Comparative Analysis of Primary and Second Primary Multiple Myeloma: A Propensity Score-Matched Study

Abstract

Background:

With the increasing number of cancer survivors, second primary malignancies (SPMs) are attracting clinical interest. Although SPMs following multiple myeloma (MM) have been studied, data on second primary multiple myeloma (SPMM) remain limited. This study aimed to compare the clinical characteristics and outcomes of SPMM with those of primary MM through a retrospective analysis.

Methods:

We retrospectively reviewed 183 patients with primary MM and 12 patients with SPMM treated at a single center between 2003 and 2022. To reduce selection bias, propensity score matching (1:3) was performed based on age, sex, year of MM diagnosis, and International Staging System stage. Survival outcomes were assessed using Kaplan–Meier analysis and Cox proportional hazards models.

Results:

After matching, 48 patients (36 with primary MM and 12 with SPMM) were included in the final analysis. At the time of MM diagnosis, 83.3% of patients with SPMM had achieved complete remission of their primary malignancy. All but one received standard MM treatment. The median overall survival (OS) was 45.1 months for the primary MM group and 41.5 months for the SPMM group. There was no statistically significant difference in OS between the groups (hazard ratio: 0.72; 95% confidence interval: 0.33-1.56).

Conclusions:

Patients with SPMM, most of whom had well-controlled primary cancers, received active treatment and demonstrated clinical outcomes not significantly different from those with primary MM. These findings support the use of aggressive treatment strategies for SPMM. Larger prospective studies are warranted to establish optimal treatment strategies.

Introduction

Recent advancements in cancer treatments have significantly improved survival rates across a broad spectrum of malignancies. As long-term survival becomes more common, attention has increasingly shifted toward the late effects of cancer treatment, particularly the development of second primary malignancies (SPMs). SPMs are defined as distinct neoplasms that occur either synchronously or metachronously in individuals who have survived a first primary malignancy. ¹ The reported incidence of SPMs ranges from 7.04% to approximately 20%, with prior exposure to chemotherapy or radiotherapy, as well as genetic predisposition, recognized as major contributing factors.^2-5

Multiple myeloma (MM) is a malignant plasma cell disorder, with approximately 160,000 new cases and 106,000 deaths estimated annually, worldwide. ⁶ According to the 2021 Korean cancer statistics, 2018 individuals were newly diagnosed with MM. ⁷ MM is a multifactorial condition influenced by factors such as advanced age, male sex, African American ethnicity, and occupational and genetic predispositions.^8,9

The development of SPMs in MM survivors has been increasingly recognized. Identified risk factors include patient-related characteristics (for example, older age, smoking history, obesity, male sex, and ethnicity), disease-related mechanisms (notably clonal hematopoiesis), and treatment-related exposures (e.g., alkylating agents, radiation therapy, lenalidomide, and bortezomib).^10,11 Recent studies have reported the incidence, risk stratification, and outcomes of SPMs in MM survivors, underscoring the need for ongoing surveillance.^12-14 However, only a limited number of retrospective studies have examined second primary multiple myeloma (SPMM) that developed after other primary cancers.^15,16 This study aimed to investigate the clinical characteristics and outcomes of patients with SPMM in comparison to those with primary MM.

Methods

Study design and patient selection

We conducted a retrospective analysis of patients diagnosed and treated for MM at Korea Cancer Center Hospital between January 2003 and December 2022. Eligible cases were selected consecutively during the study period based on predefined inclusion and exclusion criteria. Primary MM was defined as a pathologically confirmed diagnosis of MM. SPMM was defined as MM diagnosed either synchronously or metachronously in individuals with a history of a prior primary malignancy. Patients without pathological confirmation or those diagnosed without a treatment plan were excluded. Patients with missing data for key variables were excluded from the corresponding analyses. In total, 183 patients with primary MM and 12 patients with SPMM were included in the study. This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies. A completed STROBE checklist is provided as Supplementary File 1. ¹⁷

Propensity score matching and statistical analysis

To reduce potential confounding and improve comparability between the 2 groups, propensity score matching was performed using a 1:3 nearest-neighbor algorithm without replacement and with a caliper width of 0.1. The propensity scores were calculated based on sex, age, year of MM diagnosis, and International Staging System (ISS) stage. Balance between groups before and after matching was assessed using absolute standardized mean differences (SMDs), with values below 0.1 indicating acceptable balance. ¹⁸ Categorical variables were presented as frequencies and percentages, while continuous variables were reported as medians with ranges. Group comparisons were performed using Fisher’s exact or chi-square tests, as appropriate, for categorical variables. Survival outcomes were evaluated using Kaplan–Meier curves, and comparisons between groups were made using the Cox proportional hazards model. All statistical analyses were conducted using the R software version 4.1.2 (R Core Team).

