Association between radiotherapy and overall survival or cancer-specific survival in patients with solitary plasmacytoma of bone at pre-B cell grade: a real-world study using the SEER database.

Background

Plasmacytoma, characterized by the clonal proliferation of malignant plasma cells, encompasses a spectrum of B-cell neoplasms. These disorders are defined by the production of monoclonal immunoglobulins and can manifest as solitary lesions, referred to as solitary plasmacytoma (SP), or as multiple lesions in the form of multiple myeloma (MM) [ 1 , 2 ]. Solitary plasmacytoma of bone (SPB) is characterized by a single lytic bone lesion caused by monoclonal plasma cell infiltration, with or without soft tissue extension, while extramedullary plasmacytoma (EMP) presents as a soft tissue mass that is not in contact with bone [ 3 – 5 ]. SPB accounts for approximately 3–7% of all plasma cell tumors and most commonly affects the vertebral column, followed by the pelvis, femur, humerus, and ribs, with skull involvement being rare [ 6 ]. The diagnosis of SPB requires confirmation of a solitary clonal plasma cell infiltration in the absence of other characteristics of MM [ 7 ], such as anemia, hypercalcemia, renal impairment, or multiple lytic bone lesions. In its early stages, SPB lacks specific symptoms, with pain being the most common presentation, followed by soft tissue swelling, pathological fractures, or neurological compression symptoms. Patients with SPB, especially those with an increased plasma cell count in the bone marrow (BM), face a higher risk of developing symptomatic MM. Approximately 50% of patients with SPB and 30% of patients with EMP progress to MM within 10 years of their initial diagnosis [ 8 – 10 ].

The treatment landscape for SPB has evolved over the years, with radiation therapy (RT) emerging as a cornerstone of management [ 11 ]. However, comparative analyses of overall survival (OS) and cancer-specific survival (CSS) in patients with SPB treated with RT within population-based cohorts remain limited in the literature [ 3 , 12 ].

We performed a retrospective cohort analysis using the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the effectiveness of RT on OS and CSS in patients with SPB at pre-B cell grade.

Materials and methods

Study population and data collection

All data for this study was obtained using SEER∗Stat software, version 8.4.3. The study utilized the Incidence - SEER Research Data, 17 Registries, Nov 2023 Sub (2000–2021) database. Patients with SPB (ICD-O-3 code 9731/3) between 2010 and 2017 were included. Patients with peripheral blood, BM, or other extramedullary organ involvement, as well as those with incomplete information, were excluded from this study. Clinical information included demographic data (sex, age at diagnosis, race, and marital status), tumor diagnosis (primary site, first malignant primary indicator, etc.), primary treatments (surgery, radiation, and chemotherapy), and prognostic information (survival months, cause of death (COD) to site recode, and SEER cause-specific death classification). OS is defined as the time from diagnosis to death or the last follow-up, regardless of the cause of death. CSS is defined as the time from diagnosis to death specifically due to myeloma, as determined using cause-of-death information provided by the SEER database. The flow diagram illustrating patient inclusion is shown in Fig. 1 .

Statistical analysis

We conducted a descriptive analysis of all study participants. Categorical variables are presented as proportions and percentages (%). Fisher’s exact test or the chi-square test was used to compare categorical variables between two groups. Survival curves were generated using Kaplan–Meier analysis, and the log-rank test was used to compare survival differences. Subgroup analyses were performed based on baseline characteristics to explore differences in the response to radiation therapy across various subgroups of patients. The Cox proportional hazards model was used to compare the HRs and 95% CIs for each subgroup. A forest plot was constructed to visually represent these comparisons.

To assess the robustness of our results, we performed sensitivity analyses, including crude analysis, multivariable analysis, and propensity score analysis, thereby reducing selection bias. Covariates were screened to identify potential confounders. A variable was considered a confounder if its inclusion in the model resulted in a change of more than 0.1 in the regression coefficient for radiotherapy or if it was significantly associated with survival ( p < 0.1). All statistical analyses were performed using the R statistical software package ( http://www.R-project.org , The R Foundation) and EmpowerStats ( http://www.empowerstats.com , X&Y Solutions, Inc., Boston, MA, USA). A two-sided significance level of 0.05 was applied to all statistical tests.

Results

Table 1 presents the descriptive characteristics of the 1,922 patients, comparing those who received RT with those who did not (non-RT). Of these, 1,417 (74%) patients received RT, while 505 (26%) patients underwent non-RT treatments. The table shows significant differences in age distribution, with a higher percentage of patients under 60 years in the RT group compared to the non-RT group. The percentage of patients who received chemotherapy was significantly higher in the non-RT group, while the percentage of patients who underwent surgery was lower in the non-RT group.

