An Italian real-world multicenter study of patients with refractory/relapsed functional high-risk multiple myeloma patients treated with second-line therapies.

Functional high risk multiple myeloma (FHRMM) remains a challenging entity with poor outcomes and limited survival, and there is no international consensus on optimal second-line therapeutic strategies in relapsed/refractory patients. In this multicenter real-world retrospective study, we investigated clinical characteristics and outcomes of a total of 62 FHRMM patients previously treated with a first-line daratumumab-based quadruplet regimen or who relapsed within 12 months after frontline autologous stem cell transplantation (ASCT). In our cohort, the overall response rate was 61%, with 42% of patients achieving a very good partial response (VGPR) or better. Similarly, median progression-free survival (PFS) was not reached with an estimated 12-month PFS rate of 54%, as well as median overall survival (OS) with a 12-month OS rate of 72%. Factors associated with worse PFS included extramedullary disease, prior lenalidomide maintenance, lack of ASCT consolidation, an ECOG score ≥ 2, advanced disease stage, and salvage therapy without carfilzomib-lenalidomide-dexamethasone. In conclusion, second-line management of FHRMM following daratumumab-bortezomib-thalidomide-dexamethasone induction is highly challenging and variable across centers, due to the lack of standardized international guidelines. Carfilzomib-based regimens demonstrated some clinical benefits, especially in lenalidomide-naïve patients; however, outcomes remained suboptimal in FHRMM population who may benefit from novel therapies administered as earlier treatment lines. Larger prospective trials are needed to optimize FHRMM clinical management and improve patient outcomes.