J Korean Med Sci.  2024 Jun;39(22):e175. 10.3346/jkms.2024.39.e175.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study

• Lee JY
• Lee JH
• Seo J
• Kang M
• Jung EH
• Kim SA
• Suh KJ
• Kim JW
• Kim SH
• Lee JO
• Kim JW
• Kim YJ
• Lee KW
• Kim JH
• Lee JS
• Bang SM

• KMID: 2556295
• DOI: http://doi.org/10.3346/jkms.2024.39.e175

Abstract

Background
Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Realworld data regarding SREs in MM are limited.
Methods
We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018.
Results
Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8–58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2–25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use.
Conclusion
This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Keyword

Multiple Myeloma; Skeletal-Related Events; Korean; Incidence; Risk Factors

Figure

• 

  Fig. 1 Incident skeletal-related event recurrence distribution.

• 

  Fig. 2 The cumulative incidence rate of any SRE (A), spinal cord compression (B), pathologic fracture (C), radiation to bone (D), and surgery (E).SRE = skeletal-related event.

Reference

1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011; 364(11):1046–1060. PMID: 21410373.

2. Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(8):Suppl. 1588–1594. PMID: 9362426.

3. Roodman GD. Novel targets for myeloma bone disease. Expert Opin Ther Targets. 2008; 12(11):1377–1387. PMID: 18851694.

4. Sonmez M, Akagun T, Topbas M, Cobanoglu U, Sonmez B, Yilmaz M, et al. Effect of pathologic fractures on survival in multiple myeloma patients: a case control study. J Exp Clin Cancer Res. 2008; 27(1):11. PMID: 18577267.

5. Terpos E, Berenson J, Cook RJ, Lipton A, Coleman RE. Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease. Leukemia. 2010; 24(5):1043–1049. PMID: 20376081.

6. Ramsenthaler C, Osborne TR, Gao W, Siegert RJ, Edmonds PM, Schey SA, et al. The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study. BMC Cancer. 2016; 16(1):427. PMID: 27387201.

7. Bhowmik D, Hines DM, Intorcia M, Wade RL. Economic burden of skeletal-related events in patients with multiple myeloma: analysis of US commercial claims database. J Med Econ. 2018; 21(6):622–628. PMID: 29571273.

8. Ashcroft J, Timothy B, Smith A, Wang HI, Howell D, Sayala HA, et al. Skeletal-related events in myeloma: a population-based study. Blood. 2013; 122(21):3158.

9. Nash Smyth E, Conti I, Wooldridge JE, Bowman L, Li L, Nelson DR, et al. Frequency of skeletal-related events and associated healthcare resource use and costs in US patients with multiple myeloma. J Med Econ. 2016; 19(5):477–486. PMID: 26671598.

10. Kim C, Bhatta S, Cyprien L, Fonseca R, Hernandez RK. Incidence of skeletal-related events among multiple myeloma patients in the United States at oncology clinics: observations from real-world data. J Bone Oncol. 2019; 14:100215. PMID: 30666288.

11. Terpos E, Zamagni E, Lentzsch S, Drake MT, García-Sanz R, Abildgaard N, et al. Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. Lancet Oncol. 2021; 22(3):e119–e130. PMID: 33545067.

12. Qian Y, Bhowmik D, Kachru N, Hernandez RK, Cheng P, Liede A. Utilization patterns of bone-targeting agents among patients with multiple myeloma: analysis of real-world data. Blood. 2015; 126(23):4501.

13. Kim C, Hernandez RK, Cyprien L, Liede A, Cheng PC. Patterns of bisphosphonate treatment among patients with multiple myeloma treated at oncology clinics across the USA: observations from real-world data. Support Care Cancer. 2018; 26(8):2833–2841. PMID: 29516168.

14. Kim DS. Introduction: health of the health care system in Korea. Soc Work Public Health. 2010; 25(2):127–141. PMID: 20391257.

15. Aly A, Onukwugha E, Woods C, Mullins CD, Kwok Y, Qian Y, et al. Measurement of skeletal related events in SEER-Medicare: a comparison of claims-based methods. BMC Med Res Methodol. 2015; 15(1):65. PMID: 26286392.

16. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373–383. PMID: 3558716.

17. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999; 18(6):695–706. PMID: 10204198.

18. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd, Khaltaev N. A reference standard for the description of osteoporosis. Bone. 2008; 42(3):467–475. PMID: 18180210.

19. Terpos E, Kanellias N, Moulopoulos LA, Christoulas D, Gavriatopoulou M, Migkou M, et al. Incidence of skeletal-related events at diagnosis and at the time of first relapse in 463 patients with multiple myeloma who received first line treatment in a single center. Clin Lymphoma Myeloma Leuk. 2019; 19(Suppl 1):S333.

20. Oster G, Lamerato L, Glass AG, Richert-Boe KE, Lopez A, Chung K, et al. Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer. 2013; 21(12):3279–3286. PMID: 23884473.

21. Hong S, Youk T, Lee SJ, Kim KM, Vajdic CM. Bone metastasis and skeletal-related events in patients with solid cancer: a Korean nationwide health insurance database study. PLoS One. 2020; 15(7):e0234927. PMID: 32678818.

22. Melton LJ 3rd, Kyle RA, Achenbach SJ, Oberg AL, Rajkumar SV. Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res. 2005; 20(3):487–493. PMID: 15746994.

23. Bergh C, Wennergren D, Möller M, Brisby H. Fracture incidence in adults in relation to age and gender: a study of 27,169 fractures in the Swedish Fracture Register in a well-defined catchment area. PLoS One. 2020; 15(12):e0244291. PMID: 33347485.

24. Ahn SH, Park SM, Park SY, Yoo JI, Jung HS, Nho JH, et al. Osteoporosis and osteoporotic fracture fact sheet in Korea. J Bone Metab. 2020; 27(4):281–290. PMID: 33317231.

25. Fu M, Guo J, Zhao Y, Zhang Y, Zhang Y, Wang Z, et al. Characteristics of fall-related fractures in older adults with cerebrovascular disease: a cross-sectional study. Clin Interv Aging. 2021; 16:1337–1346. PMID: 34285478.

26. Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest. 2003; 111(11):1771–1782. PMID: 12782679.

27. von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M, et al. Bortezomib inhibits human osteoclastogenesis. Leukemia. 2007; 21(9):2025–2034. PMID: 17581612.

28. Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia. 2008; 22(10):1925–1932. PMID: 18596740.

29. Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B. Bisphosphonates in multiple myeloma: an updated network meta-analysis. Cochrane Database Syst Rev. 2017; 12(12):CD003188. PMID: 29253322.