The prolonged survival of patients with Waldenström Macroglobulinemia (WM), together with the increasing use of chemoimmunotherapy and novel agents, has raised concern about long-term complications, including the development of secondary primary malignancies (SPMs). However, real-world data on the incidence and characteristics of SPMs in WM are scarce.The aim of our study was to evaluate, in a real-life multicenter cohort, the incidence, type, and risk factors associated with SPMs in WM patients treated with various therapeutic strategies, including bendamustine-rituximab (BR), dexamethasone-rituximab-cyclophosphamide (DRC), other chemoimmunotherapy (CIT) schemes including fludarabine or chlorambucil or cladribine, BTK inhibitors (BTKis), and rituximab or steroids.This retrospective analysis included 489 patients diagnosed with WM and treated across 14 Italian hematology centers from 2008 to 2024. A total of 57 SPMs were identified with a median time to diagnosis of 34.1 months (range 2.3–192 months) from the beginning of the treatment. Hematologic SPMs represented 22.8% (13/57) of all SPMs.Analyzing the entire cohort, 12.7% (21/165) of patients treated with BR developed a SPM, compared to 10.5% (16/152) with DRC, 21% (13/62) with other CIT and 5.9% (1/17) with BTKi alone. Similarly, among those treated with DRC alone (n=73), 10 SPMs occurred (13.7%) and the addition of BTKi as second line was not associated with an increased risk (4/53, 7.5%). A higher incidence was observed in patients treated with other CIT scheme as first line: 6 SPMs were registered among 22 patients (27.3%). Patients who received BTKi alone (n=16) had the lowest rate of SPMs (1/16, 6.2%).In patients receiving BR without further treatment, the median time to SPM was 30.3 months (range 3.1–89.2), while for those receiving DRC it was 21.0 months (range 2.3–137.8) and those receiving other CIT it was 34.4 months (range 13.3-186.6). Notably, patients receiving BR followed by BTKi had a median time to SPM of 42.6 months, and those receiving DRC followed by BTKi had a longer latency (61.5 months).Although BR and DRC had similar overall SPM rates, other CIT regimens were associated with a higher risk, often appearing late. Conversely, BTKis, both in untreated patients and in sequential therapy, showed a favorable SPM profile.When adjusting the SPM incidence by the competing risk of death and age at diagnosis, the risk of SPM was significantly higher for the BR/DRC group respect to the BTKi (p=0.04, HR=2.68, 95% CI: 1.07-6.38, Fine-Gray model).In our cohort, patients treated with BTKi exhibited the lowest incidence of SPMs (6.2%), in comparison to that observed with BR, DRC, or other CIT regimens. Even when BTKi was administered as second-line therapy following initial cytotoxic regimens, it did not increase the risk compared to the CIT exposure (BR: 13.8% vs 9.5%; DRC: 13.7% vs 7.5%).The pharmacodynamic profile of BTKi, targeting the MYD88-BTK axis with minimal off-target DNA damage, contrasts with alkylating agents or nucleoside analogues that pose greater mutagenic risk.Unlike fixed-duration CIT, continuous BTKi exposure does not appear to culminate in cumulative carcinogenic risk. Based on lower SPM incidence, favorable latency profiles, and minimal contribution to hematologic second cancers, BTKi seemed to emerge as a strategic therapeutic choice in patients with prolonged expected survival, where minimizing long-term toxicity is crucial. In conclusion, our large real-world multicenter study confirms that SPMs are a relevant long-term complication in WM, with variable incidence according to treatment exposure, despite the limitation of a smaller BTKi group and its shorter median follow-up time. BR and DRC are associated with moderate SPM risk, not increased by subsequent BTKi. Other CIT schemes, nowadays less administered, appeared to confer a too high risk of SPMs. BTKi seemed to demonstrate a significant advantage in limiting SPM, both solid and hematological. Although retrospective, our findings support the integration of BTKi early in treatment algorithms to reduce SPM risk. Prospective registries, longer-term follow-up and comparison with other casistics will be critical to define cumulative risk, especially as next-generation BTKi show promising results with even better selectivity and tolerability.

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2025
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