PERSEUS Trial Shows Daratumumab Regimen Deepens Responses in NDMM

Combining daratumumab (Darzalex) with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (DVRd) produced deep, durable responses vs VRd alone among patients with newly diagnosed multiple myeloma (NDMM), according to updated findings from the phase 3 PERSEUS study (NCT03710603) presented at the 23rd Annual International Myeloma Society (IMS) Meeting & Exposition.

What were the efficacy findings from the PERSEUS trial?

With a median follow-up of 81.3 months, the median progression-free survival (PFS) was not reached (NR) with DVRd followed by DR maintenance vs 81.45 months with VRd followed by lenalidomide maintenance (HR, 0.35; 95% CI, 0.26-0.46; P <.0001). The 72-month PFS rates were 81.1% vs 56.1% in each respective arm. With a PFS HR of 0.27 in the standard-risk population, daratumumab-based treatment extended a PFS benefit to all clinically relevant subgroups vs VRd.

The overall MRD-negative complete response (CR) or better rate was 77.2% in the DVRd arm vs 50.3% in the VRd arm at the 10^–5 threshold (OR, 3.41; 95% CI, 2.46-4.73; P <.0001). Based on the 10^–6 threshold, these rates were 68.7% vs 36.7%, respectively (OR, 3.88; 95% CI, 2.83-5.31; P <.0001). Patients in the DVRd arm were more likely to experience MRD conversion from the end of consolidation therapy to MRD negativity during maintenance treatment at the 10^–5 threshold (OR, 1.86; 95% CI, 1.15-2.99; P = .0108) and the 10^–6 threshold (OR, 2.76; 95% CI, 1.86-4.10; P <.0001). At both thresholds, sustained MRD-negative CRs for at least 12, 24, or 36 months were more likely with DVRd-DR vs VRd followed by lenalidomide maintenance.

Regarding PFS on the next line of therapy (PFS2), the median value was NR in either arm, although outcomes favored the DVRd arm (HR, 0.50; 95% CI, 0.37-0.69; P <.0001). Additionally, 14.2% and 39.2% of the patients in the DVRd and VRd arms, respectively, received subsequent second-line therapy, which included anti-CD38 agents in 16.0% and 72.8% of those patients.

Although overall survival (OS) data were immature at the time of the analysis, the median OS was NR in both arms. The 72-month OS rates were 85.9% with DVRd and 78.6% with VRd.

“After 7 years of median follow-up, the PERSEUS [trial] confirms deep and durable benefit of the daratumumab-based treatment arm, including induction, consolidation, and maintenance…No safety signals were observed with an additional 3 years of follow-up,” lead study investigator Pieter Sonneveld, MD, PhD, a professor of hematology at Erasmus MC Cancer Institute in Rotterdam, the Netherlands, said while presenting these findings. “DVRd plus [daratumumab/lenalidomide maintenance] demonstrated among the deepest and most durable responses in newly diagnosed patients, even after protocol MRD-guided discontinuation of daratumumab maintenance.”

How was the PERSEUS trial designed?

Investigators of the PERSEUS study enrolled 709 patients with transplant-eligible NDMM who were 18 to 70 years old with an ECOG performance status of 0 to 2. Patients were randomly assigned 1:1 to receive induction therapy with VRd or DVRd followed by single transplant. After receiving the same regimens in the consolidation phase, maintenance treatment consisted of lenalidomide alone in the comparator arm or daratumumab/lenalidomide for at least 2 years in the experimental arm. Patients who were MRD positive after maintenance in the experimental arm continued their treatment until progressive disease; those who achieved MRD negativity were eligible to stop daratumumab after at least 24 months and were instructed to restart daratumumab upon confirmed loss of MRD-negative status or loss of CR without progressive disease.

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

In the DVRd (n = 355) and VRd (n = 354) arms, 20.0% and 29.9% of patients discontinued study treatment, including 14.4% and 23.7% due to death. The total median duration of therapy was 68.7 months (range, 0.49-88.25) and 42.2 months (range, 0.07-87.72) in each arm.

Among 351 evaluable patients in the DVRd arm during the maintenance phase, 73.3% (n = 236) of patients stopped daratumumab, and 74.2% (n = 175) of these patients did not restart daratumumab. Regarding these data, Sonneveld reinforced the feasibility of the sustained MRD-guided daratumumab discontinuation during maintenance therapy.

“[Because] we see a plateau in the [PFS] and a clear benefit for [OS] already, we can tell the patient that if they are MRD negative and remain MRD negative, they have a very good probability of long-term [PFS] and also [OS],” Sonneveld stated in a conversation with CancerNetwork® about how clinicians can counsel patients with transplant-eligible NDMM based on MRD clearance. “The long-term outcomes for this group of patients, those who are MRD negative with no signals of [multiple] myeloma, are projected to be very good, and they may be somewhere between 10 and 17 years in the future.”

Reference

Sonneveld P, Boccadoro M, Dimopoulos MA, et al. Long-term outcomes with daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) versus VRd in transplant-eligible newly diagnosed multiple myeloma (TE-NDMM) in the phase 3 PERSEUS study. Presented at: 23rd International Myeloma Society Annual Meeting; September 23–26, 2026; Glasgow, Scotland. Abstract LBA-07.