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

INTRODUCTION

Multiple myeloma (MM) is a malignant plasma cell neoplasm characterized by clonal proliferation of malignant plasma cells in bone marrow, generation of monoclonal immunoglobulin, and end-organ damage, including hypercalcemia, renal insufficiency, anemia, and/or bone disease with lytic lesions. 1 Up to 80% of patients with MM have bone lesions. These conditions are commonly complicated by skeletal-related events (SREs), which include pathologic fracture, spinal cord compression, radiation to the bone, and bone surgery. 2 , 3 SREs are associated with a decline in quality of life, an increase in mortality, and high costs for healthcare resources. 4 , 5 , 6 , 7

Although the bone disease of MM is a critical problem, real-world data on SREs in MM patients are limited. A variety of factors, including differences in the definition of SREs, selection bias, recording bias, and discrepancies in the follow-up time, contribute to the inconsistent reporting of the incidence of SREs found in earlier data. According to the United Kingdom population-based dataset, 32% of myeloma patients diagnosed between 2004 and 2009 experienced at least one SRE. 8 An analysis of the United States retrospective cohort study found a 58% SREs rate among patients with MM diagnosed between 2005 and 2011. 9 In recent US population data, 34% of myeloma patients diagnosed between 2011 and 2016 experienced SREs. 10

The International Myeloma Working Group (IMWG) recommends initiating bone-targeting drugs, such as bisphosphonates or denosumab, in newly diagnosed and relapsed or refractory MM patients. 11 Little is known about the pattern of bone-targeting agent utilization among MM patients in actual clinical practice. Previous research has found that the use of bone-targeting agents in patients with MM was suboptimal compared to what is suggested by guidelines. 12 , 13 In Korea, intravenous bisphosphonates like pamidronate or zoledronic acid are approved as bone-targeting drugs for treating evident bone lesions in MM. Denosumab, another bone-targeting drugs, was not included in this study based on the Health Insurance Review and Assessment Service (HIRA) data since it is not covered by the National Health Insurance.

Using a national healthcare database, this study aimed to investigate the incidence and risk factors of SREs as well as the management of bisphosphonates among patients with MM in a real-world setting in South Korea.

METHODS

Data source

The HIRA is a government-affiliated organization that has received claims made by all medical institutions in Korea since 2000. 14 The databases contain patient demographic data, diagnoses, procedures, and prescriptions from the inpatient and outpatient care of over 50 million Koreans.

Study population

We identified patients diagnosed with MM (C90.0) between January 1, 2007 and December 31, 2018 who were at least 19 years old. Diagnoses were codified according to the International Classification of Disease-10 th Revision-Clinical Modification (ICD-10-CM). Patients with only plasma cell leukemia, extramedullary plasmacytoma, or solitary plasmacytoma diagnosis codes were excluded. For the washout period, we excluded patients whose MM diagnostic code was recorded before January 1, 2008, or after January 1, 2018. We also excluded patients with systemic light chain amyloidosis and those with cancers other than MM in the year prior to the MM diagnosis. Patients who had received anti-myeloma therapy and had at least one year of follow-up after MM diagnosis were included. A detailed patient enrollment flow is described in Supplementary Fig. 1 .

Definition of SREs

The primary objective was to analyze the occurrence of SREs. SREs were defined as spinal cord compression, pathologic fracture, radiation to bone, and surgery to bone. Person-years (PYs) were calculated by tracking patients from the index date until the occurrence of an SRE. We calculated the incidence of initial and multiple SREs for each patient, treating multiple SREs occurring within a 21-day period as a single event. 15 Prior SRE history and comorbidities were assessed using healthcare utilization data from the one-year period before the index date. In our study, ‘prior SREs’ refers to any SRE, including spinal cord compression, pathologic fractures, radiation to bone, or surgery to bone, that occurred within the 12 months before the MM diagnosis or within the first 60 days following the diagnosis. This time frame was chosen to assess the baseline skeletal health of patients and to evaluate the pre-existing burden of skeletal complications prior to initiating new therapeutic interventions. Additionally, all patients were monitored for at least one year to confirm the presence of SREs.

