Background Multiple myeloma (MM) is the second-most common hematologic cancer in the United States. Novel agents have extended median survival beyond 6 years but have simultaneously lengthened the window for therapy-related secondary primary malignancies (SPMs) such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Two seminal SEER analyses covering the alkylator and early-IMiD eras documented a six- to seven-fold excess risk of AML with an absolute 10-year incidence near 1 %. Since 2015, anti-CD38 monoclonal antibodies (daratumumab, isatuximab) have become a backbone of modern regimens and appear not to raise overall SPM risk, although long-term data are sparse and mainly limited to cutaneous tumours . Whether widespread anti-CD38 use has modified the previously observed leukemogenic signal is unknown; our population-based study addresses this evidence gap by comparing SPM patterns across IMiD- and anti-CD38-dominant treatment eras.

Methods Surveillance, Epidemiology, and End Results (SEER) program data from the SEER -17 database for adults was compiled using SEER*Stat version 9.0.41 to explore the development of secondary primary malignancy (SPM) among 3,641 individuals aged 18 or older with a primary diagnosis of multiple myeloma (MM) during two therapeutically distinct periods: the IMiD era (2006–2012) and the anti-CD38 era (2015–2021). Outcomes of interest included total number of SPM diagnoses, mortality, and acute myeloid leukemia (AML) development. Demographic characteristics including patient sex, race/ethnicity, and age at MM diagnosis were also explored. Frequencies and percentages were used to describe the characteristics of the study population, and chi-square tests were performed in SAS 9.4 to assess associations between therapeutic period and outcomes of interest.

Results Among 3,641 multiple-myeloma patients who developed at least one secondary primary malignancy (SPM) 2,147 were in the immunomodulatory-agent (IMiD) era and 1,494 were in the anti-CD38 era. men predominated by 61 percent. Most were non Hispanic White with 64% . The anti-CD38 cohort was older, with 45 percent aged ≥ 70 years versus 34 percent in the IMiD cohort. Most patients experienced a single SPM, and the proportion with two or more SPMs fell from 11.8 percent to 9.2 percent between eras (p = 0.008), while triple SPMs declined from 1.9 percent to 1.1 percent. Therapy-related acute myeloid leukaemia occurred in 89 patients (2.4 percent overall) with a nonsignificant absolute reduction from 2.8 percent to 2.0 percent (29 percent relative, p = 0.155).Across the full Multiple Myeloma population with at least 1 SPM, death during follow-up fell dramatically from 73.0 % in the IMiD era to 43.0 % in the anti-CD38 era (p < 0.001). This survival improvement, together with the older age profile, underscores the competing-risk context in which contemporary SPMs arise

Conclusions In this population-based analysis, the therapeutic shift from IMiD-centred care to anti-CD38-anchored regimens coincided with (i) a lower burden of multiple SPMs, (ii) a clinically meaningful—though statistically non-significant—29 % reduction in therapy-related AML incidence, and (iii) a striking improvement in overall MM survival. These data provide the first real-world signal that modern, less genotoxic anti-CD38 strategies may be mitigating leukemogenic risk. Ongoing surveillance and era-specific survivorship counselling remain essential as treatment landscapes continue to evolve.

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2025
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