CEPHEUS: Frailty subgroup analysis of DVRd vs VRd in NDMM

Results from a frailty subgroup analysis of the randomized, phase III CEPHEUS trial (NCT03652064), evaluating daratumumab + bortezomib + lenalidomide + dexamethasone (DVRd) vs bortezomib + lenalidomide + dexamethasone (VRd) in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma (NDMM), were published in Leukemia by Zweegman et al. Using the protocol defined International Myeloma Working Group (IMWG) frailty scale, 256 patients were categorized as fit (DVRd, n = 124; VRd, n = 132) and 139 patients as intermediate-fit (DVRd, n = 73; VRd, n = 66). In a post hoc analysis using the Intergroupe Francophone du Myélome (IFM) simplified frailty scale, 297 patients were categorized as nonfrail (DVRd, n = 140; VRd, n = 157) and 98 as frail (DVRd, n = 57; VRd, n = 41).

Key data: DVRd improved progression-free survival (PFS) vs VRd across all frailty subgroups: IMWG fit (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39–0.91; p = 0.0149), IMWG intermediate-fit (HR, 0.56; 95% CI, 0.34–0.91; p = 0.0189), IFM nonfrail (HR, 0.58; 95% CI, 0.39–0.86; p = 0.0054), and IFM frail (HR, 0.51; 95% CI, 0.28–0.93; p = 0.0242). Measurable residual disease (MRD)-negativity ≥complete response (CR) rates, at a sensitivity of 10^-5 and 10^-6, were also higher with DVRd across all subgroups. Bortezomib discontinuation due to treatment-emergent adverse events (TEAEs) was lower with DVRd vs VRd in frailer subgroups (IMWG intermediate-fit: 9.6% vs 19.0%; IFM frail: 12.4% vs 25.6%), while discontinuation due to peripheral sensory neuropathy was lower with DVRd across all frailty subgroups. Serious infection rates with DVRd vs VRd were 35.5% vs 32.6% in IMWG-fit, 46.6% vs 41.3% in IMWG intermediate-fit, 36.4% vs 30.8% in IFM-nonfrail, and 47.4% vs 53.8% in IFM-frail patients.

Key learning: In this analysis, DVRd was associated with improved PFS and higher MRD-negative ≥CR rates vs VRd across IMWG fit and intermediate-fit and IFM nonfrail and frail subgroups, supporting its use across the frailty subgroups evaluated in transplant-ineligible or transplant-deferred patients with NDMM.