P167 | OUTCOMES OF SECOND-LINE THERAPY IN FUNCTIONAL HIGH-RISK MULTIPLE MYELOMA AFTER DARATUMUMAB-BASED INDUCTION: AN ITALIAN REAL-WORLD STUDY

Introduction Functional high risk multiple myeloma (FHRMM), defined by refractoriness or early relapse after first-line therapy, remains a critical unmet clinical need, associated with limited survival. Although daratumumab-based quadruplet regimens have improved first-line treatment for transplant-eligible patients, no standardized second-line approaches have been established for FHRMM after initial failure. In this Italian multi-center retrospective study, we investigated the clinical features and second-line treatment outcomes of FHRMM patients previously treated with daratumumab-based quadruplets. Methods A total of 62 FHRMM patients across 13 Italian Hematology Units were enrolled between January 2022 and November 2024, and clinical characteristics are summarized in Fig 1A (median follow-up, 14 months; range, 11.6-16.3). Eligible patients had refractory disease or early relapse within 18 months after daratumumab-bortezomib-thalidomide-dexamethasone (dara-VTD) induction or within 12 months after autologous stem cell transplantation (ASCT). Results In this cohort, 45% of patients had high-risk abnormalities, and 27% had extramedullary disease (EMD). Most patients presented with advanced stages (R-ISS II: 63%; R-ISS III: 33%). Carfilzomib-lenalidomide-dexamethasone (KRD) was the predominant second-line regimen (86%), while standard chemotherapy, such as D-PACE or PAD, was used in 8% of cases. At the data cut-off, 34% of patients were still receiving second-line therapy, and 26% had proceeded to a consolidation ASCT. The ORR was 61%, with 42% of patients achieving very good partial response or better. Median PFS (Fig. 1B) and OS were not reached, with estimated 12-month PFS and OS of 54% and 72%, respectively. Subgroup analysis revealed that EMD, lack of ASCT consolidation, ECOG ≥2, advanced R-ISS stage, and non-KRD-based reinduction (Fig. 1C) were associated with inferior PFS. Conclusion Second-line management of FHRMM after dara-VTD failure remains challenging and heterogeneous across centers, due to the lack of standardized international algorithms. Carfilzomib-based regimens provided modest clinical benefits, but outcomes remained unsatisfactory. Our data underscore the urgent need to integrate innovative immunotherapeutic strategies, such as T-cell redirecting therapies, earlier in the treatment course for this high-risk population. Prospective multicenter trials are critically needed to establish tailored algorithms and improve survival in FHRMM.