Frail subgroups determine heterogeneous outcomes in older patients with NDMM: long-term follow-up of the HOVON 143 trial

Frailty, rather than age alone, is a key determinant of outcomes in older patients with multiple myeloma (MM), yet frailty assessments are often lacking in clinical trials. Consequently, data on the efficacy and tolerability of novel treatments in frail patients remain scarce. Moreover, there is substantial heterogeneity among frail patients, with some classified as frail solely due to age (>80 years) and others due to geriatric impairments and/or comorbidities. To our knowledge, the HOVON 143 trial was the first trial that was specifically designed for frail patients with newly diagnosed MM (NDMM) using the International Myeloma Working Group Frailty Index (IMWG-FI). After a median follow-up of >5 years, we report the long-term progression-free survival (PFS) and overall survival (OS) outcomes, with detailed analyses of frail subgroups. Patients who were classified as frail according to the IMWG-FI were treated with 9 induction cycles of ixazomib, daratumumab, and low-dose dexamethasone, followed by maintenance therapy until progression for a maximum of 2 years. Median PFS was 13.8 months, and median OS was 34.0 months. However, frail subgroup analyses based on geriatric impairments and comorbidities besides age revealed pronounced heterogeneity in outcomes. Both early relapse–related and nonrelapse-related mortality rates were higher in ultrafrail patients and patients who were frail due to impairments than in patients who were frail based on age alone. These findings highlight the need for a more precise frailty definition to identify patients at the highest risk of early mortality. This trial was registered at www.clinicaltrialsregister.eu as EudraCT #2016-002600-90.