Advertisement

Venous thromboembolism in relapsed or refractory multiple myeloma patients treated with lenalidomide plus dexamethasone

  • Junghoon Shin
  • Je-Jung Lee
  • Kihyun Kim
  • Chang-Ki Min
  • Jeong-Ok Lee
  • Cheolwon Suh
  • Jin Seok Kim
  • Yoo Jin Lee
  • Sung-Soo Yoon
  • Jae-Cheol Jo
  • Ho Sup Lee
  • Soo-Mee Bang
  • Korean Multiple Myeloma 151 Investigators
Original Article

Abstract

Lenalidomide plus dexamethasone (LD) is currently the mainstay of treatment for both untreated and relapsed or refractory multiple myeloma (RRMM). Although lenalidomide-associated venous thromboembolism (VTE) is a major clinical concern, its incidence and prognostic impact have not been delineated. In this nationwide retrospective cohort study, we aimed to determine the cumulative incidence of VTE and its prognostic value using two consecutive cohorts of LD-treated RRMM patients: the KMM151 cohort (N = 542) and the HIRA cohort (N = 1559). Data were collected from medical records for the KMM151 cohort and healthcare insurance claims database for the HIRA cohort. Throughout the study period, 24 patients (4.4%) in the KMM151 cohort and 80 patients (5.1%) in the HIRA cohort developed VTE. The cumulative incidence reached a plateau approximately 2 years after LD initiation. The 2-year incidence was 4.9% in the KMM151 cohort and 8% in the HIRA cohort. Higher starting dose of lenalidomide, previous history of VTE, and older age were associated significantly with an increased VTE risk. Early-onset VTE was associated significantly with poor survival. In conclusion, VTE occurred in 5–8% of RRMM patients treated with LD over 2 years, and early-onset VTE was a strong indicator of poor prognosis.

Keywords

Multiple myeloma Venous thromboembolism Lenalidomide Incidence Survival 

Notes

Acknowledgements

The authors thank the Korean Multiple Myeloma Working Party for developing and managing the KMM151 database and the KMM151 Investigators for contributing the data. We also thank Ju Hyun Lee, a data analyst at Seoul National University Bundang Hospital, for performing the statistical analysis. This work was supported by grants from the Korean Society on Thrombosis and Hemostasis (KSTH 2016-002) and Seoul National University Bundang Hospital (04-2012-003). This manuscript was edited by native English-speaking experts from BioScience Writers, Houston, TX, USA.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12185_2018_2540_MOESM1_ESM.pdf (123 kb)
Supplementary material 1 (PDF 122 KB)