The secondary objective was to identify SRE-related risk factors. For this purpose, the Charlson Comorbidity Index was utilized as a covariate to evaluate these risk factors. 16 First-line chemotherapy regimens for MM were classified into two groups: those containing bortezomib or lenalidomide, and those not containing either of these drugs. Bisphosphonate therapy was defined as the intravenous infusion of pamidronate or zoledronic acid. The code lists for the covariates are shown in Supplementary Table 1 .

Statistical analysis

We computed the cumulative incidence of SRE in MM patients, assuming death to be a competing risk. 17 Incidence rates of SREs (per 100 PYs) were calculated for all person-time following cohort entry. Categorical data were presented as frequencies and analyzed using the χ 2 test. Continuous variables were compared using the Mann–Whitney U test. Multiple logistic regression analysis was performed using a forced entry method to examine the associations of the variables with the risk of bleeding events. The odds ratio (OR) and 95% confidence interval (CI) for each independent variable were calculated. A two-sided P value ≤ 0.05 was considered statistically significant. All statistical analyses were conducted using SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC, USA).

Ethics statement

This study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital. The need for informed consent from each patient was waived because the authors did not have access to identifiable information (IRB No: X-2105-684-903).

RESULTS

Baseline characteristics

During the 12-year study period, we identified 6,717 patients who developed symptomatic MM (2008–2017). The patients' clinical features are summarized in Table 1 . Of the patients, 52.0% were male, and 67.0% were aged 60 years or older. The most prevalent comorbidities among the patients were chronic pulmonary disease (38.8%), mild liver disease (33.8%), and diabetes without complications (27.9%). A prior SRE history was observed in 43.9% of patients at baseline. Bortezomib- or lenalidomide-containing chemotherapy was administered as their first-line treatment to 3,579 patients (53.3%).

Incidence of SREs

The median follow-up duration was 35.1 months (interquartile range [IQR], 20.8–58.2 months), starting from 60 days after the MM diagnosis. A total of 2,926 patients (43.6%) had at least one SRE. At one year and two years of follow-up, SREs occurred in 55.5% and 73.5% of patients, respectively. A substantial 20.0% of patients encounter pathologic fractures within the first year after follow-up. The median time to the first SRE was 9.6 months (IQR, 1.2–25.8 months). Patients with a prior SRE had a considerably shorter time to their first SRE compared to those without a prior SRE (3.0 months versus 19.8 months, P < 0.001). Of the patients with SRE, 556 (19.0%) had 2 SREs, 337 (11.5%) had 3 SREs, and 1,158 (39.6%) had ≥ 4 SREs ( Fig. 1 ).

Fig. 2 shows the cumulative incidence rates of any SREs and their subtypes. The incidence rate of total SREs peaked during the initial three months of follow-up and subsequently declined. This pattern was also observed for pathologic fractures ( Fig. 2C ) and surgeries ( Fig. 2E ) categorized as SREs. However, there was a considerable rise in the incidence rate of spinal cord compression ( Fig. 2B ) and radiation to bone ( Fig. 2D ) after 36 months of follow-up. Numbers for cumulative incidence rates are presented in Supplementary Table 2 . The incidence rate of any SRE was 33.6 per 100 PYs at one year of follow-up. The most common type of SRE was pathologic fracture, followed by radiation to bone, surgery to bone, and spinal cord compression. At 12 months, the proportions of patients with pathologic fracture, radiation to bone, surgery to bone, and spinal cord compression were 20.0%, 2.9%, 0.8%, and 0.4%, respectively. Patients with a prior SRE had a higher incidence rate of SREs compared to those without such a history. At the 12-month mark, the incidence rates were 46.4 per 100 PYs for the group with prior SRE and 12.9 per 100 PYs for the group without prior SRE ( P < 0.001), as detailed in Supplementary Table 3 .

