Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

Category: Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

Efficacy of daratumumab-bortezomib-lenalidomide-dexamethasone (DVRd) vs daratumumab-lenalidomide-dexamethasone (DRd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM)

(PA-453) Efficacy of Daratumumab-bortezomib-lenalidomide-dexamethasone (DVRd) vs Daratumumab-lenalidomide-dexamethasone (DRd) in Transplant-ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Wednesday, September 17, 2025

Saad Z. Usmani, MD, MBA, FACP, FASCO

Chief Attending, Myeloma Service
Memorial Sloan Kettering Cancer Center

Introduction: The CEPHEUS trial was a phase 3 study in transplant-ineligible (TIE) patients with NDMM and patients for whom transplant was not planned as initial therapy. DVRd demonstrated superiority with respect to the overall minimal residual disease-negative complete response or better (MRD-negative CR) rate and progression-free survival (PFS) over bortezomib-lenalidomide-dexamethasone (VRd) in CEPHEUS. The current standard of care for the treatment of TIE patients with NDMM is DRd, based on data from the MAIA trial; however, the comparative efficacy of DVRd vs DRd has not been assessed.

Methods: An unanchored, indirect treatment comparison (ITC) of DVRd vs DRd was performed based on individual patient-level data (IPD) from the CEPHEUS and MAIA trials. As MAIA enrolled only TIE patients and CEPHEUS excluded patients aged >80 years, only TIE patients aged ≤80 years at enrollment in CEPHEUS and MAIA were included in this ITC. Inverse probability of treatment weighting (IPTW) was used to balance the DVRd and DRd treatment cohorts on the following baseline patient characteristics: International Staging System stage, cytogenetic risk, age, Eastern Cooperative Oncology Group performance status, multiple myeloma immunoglobulin isotype, extramedullary disease, frailty status (per the simplified International Myeloma Working Group frailty score), sex, estimated glomerular filtration rate, anemia, and lactate dehydrogenase. To assess the relative efficacy of DVRd and DRd with respect to MRD-negative CR rate, PFS, and overall survival (OS), weighted logistic regression, Cox regression, and Kaplan-Meier estimates were used. Because the COVID-19 pandemic impacted CEPHEUS more than MAIA, an OS sensitivity analysis was performed, in which deaths attributed to COVID-19 in both studies were censored.

Results: In total, 144 CEPHEUS DVRd patients (TIE subgroup) and 313 MAIA DRd patients (age ≤80 years subgroup) were included in the analysis. After IPTW, baseline patient characteristics were well balanced across the 2 treatment cohorts. For the MRD-negative CR rate, the adjusted odds ratio for DVRd vs DRd was 3.04 (95% CI, 2.01–4.61; 61.2% vs 34.2%). For PFS, the adjusted hazard ratio (HR) for DVRd vs DRd was 0.62 (95% CI, 0.44–0.88). For OS, the adjusted HR for DVRd vs DRd was 0.80 (95% CI, 0.53–1.19). When censoring the COVID-19 deaths, the adjusted OS HR for DVRd vs DRd was 0.63 (95% CI, 0.41–0.98).

Conclusions: Results from this ITC using IPD from the CEPHEUS and MAIA trials show that treatment with DVRd leads to a statistically significant improvement in the MRD-negative CR rate and PFS as well as an improved OS trend compared with DRd in TIE patients with NDMM ≤80 years. When COVID-19 deaths were censored, treatment with DVRd led to a statistically significant improvement in OS. In the absence of a head-to-head trial, this ITC may inform and guide appropriate treatment selection for maximum benefit in TIE patients with NDMM aged ≤80 years.