Establishing D-VRd Efficacy for Transplant-Ineligible Multiple Myeloma

The CEPHEUS phase 3 clinical trial, published in 2025 in Nature Medicine, investigated the efficacy and safety of adding daratumumab to the standard triplet VRd (bortezomib, lenalidomide, dexamethasone) regimen for patients with newly diagnosed multiple myeloma (NDMM) who are either ineligible for transplantation or have deferred it.

With 395 patients randomized into two arms—D-VRd (daratumumab plus VRd) or VRd—this study’s data support the use of D-VRd quadruplet therapy in the first-line setting for these patients. Here’s an in-depth look at the study.

Study Design and Objectives

The trial enrolled patients with NDDM who were transplant-ineligible or deferred transplantation as initial therapy. Patients received either eight cycles of D-VRd followed by maintenance therapy with daratumumab plus lenalidomide (D-Rd) or eight cycles of VRd followed by lenalidomide alone (Rd) until disease progression.

The primary endpoint was the minimal residual disease (MRD)-negativity rate at a sensitivity threshold of 10⁻⁵, determined via next-generation sequencing. Secondary endpoints included complete response (CR) rates, progression-free survival (PFS), and sustained MRD negativity (≥12 months).

Efficacy Outcomes

The results show the efficacy of quadruplet therapy with D-VRd compared to triplet therapy with VRd in this population. At a median follow-up of 58.7 months:

• MRD-negativity rates were significantly higher in the D-VRd arm (60.9 percent) compared to VRd alone (39.4 percent), with an odds ratio of 2.37 (P < 0.0001).
• Sustained MRD negativity for ≥12 months was achieved in 48.7 percent of D-VRd patients versus 26.3 percent of VRd patients, with an odds ratio of 2.63 (P < 0.0001).
• Complete response rates (≥CR) were significantly higher in the D-VRd cohort (81.2 percent) compared to VRd (61.6 percent), with an odds ratio of 2.73 (P < 0.0001).
• PFS analysis demonstrated a 43 percent reduction in the risk of disease progression or death for D-VRd versus VRd (hazard ratio, 0.57; P = 0.0005). The median PFS was not reached for D-VRd but stood at 52.6 months for VRd.

These findings suggest that incorporating daratumumab into VRd fosters deeper and more durable responses, which could help prolong disease control in NDMM patients.

Safety and Tolerability Outcomes

Adverse events were consistent with known safety profiles of daratumumab and VRd. The most common Grade 3 or 4 toxicities were neutropenia (44.2 percent for D-VRd versus 29.7 percent for VRd) and thrombocytopenia (28.4 percent versus 20.0 percent). Grade 3 or 4 peripheral neuropathy rates were comparable between arms.

Serious treatment-emergent adverse events (TEAEs) were observed in 72.1 percent of D-VRd patients versus 67.2 percent of VRd patients. The most common serious TEAE was pneumonia (13.7 percent versus 12.8 percent for D-VRd and VRd arms, respectively).

Treatment discontinuation caused by TEAEs was 7.6 percent for D-VRd and 15.9 percent for VRd.

Implications for Clinical Practice

Results from the CEPHEUS trial support the role of frontline quadruplet D-VRd therapy in transplant-ineligible or -deferred patients with NDDM.

Taken together with previous findings from the PERSEUS study in transplant-eligible patients and the MAIA study in transplant-ineligible patients, which included frail and older patients, data from CEPHEUS further demonstrate the impact of daratumumab-based triplet and quadruplet regimens in the first-line setting for NIDDM management regardless of transplant eligibility.

In the choice between D-VRd and D-Rd, providers should consider individual patient frailty, tolerability, and treatment goals.

Conclusion

With nearly five-years of follow-up data, the CEPHEUS trial provides evidence supporting the addition of daratumumab to frontline VRd in patients with NDDM by demonstrating enhanced MRD negativity, ≥CR, and sustained MRD negativity (≥12 months) rates and clinically relevant prolonged PFS. The safety profile of the D-VRd regimen was consistent with the known safety profile of individual agents.

These findings help refine first-line treatment strategies for NDMM, providing oncologists with an option that may provide deeper responses while maintaining a manageable safety profile.

Reference:

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 study. Nat Med. Published online February 5, 2025. doi:10.1038/s41591-024-03485-7