Long-Term Outcomes Offer Reassurance on Quadruplet Use in Transplant-Ineligible NDMM

Saad Z. Usmani, MD, MBA, FACP, chief of the myeloma service at Memorial Sloan Kettering Cancer Center, discusses long-term follow-up data from the phase 3 CEPHEUS trial (NCT03652064), which evaluated the addition of daratumumab (Darzalex) to the standard bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) regimen, creating a potent daratumumab-VRd (D-VRd) quadruplet for patients with transplant-ineligible newly diagnosed multiple myeloma. At a mature median follow-up of 76 months reported at the 2026 ASCO Annual Meeting, the quadruplet combination demonstrated overwhelming superiority over standard triplet therapy. The trial reported significantly higher minimal residual disease (MRD) negativity rates, alongside vastly superior sustained MRD negativity rates extending beyond both the 12-month and 24-month milestones.

The progression-free survival (PFS) outcomes heavily favored the D-VRd experimental arm. At the 6-year mark, the PFS rate remained a robust 59.3% for the quadruplet group, compared with just 38.3% for the triplet VRd cohort. The median PFS has still not been reached in the D-VRd arm after 6 years of monitoring, whereas the median PFS for the standard VRd triplet was approximately 50 months, translating to a 45% reduction in progression or death. This profound survival advantage proved generally consistent across all prespecified patient subgroups, offering encouragement for this typically older patient population.

Usmani notes that upfront quadruplet therapy requires careful, individualized patient selection. The CEPHEUS study specifically enrolled patients categorized as fit or intermediate fit according to the International Myeloma Working Group (IMWG) frailty score. Clinicians must remain highly selective, as more fragile patients may tolerate a less intensive regimen better. For these frail individuals, data from trials like the MAIA study (NCT02252172), which explored a lighter daratumumab/lenalidomide/dexamethasone regimen, might offer a safer alternative. Ultimately, the final analysis from the CEPHEUS trial confirms that the D-VRD quadruplet introduces no new safety signals over time, providing strong reassurance to community oncologists that transplant-ineligible patients can derive continuous, safe, and durable benefits from this frontline approach.