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Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study

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Abstract

Although novel agents for multiple myeloma (MM) have a better response rate and survival in both newly diagnosed and relapsed/refractory MM patients, concerns regarding the association between MM treatments and thromboembolic events have been raised. The aim of this population-based study was to examine the association between different combinations of MM treatments and the risk of thromboembolic events. We conducted a nested case-control study using the Taiwan Cancer Registry (TCR) and National Health Insurance Research Database (NHIRD). Adult patients newly diagnosed with MM and treated with at least one of the immunomodulatory agents between 2008 and 2016 were identified. Among them, we further identified patients who developed thromboembolic events as cases and selected controls matched by age, sex and duration of MM diagnosis at a ratio of 1:5. The index date was defined as the day one year before the diagnosis date of thromboembolic events in the case group and the corresponding date in the control group. Conditional logistic regression was used to examine the association between different MM treatment regimens and the risk of thromboembolic events. A total of 4,180 newly diagnosed MM patients treated with at least one of the immunomodulatory agents were identified (mean age: 67.2 years; male: 55.7%). In this MM cohort, we further identified 388 cases and 1,940 matched controls (mean age: 71 years; male: 64.2%). The use of a thalidomide/bortezomib/steroid combination (odds ratio (OR) 2.95 [95% confidence interval (CI) 1.47–5.95]), thalidomide monotherapy (OR 3.33; 95% CI, 1.59–6.94), and a thalidomide/steroid combination (OR 4.24; 95% CI, 2.00-8.98) were associated with an increased risk of thromboembolic events. Other risk factors, particularly a history of thromboembolic events, including ischemic heart disease and pulmonary embolism, were significantly associated with increased risk of thromboembolic events. We found that the use of thalidomide alone and in specific combinations was associated with an increased risk of thromboembolic events.

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References

  1. Munshi NC, Longo DL, Anderson KC (2018) Plasma Cell Disorders. In: Jameson JL, Fauci AS, Kasper DL et al (eds) Harrison’s principles of Internal Medicine, 20e. McGraw-Hill Education, New York, NY

    Google Scholar 

  2. Singhal S, Mehta J, Desikan R et al (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571

    Article  CAS  PubMed  Google Scholar 

  3. Rajkumar SV, Blood E, Vesole D et al (2006) 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 24:431–436

    Article  CAS  PubMed  Google Scholar 

  4. Dimopoulos M, Spencer A, Attal M et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132

    Article  CAS  PubMed  Google Scholar 

  5. Benboubker L, Dimopoulos MA, Dispenzieri A et al (2014) Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906–917

    Article  CAS  PubMed  Google Scholar 

  6. Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498

    Article  CAS  PubMed  Google Scholar 

  7. Sherbenou DW, Mark TM, Forsberg P (2017) Monoclonal antibodies in multiple myeloma: a new wave of the future. Clin Lymphoma Myeloma Leuk 17:545–554

    Article  PubMed  Google Scholar 

  8. Kristinsson SY, Pfeiffer RM, Björkholm M et al (2010) Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood The Journal of the American Society of Hematology 115:4991–4998

    CAS  Google Scholar 

  9. Kato A, Takano H, Ichikawa A et al (2013) A retrospective cohort study of venous thromboembolism (VTE) in 1035 japanese myeloma patients treated with thalidomide; lower incidence without statistically significant association between specific risk factors and development of VTE and effects of thromboprophylaxis with aspirin and warfarin. Thromb Res 131:140–144

    Article  CAS  PubMed  Google Scholar 

  10. Bradbury CA, Craig Z, Cook G et al (2020) Thrombosis in patients with myeloma treated in the myeloma IX and myeloma XI phase 3 randomized controlled trials. Blood. J Am Soc Hematol 136:1091–1104

    CAS  Google Scholar 

  11. Schoen MW, Carson KR, Luo S et al (2020) Venous thromboembolism in multiple myeloma is associated with increased mortality. Res Pract Thromb haemostasis 4:1203–1210

    Article  CAS  Google Scholar 

  12. Chakraborty R, Bin Riaz I, Malik SU et al (2020) Venous thromboembolism risk with contemporary lenalidomide-based regimens despite thromboprophylaxis in multiple myeloma: a systematic review and meta‐analysis. Cancer 126:1640–1650

    Article  CAS  PubMed  Google Scholar 

  13. Zangari M, Barlogie B, Anaissie E et al (2004) Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation. Br J Haematol 126:715–721

    Article  CAS  PubMed  Google Scholar 

  14. Sanfilippo KM, Luo S, Wang TF et al (2019) Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score. Am J Hematol 94:1176–1184

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li A, Wu Q, Luo S et al (2019) Derivation and validation of a risk assessment model for immunomodulatory drug–associated thrombosis among patients with multiple myeloma. J Natl Compr Canc Netw 17:840–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Carrier M, Le Gal G, Tay J et al (2011) Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 9:653–663

    Article  CAS  PubMed  Google Scholar 

  17. Weber DM, Chen C, Niesvizky R et al (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142

    Article  CAS  PubMed  Google Scholar 

  18. Bondili SK, Bagal B, Zawar A et al (2021) Real-world outcomes with generic pomalidomide in relapsed refractory multiple myeloma—experience from a Tertiary Care Cancer Center. JCO Global Oncology 7:361–367

    Article  PubMed  Google Scholar 

  19. Li A, Wu Q, Warnick G et al (2020) The incidence of thromboembolism for lenalidomide versus thalidomide in older patients with newly diagnosed multiple myeloma. Ann Hematol 99:121–126

