CEPHEUS Data Show Deeper MRD Response With D-VRd in Newly Diagnosed Myeloma

Daratumumab (Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) produced higher and more durable rates of minimal residual disease (MRD) negativity than bortezomib, lenalidomide, and dexamethasone (VRd) alone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma (NDMM), according to an expanded MRD analysis of the phase 3 CEPHEUS trial (NCT03652064) published in Blood Advances.¹

The study randomly assigned 395 patients with NDMM who were transplant ineligible or had deferred transplant to D-VRd (n = 197), followed by daratumumab plus lenalidomide/dexamethasone (D-Rd), or VRd (n = 198), followed by lenalidomide/dexamethasone (Rd). At a median follow-up of 58.7 months, overall MRD-negativity rates were significantly higher with D-VRd vs VRd at the 10^-5 sensitivity threshold (60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; P <.0001) and at the more stringent 10^-6 threshold (46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P =.0001).

Trial Design

CEPHEUS led to the FDA approval of D-VRd in transplant-ineligible NDMM, and continued to show efficacy in long-term findings.

Eligible patients were younger than 80 years, had a frailty index score less than 2, and had an ECOG performance status of 0 to 2. All patients received 8 cycles of VRd, with the D-VRd group also receiving weekly to monthly subcutaneous daratumumab; from cycle 9 onward, bortezomib was discontinued and patients continued Rd alone with or without daratumumab until disease progression or unacceptable toxicity. Overall MRD negativity, the primary end point, was defined as the proportion of patients achieving complete response (CR) or better with MRD-negative status by next-generation sequencing. The median patient age was 70 years, and 13.2% had high-risk cytogenetics.

Sustained and Cumulative MRD Findings

Sustained MRD negativity of at least 12 months was 49.2% with D-VRd vs 27.3% with VRd at the 10^-5 threshold (OR, 2.56; 95% CI, 1.69-3.89; P <.0001) and the 10^-6 threshold (34.0% vs 16.2%, respectively; OR, 2.66; 95% CI, 1.65-4.30; P <.0001), with similar benefits observed at 24 and 36 months. MRD negativity rates with D-VRd continued to increase over 3 years of follow-up, in contrast to a plateau observed in the VRd group beginning at approximately 18 months. Among patients with at least 1 negative MRD test, 14.8% in the D-VRd group lost MRD negativity before disease progression compared with 33.3% in the VRd group.

PFS by MRD Status

Greater progression-free survival (PFS) benefit was observed among patients who achieved MRD-negative status regardless of treatment arm, but a favorable treatment effect for D-VRd persisted within both MRD-negative and MRD-positive subgroups. At the 10^-5 threshold, the treatment effect trended in favor of D-VRd among MRD-negative patients (HR, 0.61; 95% CI, 0.35-1.06; P =.0755) and MRD-positive patients (HR, 0.82; 95% CI, 0.54-1.24; P =.3402). At the 10^-6 threshold, patients with MRD-negative status who received D-VRd had a 54-month PFS rate of 86.2% vs 79.0% with VRd, and patients with MRD-positive status who received D-VRd had improved median PFS (60.3 vs 38.7 months; HR, 0.74; 95% CI, 0.51-1.06; P =.1022).

High Cytogenetic Risk Subgroup

The treatment effect of D-VRd was less pronounced in the small subgroup of patients with high cytogenetic risk (n = 25 for D-VRd; n = 27 for VRd), a finding the study authors attributed in part to unexpectedly high MRD-negativity rates among high-risk patients in the VRd group and to a greater proportion of missing postbaseline MRD data in the high-risk D-VRd group following earlier treatment discontinuation. Among high-risk patients who did achieve MRD negativity at the 10^-5 threshold, a trend favoring PFS benefit was still observed with D-VRd vs VRd (HR, 0.33; 95% CI, 0.07-1.57; P =.1419).

Broader Context Across Daratumumab Trials

The study authors noted that CEPHEUS is the fifth phase 3 trial to demonstrate favorable outcomes with the addition of daratumumab to standard-of-care regimens across the NDMM spectrum, following ALCYONE (NCT02195479), MAIA (NCT02252172), CASSIOPEIA (NCT02541383), and PERSEUS (NCT03710603). Overall MRD negativity rates at the 10^-5 threshold were lower in ALCYONE and MAIA, which the authors said reflects the added benefit of a quadruplet regimen in patients able to tolerate it, although the different trial populations could not be compared directly. In the transplant-eligible PERSEUS trial, D-VRd similarly produced higher overall (75.2% vs 47.5%) and sustained (64.8% vs 29.7%) MRD-negativity rates than VRd at the 10^-5 threshold, at a median follow-up of 47.5 months.²

Clinical Implications

The study authors concluded that deep and durable MRD responses with D-VRd translated into favorable long-term outcomes, including a previously reported PFS improvement (HR, 0.57; 95% CI, 0.41-0.79; P =.0005) and a numerical reduction in risk of death (HR, 0.85; 95% CI, 0.58-1.24) with D-VRd vs VRd in the intent-to-treat population, with follow-up ongoing.³ They stated that the findings support D-VRd as a standard-of-care treatment for patients with NDMM who are transplant-ineligible or for whom transplant is deferred.¹

REFERENCES

1. Zweegman S, Facon T, Hungria V, et al. Daratumumab in transplant-ineligible or -deferred newly diagnosed multiple myeloma: minimal residual disease in CEPHEUS. Blood Adv. 2026;10(16):5594-5606. doi:10.1182/bloodadvances.2026019937

2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

3. 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