Daratumumab Combo Improves Outcomes in Transplant-Ineligible NDMM Subgroups

"In this post hoc analysis, results showed consistency with overall MRD negativity, 12-month sustained MRD negativity rates, and 24-month sustained MRD negativity rates being higher in the D-VRd arm,” according to study author Saad Z. Usmani, MD, MBA, FACP, FASCO.

Combining daratumumab (Darzalex) with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) improved responses and survival compared with VRd alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), according to subgroup analysis findings from the phase 3 CEPHEUS trial (NCT03652064) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

At a threshold of 10–5, the overall minimal residual disease (MRD)–negative complete response (CR) or better rate was 60.4% with D-VRd vs 39.3% with VRd (OR, 2.37; 95% CI, 1.47-3.80; P = .0004). At a threshold of 10–6, these rates were 45.8% vs 26.9%, respectively (OR, 2.28; 95% CI, 1.40-3.73). A sustained MRD-negative CR or better for at least 12 months was observed in 47.2% vs 28.3% in each arm at a threshold of 10–5 (OR, 2.28; 95% CI, 1.40-3.72; P = .0010) and 33.3% vs 16.6% at a threshold of 10–6 (OR, 2.50; 95% CI, 1.43-4.36; P = .0011). Additionally, a sustained MRD-negative CR or better occurred in 40.3% vs 22.8% at a threshold of 10–5 (OR, 2.30; 95% CI, 1.37-3.83; P = .0015) and 27.1% vs 13.8% at a threshold of 10–6 (OR, 2.31; 95% CI, 1.27-4.20; P = .0056).

After a median follow-up of 58.7 months, the median PFS was not reached with D-VRd vs 49.6 months with VRd among those with transplant-ineligible disease (HR, 0.51; 95% CI, 0.35-0.74; P = .0003). The PFS rate was 69.0% vs 48.0% in each arm at 54 months.

Among patients with transplant ineligibility, D-VRd trended toward an improvement in overall survival (OS; HR, 0.66; 95% CI, 0.42-1.03; P = .0682). The OS improvement with D-VRd became statistically significant when censoring for deaths associated with COVID-19 (HR, 0.55; 95% CI, 0.34-0.90; P = .0159). Of note, the OS improvement in the D-VRd arm was higher in the transplant-ineligible subgroup compared with the intent-to-treat (ITT) population.

Overall, the treatment effects for MRD-negative CRs or better and PFS were generally consistent with D-VRd across prespecified subgroups.

“The phase 3 CEPHEUS trial had previously demonstrated improved efficacy outcomes with D-VRd compared with VRd in patients with transplant-ineligible or transplant-deferred [NDMM].2 In this post hoc analysis, results showed consistency with overall MRD negativity, 12-month sustained MRD negativity rates, and 24-month sustained MRD negativity rates being higher in the D-VRd arm,” study author Saad Z. Usmani, MD, MBA, FACP, FASCO, chief of myeloma service at Memorial Sloan Kettering Cancer Center in New York, New York, said in the presentation.1 “No new safety concerns were observed.”

Overall, investigators noted that these post hoc analysis findings reinforced D-VRd as a standard of care for patients with transplant-ineligible NDMM.

In the CEPHEUS trial, 395 patients with transplant-ineligible or transplant-deferred NDMM were assigned to receive VRd or D-VRd for the first 8 cycles of treatment; 145 and 144 patients with transplant-ineligible disease made up each respective arm. For cycle 9 and onward, patients then received Rd or DRd until disease progression or unacceptable toxicity. The post hoc subgroup analysis exclusively pertained to those with transplant-ineligible NDMM, who accounted for approximately 75% of the ITT population.

The study’s primary end point was overall MRD-negative status with a CR or better. Secondary end points included PFS, sustained MRD-negative status with a CR or better, the CR or better rate, and OS.

Those with an ECOG performance status of 0 to 2 and an International Myeloma Working Group frailty score of 0 or 1 were eligible for enrollment.

Baseline characteristics were generally comparable between the D-VRd and VRd arms in the subgroup analysis. Of note, 47.2% vs 44.8% of patients in each respective arm were aged 70 to 75 years, and 28.5% vs 31.0% were older than 75 years. Additionally, 33.3% and 24.1% of patients in each arm had frailty defined as an Intergroupe Francophone du Myélome score of 2 or higher, 27.8% and 27.6% had International Staging System stage III disease, and 13.9% and 12.4% had high-risk cytogenetics.

In the D-VRd and VRd arms, respectively, 79.9% vs 79.6% had grade 3/4 treatment-emergent adverse effects (TEAEs), 72.2% vs 69.7% had serious TEAEs, and 22.9% vs 32.4% died during the study. Additionally, 7.6% and 19.0% from each arm discontinued study therapy due to TEAEs, and 9.7% and 11.3% developed second primary malignancies.

The most common grade 3/4 TEAEs in the D-VRd and VRd arms included neutropenia (43.8% vs 31.7%), thrombocytopenia (30.6% vs 23.2%), and anemia (12.5% vs 12.7%). Of note, peripheral sensory neuropathy of any grade affected 59.7% in the D-VRd arm and 63.4% in the VRd arm; grade 3/4 events occurred in 9.7% and 8.5% of patients, respectively.

References

1. 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
2. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7