Use of bisphosphonate

During the time of follow-up, 5,270 patients (78.5%) received a bisphosphonate. The median time from MM diagnosis to the first bisphosphonate treatment was 15 days (IQR, 0–58 days). Pamidronate was the predominant bisphosphonate (95.8% of patients received ≥ 1 administration). The rate of bisphosphonate treatment was statistically significantly higher in the group with prior SREs than in the group without prior SREs (88.9% vs. 70.4%, P < 0.001).

Risk factors for the occurrence of SREs

In univariate analysis, statistically significant risk factors included sex, age, congestive heart failure, cerebrovascular disease, mild liver disease, diabetes with complications, renal disease, prior SRE, first-line therapy, and bisphosphonate use ( Supplementary Table 4 ). According to the WHO definition of osteoporosis, approximately 6.3% of men over 50 and 21.2% of women within the same age range are globally affected by the disease. 18 Consequently, the risk of SREs varies with gender and age. Patients were categorized as follows: males under 50 years of age, males 50 years or older, females under 50 years of age, and females 50 years or older. Our analysis reveals that there is a statistically significant increased risk of SREs in women aged 50 and above when compared to men under 50 (OR 1.48, P < 0.001).

In a multiple logistic regression analysis, female (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). were identified to be significant risk factors for SREs.

In contrast to the expected protective effect of bisphosphonates on SREs, our analysis showed that the group not using bisphosphonates had a significantly lower risk of SREs compared to the group using them (OR, 0.48; P < 0.001), as detailed in Supplementary Table 4 . In the group with prior SREs, the rate of bisphosphonate treatment was markedly higher than in the group without prior SREs. Given the statistically significant correlation between prior SREs and bisphosphonate use, we created groups based on these two indicators for further analysis. In multiple logistic regression analysis, the risk of developing an SRE was significantly higher in the group with prior SREs and bisphosphonate use (OR, 5.79; P < 0.001), in the group with prior SREs without bisphosphonate use (OR, 4.79; P < 0.001), and in the group without prior SREs but with bisphosphonate use (OR, 1.74; P < 0.001) compared to the groups without prior SREs and without bisphosphonate use ( Table 2 ).

DISCUSSION

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 , 9 , 10 , 19 Although a direct comparison of our data with earlier studies is challenging due to changes in the definition of SREs, numerous biases, and variances in follow-up time, our results are still comparable in certain respects.

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-up. 20 , 21 The current study has findings similar to the previous research by Melton et al. 22 where SREs occurred most frequently at three months after follow-up and then continued to occur steadily. This pattern can be attributed to one of the primary characteristics of MM, which is osteolytic bone disease. Consequently, the majority of patients are initially diagnosed through SREs, and as the disease progresses, there is a continuous risk of SREs. In line with the study by Kim et al., 10 pathologic fractures were the most common SRE, followed by bone radiation.

According to the recent IMWG guidelines, zoledronic acid is recommended as the first option for patients with newly diagnosed MM, regardless of the presence of myeloma-related bone disease on imaging, and pamidronate is recommended as the second option. 11 In this study, 78.5% of the patients used bisphosphonates, predominantly pamidronate. The reason for the leading prescription of pamidronate, as the initial bone-targeting treatment for patients with myeloma-related bone disease on imaging, is that only pamidronate was refunded by national insurance until December 2020 in Korea. Denosumab is considered for patients with renal impairment, but it is not currently reimbursed in Korea.

