Impact of continuous lenalidomide on second primary malignancies in patients with multiple myeloma

Abstract Background Approved in 2017, lenalidomide quickly became a cornerstone for maintenance therapy of multiple myeloma (MM). However, emerging data indicates a potential increased risk of second primary malignancies (SPMs) in MM patients receiving lenalidomide, particularly hematologic cancers. This study examines the risk of site-specific SPMs and associated demographic factors, and how they differ between patients treated before and after the adoption of lenalidomide as a maintenance therapy. Methods A retrospective cohort study was performed using data from the Surveillance, Epidemiology, and End Results (SEER-17) database. Patients with confirmed histopathologic diagnosis of plasma cell myeloma (ICD-O-3 9732) between 2000 and 2022, were included. While cases identified solely through death certificates or autopsies were excluded. Second primary malignancies (SPMs) were defined as cancers diagnosed more than 60 days after the initial multiple myeloma diagnosis, with latency defined as the interval between the diagnosis of multiple myeloma and the subsequent SPM. Standardized incidence ratios (SIRs) were calculated using SEER*Stat software, and individual patient data were analyzed with SPSS. Results A total of 92,891 patients were identified. SPMs were reported in 6,778 (7.3%) patients. Notably, the patients who were diagnosed before 2017 had a higher rate of SPM compared to those diagnosed after 2017 (9.0% vs 3.8%). MM patients were at a significantly higher risk of SPM compared to the general population (SIR 1.04, 95% CI 1.02-1.07). The risk was significantly greater irrespective of the year of diagnosis before 2017 (SIR 1.04, 95% CI 1.01-1.06) or after 2017 (SIR 1.07, 95% CI 1.01-1.14). Patients diagnosed before 2017 had a significantly lower risk of developing second primary malignancies (SPMs) involving all solid tumors compared with the general population (SIR 0.93; 95% CI, 0.90–0.96). In contrast, no significant difference was observed in those diagnosed after 2017 (SIR 1.02; 95% CI, 0.95–1.09). A similar pattern was seen for respiratory system tumors, with a significantly reduced risk before 2017 (SIR 0.85; 95% CI, 0.79–0.92) that was no longer evident after 2017 (SIR 0.89; 95% CI, 0.74–1.05). The risk of second primary malignancies (SPMs) was significantly lower for tumors of the female genital tract (SIR 0.83; 95% CI, 0.72–0.96) and male genital tract (SIR 0.80; 95% CI, 0.74–0.86) before 2017, but this reduction was not observed after 2017. In contrast, the risk of kidney and renal pelvis tumors was significantly elevated in patients diagnosed before 2017 (SIR 1.29; 95% CI, 1.13–1.46) but not afterwards (SIR 1.17; 95% CI, 0.86–1.56). Hodgkin lymphoma followed a similar trend, with a significantly increased risk before 2017 (SIR 2.25; 95% CI, 1.45–3.32) that was no longer statistically significant after 2017 (SIR 2.38; 95% CI, 0.77–5.55). In contrast, non-Hodgkin lymphoma demonstrated a significantly higher risk only in patients diagnosed after 2017 (SIR 1.36; 95% CI, 1.03–1.75), while the risk was not significant prior to 2017 (SIR 1.13; 95% CI, 0.99–1.28). Patients over 65 years consistently showed a higher risk of SPM (SIR 1.29, 95% CI 1.23–1.36). However, among those aged 65–75 years, the risk was significantly elevated only before 2017 (SIR 1.06, 95% CI 1.02–1.11). In contrast, patients older than 75 had a significantly lower risk before 2017 (SIR 0.91, 95% CI 0.87–0.95) but not afterward. Sex-specific patterns were also observed: males showed a significantly increased risk only after 2017 (SIR 1.12; 95% CI, 1.04–1.20), whereas females exhibited an elevated risk exclusively before 2017 (SIR 1.06; 95% CI, 1.02–1.11). Racial analysis revealed no significant difference among Caucasian patients, while African-American, Asian, and Pacific Islander patients consistently had higher SPM risks than the general population, regardless of diagnosis year. For American Indian or Alaskan Native individuals, the risk was significantly elevated only in those diagnosed before 2017 (SIR 1.86, 95% CI 1.29–2.61). Conclusion MM patients were at an elevated risk of SPM irrespective of year of diagnosis. This SEER database analysis suggests an increased risk of non-Hodgkin lymphomas, contributing to the growing body of evidence that second primary malignancies have become more frequent in this population compared with the general population since 2017.