References

  1. 1.
    Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau J-L, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32.CrossRefGoogle Scholar
  2. 2.
    Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–52.CrossRefGoogle Scholar
  3. 3.
    Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621–34.CrossRefGoogle Scholar
  4. 4.
    Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519–27.CrossRefGoogle Scholar
  5. 5.
    Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319–31.CrossRefGoogle Scholar
  6. 6.
    Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.CrossRefGoogle Scholar
  7. 7.
    Kumar SK, Callander NS, Alsina M, Atanackovic D, Biermann JS, Chandler JC, et al. Multiple myeloma, version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:230–69.CrossRefGoogle Scholar
  8. 8.
    Kimpton M, Buyting R, Corsi DJ, Rupani N, Carrier M, McCurdy A. Incidence and risk factors of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory agents. Blood. 2016;128:2624-.CrossRefGoogle Scholar
  9. 9.
    Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. 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;24:431–6.CrossRefGoogle Scholar
  10. 10.
    Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–42.CrossRefGoogle Scholar
  11. 11.
    Musallam KM, Dahdaleh FS, Shamseddine AI, Taher AT. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb Res. 2009;123:679–86.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414–23.CrossRefGoogle Scholar
  14. 14.
    Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, 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;23:2147.CrossRefGoogle Scholar
  15. 15.
    Carrier M, Le Gal G, Tay J, Wu C, Lee AY. Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost. 2011;9:653–63.CrossRefGoogle Scholar
  16. 16.
    Koh Y, Bang SM, Lee JH, Yoon HJ, Do YR, Ryoo HM, et al. Low incidence of clinically apparent thromboembolism in Korean patients with multiple myeloma treated with thalidomide. Ann Hematol. 2010;89:201–6.CrossRefGoogle Scholar
  17. 17.
    Wu S-Y, Yeh Y-M, Chen Y-P, Su W-C, Chen T-Y. Low incidence of thromboembolism in relapsed/refractory myeloma patients treated with thalidomide without thromboprophylaxis in Taiwan. Ann Hematol. 2012;91:1773–8.CrossRefGoogle Scholar
  18. 18.
    Zangari M, Tricot G, Polavaram L, Zhan F, Finlayson A, Knight R, et al. Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone. J Clin Oncol. 2010;28:132–5.CrossRefGoogle Scholar
  19. 19.
    Song SO, Jung CH, Song YD, Park C-Y, Kwon H-S, Cha BS, et al. Background and data configuration process of a nationwide population-based study using the Korean National Health Insurance system. Diabetes Metab J. 2014;38:395–403.CrossRefGoogle Scholar
  20. 20.
    Jang MJ, Bang SM, Oh D. Incidence of venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database. J Thromb Haemost. 2011;9:85–91.CrossRefGoogle Scholar
  21. 21.
    Hong J, Lee JH, Yhim H-Y, Choi W-I, Bang S-M, Lee H, et al. Incidence of venous thromboembolism in Korea from 2009 to 2013. PLoS One. 2018;13:e0191897.CrossRefGoogle Scholar
  22. 22.
    Kim J-A, Yoon S, Kim L-Y, Kim D-S. Towards actualizing the value potential of korea health insurance review and assessment (HIRA) data as a resource for health research: strengths, limitations, applications, and strategies for optimal use of HIRA data. J Korean Med Sci. 2017;32:718–28.CrossRefGoogle Scholar
  23. 23.
    Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.CrossRefGoogle Scholar
  24. 24.
    Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol. 1983;1:710–9.CrossRefGoogle Scholar
  25. 25.
    Kim HJ, Yoon S-S, Eom HS, Kim K, Kim JS, Lee J-J, et al. Use of lenalidomide in the management of relapsed or refractory multiple myeloma: expert recommendations in Korea. Blood Res. 2015;50:7–18.CrossRefGoogle Scholar
  26. 26.
    Sanfilippo KM, Edwin NC, Gage BF, Luo S, Calverley D, Carson K. Risk of venous thromboembolism in multiple myeloma: identification of risk factor. Blood. 2016;128:4726-.Google Scholar
  27. 27.
    Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162:1182–9.CrossRefGoogle Scholar
  28. 28.
    Menon SP, Rajkumar V, Lacy M, Falco P, Palumbo A. Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer. 2008;112:1522–8.CrossRefGoogle Scholar
  29. 29.
    Chen C, Reece DE, Siegel D, Niesvizky R, Boccia RV, Stadtmauer EA, et al. Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Br J Haematol. 2009;146:164–70.CrossRefGoogle Scholar
  30. 30.
    Kim K, Kim SJ, Voelter V, Suh C, Yoon S-S, Lee J-J, et al. Lenalidomide with dexamethasone treatment for relapsed/refractory myeloma patients in Korea—experience from 110 patients. Ann Hematol. 2014;93:113–21.CrossRefGoogle Scholar
  31. 31.
    Johnson DC, Corthals S, Ramos C, Hoering A, Cocks K, Dickens NJ, et al. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping. Blood. 2008;112:4924–34.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Junghoon Shin
    • 1
  • Je-Jung Lee
    • 2
  • Kihyun Kim
    • 3
  • Chang-Ki Min
    • 4
  • Jeong-Ok Lee
    • 1
  • Cheolwon Suh
    • 5
  • Jin Seok Kim
    • 6
  • Yoo Jin Lee
    • 7
  • Sung-Soo Yoon
    • 8
  • Jae-Cheol Jo
    • 9
  • Ho Sup Lee
    • 10
  • Soo-Mee Bang
    • 1
  • Korean Multiple Myeloma 151 Investigators
  1. 1.Division of Hematology-Oncology, Department of Internal MedicineSeoul National University Bundang HospitalSongnamRepublic of Korea
  2. 2.Department of Internal MedicineChonnam National University Hwasun HospitalHwasunRepublic of Korea
  3. 3.Department of Internal Medicine, Samsung Medical Center, School of MedicineSungkyunkwan UniversitySeoulRepublic of Korea
  4. 4.Division of Hematology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  5. 5.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  6. 6.Department of Internal MedicineYonsei University College of MedicineSeoulRepublic of Korea
  7. 7.Department of Internal MedicineKyungpook National University HospitalDaeguRepublic of Korea
  8. 8.Department of Internal MedicineSeoul National University HospitalSeoulRepublic of Korea
  9. 9.Department of Internal MedicineUlsan University HospitalUlsanRepublic of Korea
  10. 10.Department of Internal MedicineKosin University College of MedicineBusanRepublic of Korea

Personalised recommendations