Outcome measures

The primary objective of this study was to compare the clinical characteristics and survival outcomes between patients with primary MM and those with SPMM. Treatment response was assessed according to the criteria established by the International Myeloma Working Group.^19,20 Progression-free survival (PFS) was defined as the time from the diagnosis of MM to either disease progression or death from any cause, whichever occurred first. Overall survival (OS) was defined as the time from MM diagnosis to death from any cause. Survival outcomes were compared between the propensity score–matched primary MM and SPMM groups using Cox proportional hazards models, with the SPMM group designated as the reference category for hazard ratio estimation. The data cutoff date for the analysis was November 30, 2024.

Results

Study cohort and baseline characteristics

Between January 2003 and December 2022, 183 patients were diagnosed with primary MM and received treatment planning. Twelve patients developed SPMM following a prior malignancy. After 1:3 propensity score matching, 36 patients with primary MM were selected, resulting in a final cohort of 48 patients for analysis (Figure 1). Baseline characteristics of the matched cohorts are presented in Table 1. The median age at diagnosis was 72 years (range: 53-85), with 22 male patients (45.8%) and 26 female patients (54.2%). According to the ISS, 16 patients (33.0%) were classified as stage I, 21 (43.8%) as stage II, and 11 (22.9%) as stage III. The distribution by year of MM diagnosis was as follows: 14 patients (29.1%) were diagnosed between 2003 and 2010, 7 (14.6%) between 2011 and 2015, 17 (35.4%) between 2016 and 2020, and 10 (20.8%) between 2021 and 2022.

Figure 1.

Diagram of derivation of the study population. MM, multiple myeloma; SPMM, second primary multiple myeloma.

Table 1.

Baseline characteristics of the propensity score-matched cohorts.

Variables	Primary MM	SPMM	Total	SMD
Patient number	36	12	48
Sex, n (%)
Male	16 (44.4%)	6 (50.0%)	22 (45.8%)	0.11
Female	20 (55.6%)	6 (50.0%)	26 (54.2%)	0.11
Median age at the time of MM diagnosis, years (range)	72 (53-84)	73 (54-85)	72 (53-85)	0.02
Time of MM diagnosis, n (%)				0.03
2003-2010	11 (30.5%)	3 (25.0%)	14 (29.1%)
2011-2015	5 (13.9%)	2 (16.6%)	7 (14.6%)
2016-2021	15 (41.7%)	6 (50.0%)	21 (43.8%)
2022	5 (13.9%)	1 (8.3%)	6 (12.5%)
ISS Stage, n (%)
I	12 (33.3%)	4 (33.3%)	16 (33.3%)	0
II	16 (44.4%)	5 (41.6%)	21 (43.8%)	0.05
III	8 (22.2%)	3 (25.0%)	11 (22.9%)	0.06

Abbreviations: ISS, International staging system stage; MM, multiple myeloma; SPMM, second primary multiple myeloma; SMD, standardized mean difference.

MM characteristics and treatment

The characteristics and treatment outcomes of MM are summarized in Table 2. Among the 48 patients, the most common MM subtype was IgG (n = 28, 58.3%), followed by IgA (n = 11, 22.9%), and free light chain (n = 8, 16.7%). In the SPMM group, all but one patient had the IgG subtype (P = 0.052). Regarding cytogenetic abnormalities, 8 patients (32.0%) in the primary MM group exhibited trisomy 1q. In the SPMM group, 2 patients had t(4;14), and 2 others had trisomy 1q (33.3%). Hemoglobin levels <10 g/dL were observed in 17 patients (47.2%) in the primary MM group and 8 patients (66.7%) in the SPMM group (P = .404). Hypercalcemia, defined as serum calcium >11 mg/dL, was recorded in 2 patients (5.6%) in the primary MM group and in none of the SPMM group (P = 1.000). Elevated creatinine levels (>2.0 mg/dL) were found in 3 patients each in the the primary MM (8.3%) and SPMM (25.0%) groups (P = .313).

Table 2.

Clinical and laboratory characteristics at the time of multiple myeloma diagnosis.

