Daratumumab Plus VRd Yields Sustained MRD-Negativity Regardless of Cytogenetic Risk Status in NDMM

Daratumumab (Darzalex; Janssen Biotech, Inc.) plus bortezomib (Velcade; Millennium/Takeda and Janssen Pharmaceutical Companies), lenalidomide (Revlimid; Celgene Corporation) and dexamethasone (D-VRd) yielded superior progression-free survival (PFS) benefit and minimal residual disease (MRD)-negativity compared with bortezomib, lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (NDMM). The post hoc analysis data from the phase 3 CEPHEUS trial (NCT03652064) are to be presented at the 2025 ASCO Annual Meeting in Chicago, Illinois.¹

Abnormal myeloma cell growth in bone marrow | Image Credit: © Khella - stock.adobe.com

The CEPHEUS trial examined subcutaneous daratumumab plus VRd in 395 patients with transplant-ineligible/transplant-deferred (TIE/TD) NDMM or for whom transplant was not planned as the initial therapy. They were randomized 1:1 to receive either 8 cycles of D-VRd or VRd followed by daratumumab plus lenalidomide and dexamethasone (D-Rd) or Rd until progression. The trial evaluated overall MRD-negativity rates, sustained MRD negativity, complete response (≥CR) rates, and PFS. Unless otherwise noted, all MRD negativity rates were reported at a sensitivity threshold of 10^-5.²

This post hoc analysis of the trial is focused on results in patients with high-risk (HiR) cytogenetic abnormalities (HRCAs). HRCAs were assessed using fluorescence in situ hybridization (FISH), with high risk defined as the presence of one or more of the following: deletion 17p [del(17p)], translocation t(4;14), or translocation t(14;16). Revised high-risk (R-HiR) status was defined as the presence of any of these abnormalities or either gain (3 copies) or amplification (amp) of 1q (≥4 copies). Standard-risk (SR) patients had none of the original HRCAs, whereas revised standard-risk (R-SR) patients had none of the revised HRCAs.³

Of the trial participants (n = 395; D-VRd, n = 197; VRd, n = 198), 298 were classified as SR—with an equal distribution between treatment arms (D-VRd, n = 149; VRd, n = 149)—52 were classified as HiR (D-VRd, n = 25; VRd, n = 27), 184 were considered R-SR (D-VRd, n = 94; VRd, n = 90), and 167 were R-HiR (D-VRd, n = 83; VRd, n = 84).³

At 58.7 months, MRD-negativity rates in patients treated with D-VRd were superior to those who received VRd among (64% vs 38%; P < .0001) and R-SR patients (68% vs 38%; P < .0001). D-VRd also improved the rate of sustained MRD negativity for at least one year compared with VRd in both SR (51% vs 26%; P < .0001) and R-SR patients (54% vs 24%; P < .0001).³

In contrast, MRD negativity rates were similar between treatment arms among HiR patients (48% vs 56%; P = .7816) and R-HiR patients (55% vs 45%; P = .2169). Improvements in sustained MRD negativity were also comparable in the HiR (40% vs 37%; P = 1.0000) and R-HiR patients (43% vs 30%; P = .0782).³

PFS improved with D-VRd compared with VRd in both SR and R-SR groups, whereas PFS was similar between treatment arms in HiR and R-HiR groups. In MRD-negative patients, PFS did not differ significantly by treatment in the R-SR group (hazard ratio [HR], 0.63; 95% CI, 0.26–1.52; P = .3003) and in the R-HiR group (HR, 0.71; 95% CI, 0.32–1.58; P = .3995).³

Rates of CR or better, sustained MRD negativity for 2 years or more, and MRD negativity at the 10^-6 sensitivity threshold were all improved in patients receiving D-VRd in SR and R-SR groups. Outcomes between treatment arms in the HiR and R-HiR subgroups were comparable.³

The findings from the CEPHEUS trial validate the clinical benefits and safety of adding daratumumab to VRd and support its use for TIE/TD NDMM regardless of cytogenetic risk status.

REFERENCES

1. A study comparing daratumumab, velcade (bortezomib), lenalidomide, and dexamethasone (D-VRd) with velcade, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. Updated February 10, 2025. Accessed March 3, 2025. https://clinicaltrials.gov/study/NCT03652064

2. Daratumumab plus VRd yields deep, durable responses in patients with NDMM. Pharmacy Times. March 4, 2025. Accessed May 28, 2025. https://www.pharmacytimes.com/view/daratumumab-plus-bortezomib-lenalidomide-and-dexamethasone-yields-deep-durable-responses-in-patients-with-ndmm

3. Bahlis N, Usmani S, Facon T, et al. Daratumumab + bortezomib, lenalidomide, and dexamethasone (DVRd) vs VRd in transplant-ineligible (TIE)/transplant-deferred (TD) newly diagnosed multiple myeloma (NDMM): Phase 3 CEPHEUS trial cytogenetic subgroup analysis. 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL. Abstract 7529