Usmani on D-VRd's Efficacy/Safety in Transplant-Ineligible NDMM

Saad Z. Usmani, MD, MBA, FRCP, FASCO, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center, discusses the efficacy and safety findings of a subgroup analysis from the phase 3 CEPHEUS trial (NCT03652064) that were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

According to the subgroup analyses, the combination of daratumumab (Darzalex) and bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) improved both responses and survival vs VRd alone when used for the treatment of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM).

Specifically, higher overall minimal residual disease (MRD)-negative complete response (CR) or better rates were seen with D-VRd, as it led to substantially higher rates of MRD negativity at both 10⁻⁵ (60.4% with D-VRd vs 39.3% with VRd; OR, 2.37; 95% CI, 1.47-3.80; P =.0004), and at a threshold of 10^–6 (45.8% vs 26.9%), respectively (OR, 2.28; 95% CI, 1.40-3.73). A significantly higher percentage of patients on D-VRd achieved sustained MRD-negative CR or better for at least 12 months and 24 months, indicating more durable responses.

D-VRd also significantly prolonged progression-free survival (PFS). After a median follow-up of nearly 5 years, the median PFS was not reached with D-VRd, compared with 49.6 months with VRd (HR, 0.51; 95% CI, 0.35-0.74; P =.0003), representing a 49% reduction in the risk of progression or death. While overall survival (OS) showed a strong trend towards improvement with D-VRd (HR, 0.66; 95% CI, 0.42-1.03; P =.0682), it became statistically significant when accounting for deaths associated with COVID-19, suggesting a true OS benefit.

The safety profile of D-VRd was consistent with known risks, with no new concerns identified. Common adverse events were manageable, and notably, treatment discontinuation due to side effects was lower in the D-VRd arm.

These findings strongly reinforce D-VRd as a standard of care for transplant-ineligible NDMM, offering deeper and more durable responses, extended PFS, and a favorable overall risk-benefit profile.

REFERENCE:

Facon T, Zweegman S, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma (NDMM): subgroup analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. J Clin Oncol. 2025;43(suppl 16):7516. doi:10.1200/JCO.2025.43.16_suppl.7516