Background/Objectives: Despite therapeutic advances, managing relapsed/refractory multiple myeloma (RRMM) remains challenging. For patients with frailty, comorbidities, mobility limitations, or when treatment preference and drug accessibility are key considerations, the all-oral ixazomib-lenalidomide-dexamethasone (IRd) regimen offers a practical alternative. Methods: We performed a multicenter retrospective study of RRMM patients treated with IRd in Hungary between 1 January 2020 and 30 June 2025. Results: The median age at treatment initiation was 73.7 years. Treatment was initiated for clinical progression in 38.2%, biochemical progression in 53.3%, and for intolerance or toxicity of prior therapy in 8.6%. Median progression-free survival (PFS) was 18.7 months, and median overall survival (OS) was 34.7 months. Patients treated at biochemical progression had significantly longer PFS than those treated at clinical progression (24.3 vs. 15.6 months; p = 0.004), with additional benefit when IRd was initiated owing to intolerance or toxicity of previous therapy (p = 0.04). In the second-line setting, median PFS was 24.5 months, and median OS was not reached. Adverse events occurred in 68.3% of patients; dose reductions were required in 18.4%, and 21.6% discontinued treatment because of intolerance or toxicity. Most common toxicities were neutropenia (32.9%), thrombocytopenia (27.6%), diarrhoea (25%), peripheral neuropathy (25.3%), and infections (22.4%). Conclusions: IRd initiation at biochemical progression was associated with superior PFS compared with treatment at clinical progression. When compared with a recent Hungarian multicenter cohort treated with second-line daratumumab, lenalidomide, and dexamethasone, outcomes with IRd are not significantly inferior (36-month OS calculated from 2nd line treatment initiation: 65.5% for DRd vs. 60% in our cohort; p = 0.56). These real-world data support IRd as an effective, convenient, all-oral option for appropriately selected RRMM patients.
Keywords: biochemical progression; ixazomib; multiple myeloma; relapsed.