Dr Mian on Findings From a Dynamic Frailty Analysis in Transplant-Ineligible, Newly Diagnosed Multiple Myeloma

“This emphasizes that you can’t use a one-time frailty measurement; you need to be more dynamic. When we started looking at specific outcomes in terms of efficacy, minimal residual disease negativity rates, and progression-free survival, it was great to see that both for CEPHEUS and MAIA, [the addition of] daratumumab ended up helping all the subgroups dynamically across the different time points.”

Hira Mian, MD, an associate professor of medicine at McMaster University, discussed findings from a dynamic frailty analysis conducted in transplant-ineligible patients with newly diagnosed multiple myeloma enrolled in the phase 3 MAIA (NCT02252172) and CEPHEUS (NCT03652064) trials. These studies evaluated daratumumab (Darzalex) combined with lenalidomide (Revlimid) and dexamethasone (D-Rd) or bortezomib (Velcade), lenalidomide, and dexamethasone (D-VRd), respectively.

Mian emphasized that the analysis underscored the dynamic nature of frailty. In CEPHEUS, frailty status changed in 34% of patients over 4 years of follow-up, whereas in MAIA, 26% of patients experienced changes in frailty classification during the same length of time. These findings indicate that frailty is not a fixed characteristic and highlight the limitations of relying on a single baseline assessment to guide treatment decisions. Instead, ongoing evaluation of frailty is necessary to better align treatment strategies with evolving patient status, Mian noted.

Regarding efficacy, the addition of daratumumab provided consistent benefits across frailty subgroups, including patients classified as frail or ultra-frail. Improvements in minimal residual disease negativity rates and progression-free survival were observed in both trials, suggesting that daratumumab-containing regimens maintain clinical activity across varying levels of frailty. Importantly, even in patients considered ultra-frail, D-Rd and D-VRd demonstrated efficacy, supporting their use in populations often viewed as challenging to treat.

Mian noted that safety analyses indicated that daratumumab-based regimens were generally well tolerated. No unexpected toxicities emerged, and treatment discontinuations due to adverse effects did not differ significantly across frailty groups. Further research is needed to determine whether dynamic frailty changes have an independent effect on safety outcomes, but current data suggest the regimens remain manageable regardless of frailty status.

Mian concluded that these results have 2 major implications for clinical practice and future research. First, frailty should be recognized as a dynamic construct that requires repeated evaluation throughout the course of therapy. Second, future phase 3 trials should incorporate prospective, longitudinal frailty assessments to more accurately capture patient trajectories and inform tailored treatment strategies.