    Article  PubMed  Google Scholar 

  20. Dimopoulos MA, Palumbo A, Corradini P et al (2016) Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood The Journal of the American Society of Hematology 128:497–503

    CAS  Google Scholar 

  21. Siegel DS, Schiller GJ, Song KW et al (2020) Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure. Br J Haematol 188:501–510

    Article  CAS  PubMed  Google Scholar 

  22. Maharaj S, Chang S, Seegobin K et al (2017) Increased risk of arterial thromboembolic events with combination lenalidomide/dexamethasone therapy for multiple myeloma. Expert Rev Anticancer Ther 17:585–591

    Article  CAS  PubMed  Google Scholar 

  23. Lee GY, Lee YT, Yeh CM et al (2017) Risk of stroke in patients with newly diagnosed multiple myeloma: a retrospective cohort study. Hematol Oncol 35:726–733

    Article  CAS  PubMed  Google Scholar 

  24. Wu S-Y, Yeh Y-M, Chen Y-P et al (2012) Low incidence of thromboembolism in relapsed/refractory myeloma patients treated with thalidomide without thromboprophylaxis in Taiwan. Ann Hematol 91:1773–1778

    Article  CAS  PubMed  Google Scholar 

  25. Lu J, Lee JH, Huang SY et al (2017) Continuous treatment with lenalidomide and low-dose dexamethasone in transplant‐ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial. Br J Haematol 176:743–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Raghupathy R, Ayyappan S, Prabhakar D et al (2017) Retrospective study of the incidence and patterns of arterial and venous thrombosis in chinese versus african american patients with multiple myeloma. Br J Haematol 176:315

    Article  PubMed  Google Scholar 

  27. Taiwan Cancer Registry (2021) http://tcr.cph.ntu.edu.tw/main.php?Page=N1. Accessed 30

  28. National Health Insurance Research Database. https://www.nhi.gov.tw/English/Content_List.aspx?n=46A1D826CE8E2F58&topn=ED4A30E51A609E49. Accessed 30 July, 2021

  29. Schneeweiss S, Suissa S (2019) Discussion of Schuemie et al:a plea to stop using the case-control design in retrospective database studies. Stat Med 38:4209–4212

    Article  PubMed  Google Scholar 

  30. Charlson ME, Pompei P, Ales KL et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Clin Epidemiol 40:373–383

    CAS  Google Scholar 

  31. Quan H, Li B, Couris CM et al (2011) Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 173:676–682

    Article  PubMed  Google Scholar 

  32. Dimopoulos M, Zervas K, Kouvatseas G et al (2001) Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 12:991–995

    Article  CAS  PubMed  Google Scholar 

  33. Shin J, Lee J-J, Kim K et al (2019) Venous thromboembolism in relapsed or refractory multiple myeloma patients treated with lenalidomide plus dexamethasone. Int J Hematol 109:79–90

    Article  CAS  PubMed  Google Scholar 

  34. Palumbo A, Rajkumar S, Dimopoulos M et al (2008) Prevention of thalidomide-and lenalidomide-associated thrombosis in myeloma. Leukemia 22:414–423

    Article  CAS  PubMed  Google Scholar 

  35. Baz R, Li L, Kottke-Marchant K et al (2005) The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clinic Proceedings 80:1568–1574

  36. Pegourie B, Karlin L, Benboubker L et al (2019) Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study. Am J Hematol 94:635–640

    Article  CAS  PubMed  Google Scholar 

  37. Palmaro A, Rougé-Bugat ME, Gauthier M et al (2017) Real‐life practices for preventing venous thromboembolism in multiple myeloma patients: a cohort study from the french health insurance database. Pharmacoepidemiol Drug Saf 26:578–586

    Article  CAS  PubMed  Google Scholar 

  38. Musallam KM, Dahdaleh FS, Shamseddine AI et al (2009) Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb Res 123:679–686

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by a grant from the Ministry of Science and Technology, Taiwan (MOST 108-2314-B-002-118-MY3). The authors thank the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan for making available the database used in this study.

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Authors and Affiliations

  1. Graduate Institute of Clinical Pharmacy, National Taiwan University, Taipei, Taiwan

    Mei-Tsen Chen, Shih-Tsung Huang & Fei-Yuan Hsiao

  2. Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan

    Mei-Tsen Chen & Fei-Yuan Hsiao

  3. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Huai-Hsuan Huang & Bor-Sheng Ko

  4. Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Wen-Jone Chen

  5. Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei, Taiwan

    Bor-Sheng Ko

  6. School of Pharmacy, National Taiwan University, Taipei, Taiwan

    Fei-Yuan Hsiao

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  1. Mei-Tsen Chen
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  2. Shih-Tsung Huang
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  3. Huai-Hsuan Huang
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Contributions

Chen MT, Huang ST, Ko BS, Huang HH and Hsiao FY contributed to the study concept and design. Chen MT acquired and analyzed the data. Chen MT, Huang ST, Ko BS, Chen WJ, Huang HH and Hsiao FY interpreted the data. Chen MT and Hsiao FY drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bor-Sheng Ko or Fei-Yuan Hsiao.

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Chen, MT., Huang, ST., Huang, HH. et al. Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study. J Thromb Thrombolysis 56, 578–587 (2023). https://doi.org/10.1007/s11239-023-02887-7

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