The survival analysis curves revealed that patients treated with RT exhibited significantly improved survival rates compared to those who did not receive RT. Figure 2 shows that the median OS was 118 months for patients treated with RT, compared to 50 months for those without RT ( p < 0.0001). The CSS rate for the RT group was significantly higher than that of the non-RT group ( p < 0.0001).

Subgroup analyses were conducted to evaluate whether the effect of RT on both OS and CSS is consistent across the 10 subgroups. As shown in Fig. 3 , statistically significant interactions in the treatment effect for both OS and CSS were observed in 4 subgroups: Year of diagnosis, first malignant primary indicator, total number of in situ/malignant tumors, and primary site ( p < 0.05). In addition, the effect of RT on OS and CSS were homogeneous within the chemotherapy and surgery subgroups ( p < 0.05).

As indicated in Table 2 , the crude analysis provided initial estimates of HR for OS and CSS. RT was associated with significantly improved OS (HR = 0.54, 95% CI: 0.47–0.62) and CSS (HR = 0.59, 95% CI: 0.49–0.70) compared to non-RT, indicating a beneficial effect of RT on survival. After adjusting for all covariates and confounders, the multivariable analysis further validated the significant benefit of RT on OS (HR = 0.64, 95% CI: 0.55–0.74) and CSS (HR = 0.68, 95% CI: 0.56–0.82). To account for potential confounding factors, we performed a propensity-score analysis. Two sets of propensity scores (PS0 and PS1) were calculated, with PS0 including all covariates and PS1 including only confounders, and the results remained consistent. The average treatment effect on the treated (ATT), average treatment effect on the control (ATC), and average treatment effect (ATE) were estimated using propensity score matching. Inverse probability of treatment weighting (IPTW) using PS0 and PS1 was also conducted to estimate the treatment effects. The ATT, ATC, and ATE from IPTW were consistent with the findings from propensity score matching, with all estimates demonstrating a significant benefit of RT on both OS and CSS.

As indicated in Supplementary Tables 1 , 2 , among the 1,922 patients included, 446 (23%) underwent surgery. The multivariate analyses indicated that surgery improved OS (HR = 0.71, 95% CI: 0.60–0.85, p = 0.0002) and CSS (HR = 0.83, 95% CI: 0.67–1.02, p = 0.0829) in patients with SPB, though the difference was not statistically significant in CSS. Furthermore, 411 (21%) patients received chemotherapy. Chemotherapy was associated with poor OS (HR = 1.22, 95% CI: 1.04–1.42, p = 0.0136) and CSS (HR = 1.54, 95% CI: 1.27–1.85, p < 0.0001) in the multivariate analyses.

Discussion

The body of literature on MM is extensive, with substantial research focused on its pathogenesis, epidemiology, and response to various treatments [ 13 – 17 ]. On the contrary, given the rarity of SPB, large-scale population studies are challenging to conduct. While studies have examined the impact of various treatment modalities on survival outcomes in SPB [ 6 , 12 ], a population-based comparison of OS and CSS specific to RT has not been extensively explored. The SEER database, a comprehensive resource encompassing cancer incidence and survival data from across the United States, offers a unique opportunity for such analysis. Our findings underscore the significant benefit of RT in improving both OS and CSS in patients with SPB. This observation aligns with previous studies that have established RT as a cornerstone of treatment for SPB [ 18 ]. Moreover, the International Lymphoma Radiation Oncology Group guidelines further emphasize the critical role of RT in treating plasmacytoma [ 9 ].

In our study, 505 (26%) patients did not receive RT, and several potential factors may explain the phenomena. Patients with severe cardiopulmonary insufficiency, hepatic or renal dysfunction, or hematologic disorders might not have been suitable candidates for RT owing to the added physiological stress it could impose. Additionally, patients in poor condition may have been unable to lie down on the irradiation couch. In some cases, tumor characteristics might have influenced the decision to use alternative treatments. For instance, if the tumor was particularly large or paraprotein levels were elevated, other treatment modalities might have been preferred. The availability of RT facilities and the patients’ preferences also played a role. In some regions, access to RT might have been limited, leading to the use of systemic therapy as an alternative. This may have contributed to a lack of awareness or oversight of RT as the recommended treatment option. Furthermore, non-radiation oncology specialists might harbor reservations towards RT, potentially influencing treatment decisions. Variability in clinical practice may have also occurred, with some hematologists choosing systemic therapy without consulting a myeloma-tumor board that includes radiation oncologists, a practice standard in many regions.

