Introduction.

The recent introduction of novel therapies, such as anti-CD38 monoclonal antibodies, into the therapeutic landscape of Multiple Myeloma (MM) has markedly improved patient outcomes. However, their increasing use in frontline settings has also led to higher rates of refractoriness, even in early lines of therapy, posing a challenge for clinicians when selecting second-line treatment.

Methods.

This retrospective, multicenter real-world study aims to characterize an Italian MM population at first relapse, with a focus on evolving refractoriness patterns from 2019 to 2025. Based on current frontline regimens, the study also seeks to predict potential future patterns of refractoriness at the time of first relapse. Refractoriness at relapse was categorized as follows: Single exposed (not refractory), Single refractory (ref) (to lenalidomide or bortezomib/carfilzomib), Double exposed (to anti-CD38 and lenalidomide), Double ref (to anti-CD38 and lenalidomide), Daratumumab-ref (to anti-CD38 only), Triple exposed/ref (to anti-CD38, bortezomib/carfilzomib, and lenalidomide)

Results.

We analyzed data from 1,026 MM patients treated in first-line with the following regimens: chemotherapy (1%), doublets (Rd 10%, VD 1.9%, Kd 0.1%), triplets (VTD 25%, DaraRd 17%, VMP 14%, CyBorD 2%, VRD 2%, CyRd 0.1%, KRd 0.1%) and quadruplets (DaraVTD 19%, DaraVMP 5%, DaraVRD 1.5%, DaraCyBorD 1%, IsaVRD 0.1%, IsaKRD 0.1%, IsaRd 0.1%). We splitted patients into three cohorts according to relapse year: 2019–2021, 2022–2023, and 2024–2025. First relapse occurred in 132, 194, and 97 patients in each respective period, while 603 patients remained on frontline treatment consisting of continuous regimens in 43 patients (32.5%) in 2019–2021, 104 patients (54%) in 2022–2023, and 64 patients (66%) in 2024–2025. Fixed-duration treatments were used in 89 (67%), 90 (46%), and 33 (34%) patients across the three periods, respectively. Among patients still undergoing treatment, 518 (86%) were receiving continuous therapy and 85 (14%) were on fixed regimens. Over time, single exposed cases decreased from 46% in 2019–2021 period, to 30% in 2022–2023 and 20% in 2024–2025. Single ref cases also declined: 51.5%, 41%, and 37%, in the three periods, respectively. Only 2 patients were double exposed in the later periods while double ref cases rose from 2%, to 14%, and 15.5% over periods, respectively. Dara-ref patients increased from 4% in 2022–2023 to 7% in 2024–2025. Triple exposed patients rose from 10% to 20% over the last two periods. Among the 603 patients still on therapy, future relapse profiles, based on current treatments, may include: single exposed (9%), single ref (33%), double exposed (2%), double ref (24%), dara-ref (5%), and triple exposed (27%). Double ref and triple exposed cases have progressively increased, a trend likely driven by the widespread adoption of anti-CD38-based combinations in frontline therapy. Being triple exposed/ref patients the potential candidates for cilta-cel therapy, that will be approved soon in Italy, its use could increase from 20% among patients relapsed in 2024-25 to 27% in the next years.

Conclusions

In our real-world study we observed that continuous therapies are becoming more prevalent than fixed regimens, potentially contributing more to refractoriness than simple drug exposure. Moreover, our real-world study confirms that MM refractoriness patterns have evolved rapidly in recent years and are expected to continue shifting, even in earlier lines of therapy. MM population is transitioning from predominantly single ref profiles to more complex double ref or triple exposed patterns, requiring innovative therapeutic approaches in nearly half of patients. The future frontline incorporation of novel immunotherapies could further alter refractoriness trajectories, presenting new clinical challenges ahead. The recent inclusion of anti-BCMA regimens as per EHA-EMN 2025 guidelines (Dimopoulos et al. Nat Rev Clin Oncol, 2025) provides promising alternatives for these high-risk groups, addressing the urgent need for novel targets in double ref or triple exposed MM patients groups associated with poor outcomes upon retreatment.

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2025
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