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

• Frail patients as defined by the IMWG-FI have limited outcomes, with a median survival of less than 3 years.

• Frail subgroup analyses based on geriatric impairments and comorbidities besides age revealed pronounced heterogeneity in outcomes.

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. As a result, 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. The HOVON 143 trial was the first trial that was specifically designed for frail patients with newly-diagnosed MM using the International Myeloma Working Group Frailty Index (IMWG-FI). After a median follow-up of more than 5 years, we here report the long-term progression-free and overall survival outcomes, with detailed analyses of frail subgroups. Patients who were classified as frail according to the IMWG-FI, were treated with nine 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- and non-relapse related mortality rates were higher in ultra-frail patients and patients who were frail due to impairments, as compared to patients who were frail based on age alone. These findings highlight the need for a more precise frailty definition to identify patients at highest risk of early mortality. EudraCT number: 2016-002600-90