We notably identified that being female, older age, having underlying cerebrovascular disease, and receiving first-line treatment for MM that does not contain bortezomib or lenalidomide were statistically significant risk factors for SREs. The reason age and gender are important factors in SRE is that osteoporosis/osteopenia and related fractures occur more frequently with increasing age, and they are more common in men than in women. 23 The previous study by Ahn et al. 24 demonstrated that among Korean adults aged ≥ 50 years, one in four had osteoporosis, with women being approximately five times more likely than men. Cerebrovascular disease was one of the key factors in the risk of SREs, which is due to patients with cerebrovascular diseases having a reduced ability to maintain balance, leading to a higher likelihood of falls. Additionally, bone loss following a stroke increases the probability of fractures after a fall. 25 Kim et al. 10 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 treatments 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 signaling. 26 , 27 Lenalidomide has also been shown to inhibit osteoclastogenesis. 28 These findings suggest that, like bortezomib, lenalidomide may have both anti-myeloma and bone-targeting effects.

In a network meta-analysis, bisphosphonates (zoledronic acid and pamidronate) were associated with a significant reduction in the incidence of SREs compared to controls (placebo or no treatment). 29 However, this study showed an inverse relationship between bisphosphonate use and SREs. There was a statistically significant correlation between prior SREs and bisphosphonate use, prompting us to categorize the analysis into four groups for a more detailed examination. We discovered that the group with prior SREs and bisphosphonate use demonstrated a statistically significant SRE risk, approximately six times higher than those without prior SREs and bisphosphonate use. Notably, the group without prior SREs and bisphosphonate use had the lowest risk of SREs. This reduced risk could be attributed to two factors: firstly, the absence of prior SREs inherently suggests a lower baseline risk, and secondly, since bisphosphonates are reimbursed for MM patients with confirmed osteolytic lesions in Korea, the lack of bisphosphonate use might indicate the absence of detectable bone lesions, thereby correlating with a decreased risk of SREs. Patients with a higher risk of SREs tended to be prescribed more bisphosphonate therapy, creating the impression that bisphosphonate therapy is associated with an increased risk of SREs. This observation can be explained by treatment-risk bias, where patients with higher baseline risk factors are more likely to receive intensive treatment than the treatment exacerbating the SRE risk. Therefore, interpreting these results necessitates caution, and further research using next-generation bone targeting agents and co-evaluation with tumor response is essential to supplement these findings.

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 of SRE was defined through several steps, prevalent cases may be included in this study. Thirdly, 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. Fourth, while we were able to determine whether bisphosphonate therapy was utilized, the HIRA database did not include detailed records on treatment adherence factors such as treatment intervals, dosages, and duration of therapy. This limitation restricts our ability to evaluate the full impact of bisphosphonate therapy on patient outcomes and may influence the interpretation of the therapy’s effectiveness. Fifth, body mass index is one of the risk factors for osteoporosis, but it was not possible to analyze it with HIRA data. Lastly, a significant limitation of our study is the absence of survival analysis to assess the impact of SREs on overall survival in MM patients. This analysis is crucial from a public health perspective as it could provide valuable insights into how SREs influence patient outcomes over time. Recognizing the importance of this aspect, we plan to conduct further research as additional data become available.

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 with bone-targeting agents.

Footnotes

Disclosure: The authors have no potential conflicts of interest to disclose.

Author Contributions: Conceptualization: Lee JY, Lee JH, Bang SM. Data curation: Seo J, Kang M, Jung EH, Kim SA, Suh KJ. Formal analysis: Lee JY, Lee JH, Bang SM. Methodology: Lee JY, Lee JH, Bang SM. Validation: Kim JW, Kim SH, Lee JO, Kim JW. Writing - original draft: Lee JY. Writing - review & editing: Kim YJ, Lee KW, Kim JH, Lee JS.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

The code lists

Supplementary Table 2

The incidence rate of SREs

Supplementary Table 3

The incidence rate of SREs according to the baseline history of SRE

Supplementary Table 4

Univariate analysis of risk factors for SREs

Supplementary Fig. 1

Study population enrollment flow.

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Associated Data

Supplementary Materials

Supplementary Table 1

The code lists

Supplementary Table 2

The incidence rate of SREs

Supplementary Table 3

The incidence rate of SREs according to the baseline history of SRE

Supplementary Table 4

Univariate analysis of risk factors for SREs

Supplementary Fig. 1

Study population enrollment flow.