Variables	Total (n = 48)	Primary MM (n = 36)	SPMM (n = 12)	P value
MM Subtype by IFE, n (%)				.052
IgG	28 (58.3%)	17 (47.2%)	11 (91.7%)
IgA	11 (22.9%)	11 (30.5%)	0 (0.0%)
Free light chain	8 (16.7%)	7 (19.4%)	1 (8.3%)
N/A	1 (2.2%)	1 (2.8%)	0 (0.0%)
Cytogenetic features by FISH	n = 31	n = 25	n = 6	.030
Del(17p)	0 (0.0%)	0 (0.0%)	0 (0.0%)
t(4;14)	3 (9.7%)	1 (4.0%)	2 (33.3%)
t(11;14)	2 (6.5%)	2 (8.0%)	0 (0.0%)
Trisomy 1q	10 (32.2%)	8 (32.0%)	2 (33.3%)
Others	4 (12.9%)	4 (16.0%)	0 (0.0%)
Negative	12 (38.7%)	10 (40.0%)	2 (33.3%)
N/A	17 (35.4%)	11 (30.6%)	6 (50.0%)
Hemoglobin (g/dL), <10	25 (52.1%)	17 (47.2%)	8 (66.7%)	.404
Calcium (mg/dL), >11	2 (4.2%)	2 (5.6%)	0 (0.0%)	1.000
Creatinine (mg/dL), >2.0	6 (12.5%)	3 (8.3%)	3 (25.0%)	.313
Albumin (g/dL), <3.5	20 (41.6%)	11 (30.6%)	9 (75.0%)	.018
Beta-2 MG (ug/mL), >3.5	22 (45.8%)	17 (47.2%)	5 (41.7%)	1.000
MM treatment, n (%)	n = 46	n = 35	n = 11
Proteasome inhibitor	25 (54.3%)	20 (57.1%)	6 (54.5%)	1.000
Immunomodulatory agent	24 (52.1%)	21 (60.0%)	3 (27.3%)	.096
Chemotherapy	28 (60.8%)	19 (52.8%)	9 (81.8%)	.310
ASCT	5 (10.8%)	4 (11.4%)	1 (9.1%)	1.000
Untreated (N/A)	2 (4.2%)	1 (2.8%)	1 (8.3%)
Best response to first-line treatment in MM	n = 46	n = 35	n = 11	.268
CR	8 (17.3%)	7 (20.0%)	1 (9.1%)
VGPR	1 (2.2%)	0 (0.0%)	1 (9.1%)
PR	26 (56.5%)	20 (57.1%)	6 (54.5%)
SD	6 (13.0%)	5 (14.3%)	1 (9.1%)
PD	4 (8.7%)	3 (8.6%)	1 (9.1%)
N/A	1 (2.2%)	0 (0.0%)	1 (9.1%)
Untreated (N/A)	2 (4.2%)	1 (2.8%)	1 (8.3%)

Abbreviations: ASCT, autologous stem cell transplantation; Beta-2 MG, Beta-2 microglobulin; CR, complete response; FISH, fluorescence in situ hybridization; IFE, immuno fixation electrophoresis; MM, multiple myeloma; N/A, not available; PD, progressive disease; PR, partial response; SD, stable disease; SPMM, second primary multiple myeloma; VGPR, very good partial response.

Patients with missing data were not included in statistical comparisons.

Treatment was administered to 35 patients (97.2%) in the primary MM group, and 11 (91.6%) in the SPMM group, with one patient from each group not undergoing treatment. Proteasome inhibitors were administered to 20 patients (57.1%) in the primary MM group and 6 (54.5%) in the SPMM group (P = 1.000). Immunomodulatory agents were administered to 21 patients (60.0%) in the primary MM group and 3 (27.2%) in the SPMM group (P = .096). Chemotherapy was administered to 19 patients (52.8%) in the primary MM group and 9 (81.8%) in the SPMM group (P = .310). Autologous stem cell transplantation (ASCT) was performed in 4 patients (11.1%) in the primary MM group and 1 (8.3%) in the SPMM group (P = 1.000).

The best response to first-line therapy was partial response (PR), achieved by 20 patients (57.1%) with primary MM and 6 (54.5%) with SPMM. Complete response (CR) was observed in 7 patients (20.0%) in the primary MM group and 1 (9.1%) in the SPMM group. Very good partial response (VGPR) was observed in one patient (9.1%) with SPMM but none with primary MM. Stable disease (SD) was recorded in 5 patients (14.3%) in the primary MM group and 1 (9.1%) in the SPMM group. Progressive disease (PD) was observed in 3 patients (8.6%) in the primary MM group and 1 (9.1%) in the SPMM group.

