D-VRd Produces Favorable PROs and Safety Outcomes in MRD-Negative Newly Diagnosed Multiple Myeloma

The achievement of minimal residual disease (MRD) negativity following treatment with daratumumab (Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) was associated with positive patient-reported outcomes (PROs) and exposure-adjusted safety outcomes in patients with newly diagnosed multiple myeloma, according to data from an analysis of the phase 3 PERSEUS (NCT03710603) and CEPHEUS trials (NCT03652064) presented during the 22nd Annual International Myeloma Society Meeting and Exposition.1

Findings from the analysis revealed that patients who received D-VRd and achieved MRD negativity in PERSEUS (n = 242) experienced a mean change in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) score of 7.6 (standard error [SE], 2.0) from baseline to the end of cycle 34. Comparatively, patients who received the quadruplet and did not experience MRD negativity (n = 71) had a mean score change of 3.3 (SE, 3.2).

In CEPHEUS, patients with MRD negativity following D-VRd (n = 103) had a mean change in EORTC QLQ-C30 score of 8.5 (SE, 2.8) from baseline to cycle 34. Patients who were MRD positive (n = 61) had a mean score change of 4.2 (SE, 4.3) over the same time span.

Exposure-adjusted safety outcomes showed that patients in PERSEUS who achieved MRD negativity with at least a complete response (CR) experienced any-grade treatment-emergent adverse effects (TEAEs) at a rate of 156.82 events per 100 patient-months. Comparatively, patients who were MRD positive had any-grade TEAEs at a rate of 165.12 events per 100 patient-months. In CEPHEUS, the respective rates of any-grade TEAEs in the MRD-negative and -positive arms were 119.64 events per 100 patient-months and 235.78 events per 100 patient-months.

“Up to now, there is a lack of evidence regarding the impact of MRD negativity on the quality of life [QOL] of our patients,” Jesús San Miguel, MD, PhD, a professor of medicine-hematology and the director of clinical and translational medicine at the University of Navarra in Spain, said during the presentation. “We have shown for the first time that achievement of MRD negativity is associated with favorable PROs and exposure-adjusted safety outcomes.”

San Miguel noted that in April 2024, the FDA’s Oncologic Drugs Advisory Committee voted 12 to 0 in favor of using MRD as an early end point for accelerated approval in multiple myeloma clinical trials.2 “In May [2025], the Committee for Medicinal Products for Human Use of the European Medicines Agency also agreed that MRD negativity can be an end point to support conditional drug approval,” he added.

What Were the Methods of the Analysis?

In PERSEUS, patients were randomly assigned 1:1 to receive D-VRd induction/consolidation plus daratumumab and lenalidomide maintenance or VRd induction/consolidation plus lenalidomide maintenance.1 Patients enrolled in CEPHEUS were randomly assigned 1:1 to receive D-VRd or VRd.

MRD negativity rate at a threshold of 10-5 with at least a CR was a key secondary end point of PERSEUS and a primary end point of CEPHEUS. Patients with indeterminate MRD results or those who achieved MRD negativity without at least a CR were considered to be MRD positive.

PROs were evaluated at baseline and on day 1 of cycles 1 through 3, prior to autologous stem cell transplant, at cycle 5, at cycle 7, and then every 12 weeks subsequently in PERSEUS. In CEPHEUS, PROs were assessed on day 1 of cycles 1 through 8, and then every third cycle. PROs included concepts from the EORTC QLQ-C30; key outcomes included global health status.

At a median follow-up of 47.5 months, the median treatment duration in the D-VRd and VRd MRD-negative groups in PERSEUS was 46.0 months and 45.9 months, respectively. The median treatment duration in the respective arms among MRD-positive patients was 41.3 months and 30.9 months. The median age of the overall patient population was 60 years (range, 31-70).

In CEPHEUS, at a median follow-up of 58.7 months, the median treatment duration in the D-VRd and VRd MRD-negative groups was 57.5 months and 56.6 months, respectively. The respective median treatment durations were 22.5 months and 21.7 months among MRD-positive patients. The median age among all patients was 70 years (range, 31-80).

What Was the Association Between MRD Negativity and Efficacy?

Additional findings from the analysis showed that patients who received D-VRd in PERSEUS and were MRD negative (n = 267) or positive (n = 88) achieved 48-month progression-free survival (PFS) rates of 92.1% and 56.7%, respectively (HR, 0.16; 95% CI, 0.09-0.28). These respective rates were 85.1% and 50.0% among patients who received VRd and were MRD negative (n = 168) or positive (n = 186), respectively (HR, 0.21; 95% CI, 0.13-0.34).

In CEPHEUS, patients who received D-VRd and were MRD negative (n = 120) or positive (n = 77) had 48-month PFS rates of 83.7% and 47.5%, respectively (HR, 0.29; 95% CI, 0.18-0.48). These respective rates were 73.6% and 38.2% among patients who received VRd and were MRD negative (n = 78) or positive (n = 120; HR, 0.35; 95% CI, 0.22-0.55).

The overall MRD-negativity rate in the D-VRd arm (n = 355) of PERSEUS was 75.2% compared with 47.5% in the VRd arm (n = 354; odds ratio [OR], 3.40; 95% CI, 2.47-4.69; P < .0001). These respective rates were 60.9% in the D-VRd (n = 197) and 39.4% in the VRd (n = 198) arms of CEPHEUS (OR, 2.37; 95% CI, 1.58-3.55; P < .0001).

What Were the Additional Safety Findings of the Analysis?

Further safety data showed that patients in the MRD-negative and -positive groups who received D-VRd in PERSEUS experienced grade 3 or 4 TEAEs at rates of 11.89 events per 100 patient-months and 17.65 events per 100 patient-months, respectively. Patients in both arms also experienced serious TEAEs (2.21 vs 3.21), TEAEs leading to treatment discontinuation (0.19 vs 0.35), TEAEs leading to death (0.07 vs 0.19) grade 3 or 4 neutropenia (3.06 vs 4.39), and grade 3 or 4 infections (1.03 vs 1.67).

In CEPHEUS, patients in the MRD-negative and -positive groups who received D-VRd had grade 3 or 4 TEAEs at rates of 11.34 events per 100 patient-months and 13.15 events per 100 patient-months, respectively. Patients in both arms also experienced serious TEAEs (2.99 vs 3.99), TEAEs leading to treatment discontinuation (0.10 vs 0.38), TEAEs leading to death (0.25 vs 0.76) grade 3 or 4 neutropenia (1.51 vs 2.15), and grade 3 or 4 infections (0.98 vs 1.92).

“Overall, these data will reassure physicians that pursuit of MRD negativity in patients with newly diagnosed myeloma does not adversely impact the safety of the patient or their QOL,” San Miguel said in his conclusion.

Disclosures: San Miguel reported participating on advisory boards and providing consulting services on behalf of his institution for AbbVie, Amgen, BMS, Celgene, GSK, Haemalogix, Johnson & Johnson, Karyopharm, MSD, Novartis, Pfizer, Takeda, Regeneron, Sanofi, SecuraBio, and Gilead-Kite.

References

1. San Miguel J, Usmani SZ, Zweegman S, et al. Patient-reported outcomes (PROs) and safety in patients (pts) with NDMM achieving MRD negativity and ≥CR (MRDneg) in the phase 3 PERSEUS and CEPHEUS trials. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-70.
2. April 12, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/watch?v=pooME9gMaL0