In newly diagnosed multiple myeloma (NDMM), the presence of minimal residual disease (MRD) negativity is associated with better outcomes in terms of progression-free survival (PFS) and overall survival (OS). The phase 3 CEPHEUS study evaluated daratumumab plus bortezomib/lenalidomide/dexamethasone (D-VRd) versus VRd in patients with NDMM who are transplant-ineligible or for whom transplant was not planned as initial therapy (transplant- deferred).
A total of 395 patients were randomized 1:1 to receive either D-VRd (n=197) or VRd (n=198). Eligible patients had NDMM (transplant-ineligible or transplant-deferred), an ECOG Performance Status Score of 0-2, and a frailty score of 0-1. VRd was given in 21-day cycles for 8 cycles in each treatment arm (with daratumumab given in cycles 1 and 2 and cycles 3 to 8 in the D-VRd arm) followed by Rd given in 28-day cycles, until disease progression or unacceptable toxicity. The primary endpoint was overall MRD (complete response [CR] or better) negativity and key secondary endpoints included PFS, sustained MRD (CR or better) negativity (≥12 months), CR or better rate, and OS.
Baseline characteristics were well-balanced between both treatment arms. Daratumumab significantly increased the overall MRD-negativity rate and overall CR or better rate by approximately 20%. The overall MRD-negativity rate (10−5) was 60.9 for D-VRd and 39.4 for VRd, and the CR or better rate for D-VRd compared with VRd was 81.2% and 61.6%, respectively. Daratumumab also led to deeper MRD responses at 10−6 as well as a higher sustained MRD-negativity rate. Daratumumab significantly improved PFS, with a 43% reduction in the risk of disease progression or death. The median PFS for the D-VRd arm was not reached and was 52.6 months in the VRd arm. The PFS benefit with daratumumab was generally consistent across prespecified subgroups. OS showed a positive trend for the daratumumab group, which was further enhanced when excluding deaths attributed to COVID-19. Safety data were consistent with the established safety profile of each individual drug. Grade ≥3 treatment- emergent adverse events (TEAEs) were observed in 92.4% of patients in the D-VRd arm and in 85.6% of patients in the VRd arm. The proportion of TEAEs that led to discontinuation of all study drugs in the D-VRd and VRd arms was 7.6% and 15.9%, respectively.
The addition of daratumumab to VRd significantly improved the depth and duration of responses. The D-VRd quadruplet may enhance clinical outcomes for patients with NDMM who are either transplant-deferred or undergoing treatment with thalidomide and can tolerate bortezomib.
Usmani SZ, Facon T, Hungria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: International Myeloma Society 21st Annual Meeting & Exposition. September 25-28, 2024; Riocentro, Rio de Janeiro, Brazil. Abstract OA-63.
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