Clinical characteristics and treatment of patients with SPMM

Among the 12 patients with SPMM, the prior primary malignancies included cervical cancer (n = 3, 25.0%), breast cancer (n = 2, 16.7%), colorectal cancer (n = 2, 16.7%), non-small cell lung cancer (NSCLC) (n = 1, 8.3%), myxofibrosarcoma (n = 1, 8.3%), prostate cancer (n = 1, 8.3%), gastric cancer (n = 1, 8.3%), gastrointestinal stromal tumor (GIST) (n = 1, 8.3%), and hypopharyngeal cancer (n = 1, 8.3%) (Table 3). One patient (8.3%) had a history of both colon and hypopharyngeal cancers.

Table 3.

Clinical characteristics and treatment for patients with second primary multiple myeloma.

Serial number	Age at diagnosis of primary cancer, years	Primary cancer	Age at diagnosis of MM	Chemotherapy for the treatment of primary cancer	Radiotherapy for the treatment of primary cancer	Interval between primary cancer and MM diagnosis (months)	Primary cancer status at the time of MM diagnosis	ISS stage	Treatment status of MM	Year of diagnosis for MM,	Initial treatment regimen for MM	ASCT status	Current status	OS after MM diagnosis
1	76	NSCLC	76	Yes	No	5.1	Presence	1	No	2021	No	0	Dead	12.2
2	68	Myxofibrosarcoma	69	No	No	18.6	Presence	2	Yes	2021	Rd	0	Alive	36.6
3	53	Breast cancer	54	Yes	Yes	8.3	CR	1	Yes	2019	VTD	1	Alive	66.0
4	66	Cervix cancer	70	No	No	45.1	CR	1	Yes	2020	VMP	0	Dead	13.9
5	74	Prostate cancer	77	No	No	33.8	CR	3	Yes	2016	MPT	0	Dead	0.3
6	67	Cervix cancer	75	Yes	yes	90.2	CR	2	Yes	2018	VMP	0	Dead	42.6
7	63	Gastric cancer	66	No	No	47.5	CR	2	Yes	2015	VMP	0	Dead	41.5
8	68	Rectal cancer	71	Yes	Yes	39.0	CR	1	Yes	2010	MP	0	Dead	47.2
9	77	GIST	85	No	No	88.3	CR	2	Yes	2013	VMP	0	Dead	62.4
10	61	Colon cancer Hypopharynx cancer	80	No	No	233.8	CR	3	Yes	2022	VMP	0	Alive	29.5
11	71	Breast cancer	75	Yes	Yes	54.1	CR	3	Yes	2008	MP	0	Dead	17.5
12	64	Cervix cancer	71	No	No	91.0	CR	2	Yes	2005	MP	0	Dead	18.1

Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; GIST, Gastro Intestinal stromal tumor; ISS, International staging system stage; MM, multiple myeloma; MP, melphalan-prednisone; MPT, melphalan-prednisone-thalidomide; NSCLC, non-small cell lung cancer; OS, overall survival; RD, lenalidomide-dexamethasone; VMP, bortezomib-melphalan-prednisone; VTD, bortezomib-thalidomide-dexamethasone.

The median age at diagnosis of the primary cancer was 67.5 years (range: 53-77 years). Among the 12 patients, 5 (41.7%) received chemotherapy, and 4 (33.3%) received radiotherapy for their primary malignancy. The median interval between diagnosis of the primary cancer and SPMM was 46.3 months (range: 5.1-233.8 months). At the time of MM diagnosis, 10 patients (83.3%) had achieved CR of their primary cancer, while 2 patients (16.7%) had persistent disease. Multiple myeloma-specific treatment was administered to 11 patients (91.7%), while 1 patient (8.3%) did not receive treatment owing to poor performance status and ongoing disease activity. One patient (8.3%) underwent ASCT.

Treatment outcome

With a median follow-up duration of 77.3 months (95% confidence interval [CI]: 57.3-97.4), Figure 2 presents the median PFS and OS curves. The median PFS following first-line chemotherapy was 10.6 months (95% CI: 3.4-17.8) in the primary MM group and 13.4 months (95% CI: 2.8-24.0) in the SPMM group. The median OS was 45.1 months (95% CI: 24.8-65.3) in the primary MM group and 41.5 months (95% CI: 9.7-73.3) in the SPMM group. However, survival analyses showed no statistically significant differences in either PFS (hazard ratio [HR]: 0.75; 95% CI: 0.37-1.51) or OS (HR: 0.72; 95% CI: 0.33-1.56) between the 2 groups.

Figure 2.

(A) PFS of primary MM and SPMM group following first-line treatment. (B) OS of primary MM and SPMM group. HR, hazard ratio; m, months; MM, multiple myeloma; SPMM, second primary multiple myeloma; OS, overall survival; PFS, progression-free survival.

