Prospective, multicentre phase II study to evaluate the clinical benefit of reduced‐dose lenalidomide and dexamethasone based on frailty stratification in elderly, unfit patients with newly diagnosed multiple myeloma

Elderly transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) often cannot tolerate standard-dose lenalidomide-dexamethasone (Rd), leading to frequent dose reductions. We evaluated an upfront frailty-adapted Rd dosing strategy using the revised Myeloma Comorbidity Index (R-MCI) in this frail population. In a multicentre phase II trial, patients ≥70 years classified as intermediate-fit (R-MCI 4-6) or frail (R-MCI ≥7) received Rd with starting doses stratified by frailty (intermediate-fit: lenalidomide 25 mg + dexamethasone 20 mg; frail: lenalidomide 15 mg + dexamethasone 10 mg). Two-year progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Among 70 enrolled patients (69 evaluable; median age 80), 54% were intermediate-fit and 46% frail. ORR was 86.9%, with ≥VGPR (very good partial response) in ~36% of both groups. Two-year PFS was 37.4% (95% confidence interval [CI]: 26.9%-57.8%; median PFS 15.6 months) and 2-year OS was 63.0% (95% CI: 51.6%-77.0%), with no statistically significant differences between intermediate-fit and frail patients in this exploratory analysis. Grade ≥3 neutropenia occurred in 24.3% and 40.6% of intermediate-fit and frail patients, respectively, while grade ≥3 infectious complications were observed in 10.8% and 12.5%, respectively, without significant differences between groups. The frailty-guided, dose-attenuated Rd regimen in elderly unfit NDMM yielded high response rates and clinically meaningful survival with manageable toxicity. These exploratory findings suggest that frail patients may achieve outcomes approaching those of intermediate-fit patients despite reduced starting doses, warranting confirmation in adequately powered prospective studies.