We utilized a national population-based database to describe the incidence and risk factors of SREs among patients with MM in South Korea. During the median follow-up period of around three years, 43.6% of patients experienced at least one SRE, and approximately 40% had four or more SREs. The SRE incidence of previous real-world data is approximately 32–58%8–10,18. Although direct comparison of our data with earlier studies is challenging due to changes in SRE definition, numerous biases, and variance in follow-up time, they are comparable.
According to population-based studies that analyzed the cumulative incidence of SRE in patients with solid cancer and metastases to bone, most patients who experienced SRE occurred within two years of follow-up19,20. The current study is similar to the previous research by Melton et al.21, SREs occurred most frequently at three months after follow-up and then steadily happened. This is due to the fact that one of the primary characteristics of multiple myeloma is osteolytic bone disease, which is diagnosed with SRE and continuing SRE risk thereafter. Similar to the previous study by Kim et al.10, pathologic fractures were the most common among SREs, followed by bone radiation.
According to the recent IMWG guidelines, zoledronic acid (regardless of the presence of myeloma-related bone disease on imaging) for patients with newly diagnosed or relapsed/refractory MM is recommended as the first option, and pamidronate is recommended as the second option11. In this study, approximately 80% of patients used BTA, and patients with previous SRE were statistically significantly more likely to use BTA than those without a history of SRE. Possible explanations include the limitations of the HIRA health insurance system, which covers pamidronate as the initial treatment option for patients with myeloma-related bone disease on imaging until December 2020. Denosumab considers for patients with renal impairment but is not currently reimbursed in Korea.
We notably identified that females aged 50 years or older, underlying cerebrovascular disease, first-line treatment for MM not containing bortezomib or lenalidomide, and having a history of SRE and/or BTA use were statistically significant risk factors of SREs. Kim et al. observed that the incidence of SREs was similar regardless of whether patients were treated with proteasome antagonists or not. In contrast, our study found that first-line treatment containing bortezomib or lenalidomide could minimize the risk of SRE. Bortezomib, a proteasome inhibitor that induces MM cell apoptosis, has been demonstrated to improve osteoblastic activity and suppress osteoclast via inhibiting NF- κB signaling22,23. Lenalidomide has also been shown to inhibit osteoclastogenesis24. These findings suggest that, like bortezomib, lenalidomide may have both anti-myeloma and bone-targeting effects.
This study has several limitations. First, erroneous coding could result in misclassification bias, especially in the absence of laboratory validation results in HIRA databases. Second, although an incident case was defined through several steps, prevalent cases may be included in this study. Lastly, we were unable to get specific MM data from the claims database, including the presence of myeloma-related bone disease on imaging, stage of disease, or line of treatment.
In conclusion, this large population-based study demonstrated that MM patients are at high risk for SREs. These findings will assist healthcare professionals in understanding the incidence and risk factors of SREs, hence contributing to the active management of the bone disease of MM.