Discussion

Second primary multiple myeloma remains a relatively underexplored clinical entity, with most existing data derived from small, retrospective studies. In this study, 12 patients were diagnosed with SPMM over the study period. Notably, 10 of these patients had achieved CR of their primary malignancy at the time of SPMM diagnosis. All but one patient received active treatment (chemotherapy) for MM, indicating that SPMM was managed with therapeutic intent. Importantly, no statistically significant difference in OS was observed between patients with primary MM and SPMM, suggesting that SPMM may share similar clinical characteristics and prognosis with primary MM. However, this finding should be interpreted cautiously, as the small sample size may have limited the ability to detect statistically significant differences.

Previous studies have primarily focused on SPMs arising after treatment for MM, identifying several associated risk factors such as age, smoking, and clonal hematopoiesis of indeterminate potential (CHIP), as well as specific therapeutic agents. ¹¹ However, risk factors specific to SPMM have not yet been clearly established. With regard to prognosis, SPMs following MM treatment have been associated with poor outcomes, with reported median OS ranging from 8.5 months to 1.1 years.^21,22 In particular, patients with secondary myeloid neoplasms, such as acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), showed extremely poor survival, with a median OS of approximately 2.4 months. ²²

In contrast, only a few studies have investigated SPMM, which appears to be associated with relatively longer OS compared with other SPMs. One previous study found that most primary malignancies occurred before MM diagnosis and were predominantly early-stage neoplasms with favorable outcomes. In addition, the median OS differed significantly based on the presence of a prior malignancy (36.5 vs 21.4 months). ¹⁵ Another study also reported a notable difference in OS between primary MM and SPMM (46.5 months vs 24.5 months). ¹⁶ Our findings, showing a median OS of 45.1 months in the primary MM group and 41.5 months in the SPMM group, did not show a statistically significant difference. This finding aligns with prior studies showing that SPMM has longer OS than other SPMs. However, our observation of no significant difference in OS between SPMM and primary MM contrasts with previous studies. This discrepancy may be attributed to our use of propensity score matching to adjust for confounding variables such as age, sex, ISS stage, and evolving national insurance policies.

In our study, most patients had achieved CR of their primary malignancy at the time of SPMM diagnosis, and all but one received active treatment for SPMM. Although guidelines provide specific recommendations, such as CPX-351 for therapy-related AML, no standardized treatment protocols have been established for SPMM. ²³ Similar to other SPMs, SPMM is generally managed according to the treatment regimens established for the corresponding primary cancer. Consistent with this approach, most patients in our cohort were treated with conventional frontline MM therapies.

Currently, quadruplet regimens that include monoclonal antibodies are recommended for newly diagnosed MM. ²⁴ While direct evidence supporting their use in SPMM is limited, it is plausible that regimens proven effective in primary MM may provide similar clinical benefits in SPMM. Therefore, such regimens may be considered a viable option for patients with SPMM. However, as with primary MM, real-world treatment decisions for SPMM must consider the availability of therapeutic agents and health care system constraints, particularly in resource-limited settings.

Our study has certain limitations. First, it is a retrospective analysis with a relatively small cohort. Second, the limited sample size precluded the use of multivariate analysis to identify independent risk factors for SPMM. Moreover, no formal sample size calculation was performed prior to the analysis, which may have further limited the statistical power to detect significant differences between groups. Third, owing to the unavailability of fluorescence in situ hybridization and complete cytogenetic data in many cases, risk stratification was constrained. A fourth limitation of our study is the absence of a universally accepted definition of SPMM. We adopted a definition based on previously reported criteria for second primary cancers. However, this may introduce variability in interpretation and limit comparability across studies. Finally, although propensity score matching was performed to account for changes in Korea’s national insurance policy over the 20-year study period, it was not possible to fully adjust for all relevant variables, such as the approval of novel therapeutic agents for reimbursement and changes in age eligibility criteria for ASCT. These factors may have contributed to differences in OS.

Despite these limitations, to our knowledge, this is the first study in Korea to compare the clinical characteristics of SPMM with those of primary MM. Another important consideration is the small sample size in both our study and previous studies, which may have limited the ability to detect statistically significant differences. Although propensity score matching was employed to minimize the effects of confounding variables, residual imbalances, such as differences in cytogenetic abnormalities and hypoalbuminemia (Table 2), may have influenced PFS and OS. Larger, prospective studies are needed to further characterize SPMM.

Conclusion

Our findings suggest that actively treated patients with SPMM did not show significantly different clinical outcomes compared with those with primary MM. The remission status of their primary malignancies may have enabled this therapeutic approach. As treatment strategies for MM develop, active management of SPMM may be appropriate in selected cases. Further prospective studies are needed to better define optimal treatment strategies.