Chemotherapy is often administered to patients who are not candidates for RT or who are at higher risk of progression to MM. These patients may have a poorer prognosis regardless of the treatment modality [ 19 , 20 ]. However, the lack of detailed information on chemotherapy regimens in our data prevents a comparison of the impact of different chemotherapy protocols on survival. The retrospective nature of the analysis and the potential for selection bias based on the limitations of the SEER database, may have introduced bias into the final outcomes. A retrospective study involving 52 patients with SPB who received combined chemoradiotherapy or RT alone was conducted across four French centers. The chemotherapeutic regimens varied and included melphalan, vincristine, and thalidomide. Progression-free survival (PFS) and 5-year OS did not differ between the two groups [ 21 ]. The role of adjuvant systemic therapy remains to be defined, although RT is considered the standard of care for SPB and EMP. With the advent of new immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies for the treatment of MM, there is considerable interest in whether these agents could be incorporated into the treatment of SPB [ 22 – 23 ]. Currently, the potential role of lenalidomide in combination with dexamethasone after RT for improving PFS in patients with high-risk SPB is actively being investigated in a Phase 3 trial in the UK [ 24 ]. For patients with unfavorable prognostic factors, such as tumor size and the presence of clonal bone marrow plasma cells, further research is needed to determine the optimal treatment strategy. Furthermore, while our analysis suggests that surgery may have a positive impact on OS for patients with SPB, the result should be interpreted with caution due to potential selection bias. Detailed clinical information such as performance status, which is not available in the SEER database, is critical in determining the appropriateness and effectiveness of surgical intervention. Future studies with more comprehensive clinical data are needed to better understand the role of different treatment in the outcome of SPB.

Marital status at the time of diagnosis included married, divorced, widowed, and single (separated, unmarried, etc.). Compared to married patients, those in other marital status categories had worse survival outcomes, with the difference being statistically significant ( p < 0.05). This difference may be associated with social, psychological, and other factors. Evidence suggests that married patients with cancer are diagnosed earlier than unmarried patients, which increases the likelihood of receiving early treatment. In addition, having a partner offers both psychological and life support, facilitates active management and treatment of the disease, and may contribute to improved prognosis [ 25 – 27 ]. Figure 3 highlights the importance of individualizing treatment strategies based on specific patient characteristics, as patients with differing clinical characteristics may respond uniquely to the same treatment regimen.

While our study provides valuable insights, it is not without limitations. First, the retrospective nature of the analysis and the potential for selection bias present challenges, despite using regression models, subgroup analyses, and sensitivity analyses to control for confounding factors. Residual confounding effects from unmeasured or unknown variables may persist. Second, the SEER database lacks detailed information regarding the use of radiation, novel agents, or systemic chemotherapy. Specifically, key data concerning radiation, encompassing dose, frequency, technique, target volume range, and whether patients both initiated and completed radiation, are missing. Third, clinical laboratory, imaging, and pathological information—such as the extent of bone marrow involvement, M protein in the blood or urine, performance status, quality of life, and secondary parameters such as pain/pain relief or local tumor control—are unavailable. These gaps preclude a comprehensive analysis of survival outcomes. SPB is at risk of progressing to MM; however, due to the limitations in the data sources, it is challenging to perform further analysis on the incidence of SPB progression to MM and the median PFS following diagnosis. Randomized controlled trials and longitudinal studies are needed to develop personalized treatment protocols that optimize outcomes for patients with SPB in the future.

In conclusion, we investigated the effectiveness of RT on OS and CSS in patients with SPB at pre-B cell grade by performing analysis within a large, nationally representative observational epidemiological cohort. Our findings reaffirm the significant benefit of RT in improving both OS and CSS in patients with SPB compared to non-RT, which is consistent with current guidelines and previous studies that have established RT as a cornerstone in the management of SPB. The findings of this study may serve as the foundation for prospective, highly informative, and impactful clinical trials.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1: Supplementary tables

Acknowledgements

The authors acknowledge the efforts of the Surveillance Research Program in establishing and maintaining the SEER database. The authors express their gratitude to Shengli Li, a statistician from the Clinical Research Institute at The Affiliated Hospital of Xuzhou Medical University, for his valuable and insightful suggestions regarding the data, figures, and tables. We also thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Author contributions

Qiong Wu is responsible for writing, collecting data, analysis, interpretation, revision, designed the tables and figures and final approval of present article. Jinge Xu is responsible for analysis and revision. All authors reviewed and approved the final manuscript.

Funding

This study was funded by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. SJCX24_1532), the Open Project of Jiangsu Key Laboratory of Bone Marrow Stem Cell (Grant No. XZSYSKF2020037), and the General Project of Health Commission of Jiangsu Province (Grant No. H2023109).

Data availability

All analyzed data are publicly available at the SEER website ( http://www.seer.cancer.gov ), and should be requested under the approval of the SEER Program administration.

Declarations

Ethics approval and consent to participate

This study based on the publicly available SEER database, and therefore did not require institutional review board approval.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Supplementary Materials

Supplementary Material 1: Supplementary tables

Data Availability Statement

All analyzed data are publicly available at the SEER website ( http://www.seer.cancer.gov ), and should be requested under the approval of the SEER Program administration.