcia D, Cornell RF, Gailani D, Laubach J, Maglio ME, et al. Cardiovascular and thrombotic complications of novel multiple myeloma therapies: a review. JAMA Oncol. 2017;3(7):980-8.
35. Rosovsky R, Hong F, Tocco D, Connell B, Mitsiades C, Schlossman R, et al. Endothelial stress products and coagulation markers in patients with multiple myeloma treated with lenalidomide plus dexamethasone: an observational study. Br J Haematol. 2013;160:351-8.
36. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, 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;11:29-37.
37. Dimopoulos MA, Leleu X, Palumbo A, Moreau P, Delforge M, Cavo M, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573-85.
38. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24(11):1934-9.
39. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826-32.
40. Mikhael J, Rajkumar V, Roy V, Hayman SR, Fonseca R, Detweiler-Short K, et al. Efficacy of pomalidomide plus low-dose dexamethasone in multiple myeloma patients despite previous use of lenalidomide. J Clin Oncol. 2011;29(15 suppl.):A8067.
41. Mandalà M, Falanga A, Roila F; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22 Suppl 6:vi85-92.
42. Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost. 2013;11:56-70.
43. Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38(5):496-520.
44. Chalayer E, Bourmaud A, Tinquaut F, Chauvin F, Tardy B. Cost-effectiveness analysis of low-molecular-weight heparin versus aspirin thromboprophylaxis in patients newly diagnosed with multiple myeloma. Thromb Res. 2016;145:119-25.
45. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003;21(1):16-9.
46. Zangari M, Barlogie B, Anaissie E, Saghafifar F, Eddlemon P, Jacobson J, et al. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation. Br J Haematol. 2004;126:715-21.
47. Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004;89(7):826-31.
48. Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29(8):986-93.
49. Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012;119(4):933-9.
50. Leleu X, Rodon P, Hulin C, Daley L, Dauriac C, Hacini M, et al. MELISSE, a large multicentric observational study to determine risk factors of venous thromboembolism in patients with multiple myeloma treated with immunomodulatory drugs. Thromb Haemost. 2013;110(4):844-51.
51. Palmaro A, Rougé-Bugat ME, Gauthier M, Despas F, Moulis G, Lapeyre-Mestre M. Real-life practices for preventing venous thromboembolism in multiple myeloma patients: a cohort study from the French health insurance database. Pharmacoepidemiol Drug Saf. 2017;26:578-86.
52. Sweiss K, Wirth SM, Sharp L, Park I, Sweiss H, Rondelli D, et al. Collaborative physician-pharmacist-managed multiple myeloma clinic improves guideline adherence and prevents treatment delays. J Oncol Pract. 2018;14(11):e674-82.
53. Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, et al; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711-9.
54. Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, et al; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380(8):720-8.
55. Sayar Z, Czuprynska J, Patel JP, Benjamin R, Roberts LN, Patel RK, et al. What are the difficulties 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.
56. Pegourie B, Karlin L, Benboubker L, Orsini-Piocelle F, Tiab M, Auger-Quittet S, et al. Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: myelaxat, a phase 2 pilot study. Am J Hematol. 2019;94:635-40.
57. Storrar NPF, Mathur A, Johnson PRE, Roddie PH. Safety and efficacy of apixaban for routine thromboprophylaxis in myeloma patients treated with thalidomide- and lenalidomide-containing regimens. Br J Haematol. 2019;185:142-4.
All articles published and information contained in this journal such as text, graphics, logos and images is copyrighted by and proprietary to the Thai Bulletin of Pharmaceutical Sciences, and may not be reproduced in whole or in part by persons, organizations, or corporations other than the Thai Bulletin of Pharmaceutical Sciences and the authors without prior written permission.