Subcutaneous Daratumumab Combo Sustains MRD-Negative Status in NDMM

“Sustained MRD negativity was associated with a PFS benefit, with more than 95% with [at least] 12- or 24-month sustained MRD negativity remaining progression free at 48 months,” according to study author Philippe Moreau, MD.

Adding subcutaneous daratumumab (Darzalex) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) as induction and consolidation therapy followed by maintenance with daratumumab/lenalidomide sustained minimal residual disease (MRD)–negative status, produced enduring responses, and improved progression-free survival (PFS) among those with transplant-eligible newly diagnosed multiple myeloma (NDMM), according to findings from the phase 3 PERSEUS trial (NCT03710603) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Within 18 months of treatment initiation, 3.1% (n = 11/355) of patients who received D-VRd had functionally high-risk disease vs 6.8% (n = 24/354) of those who received VRd alone. When accounting for pre-progression deaths, the rates of functionally high-risk status were 5.4% (n = 19/355) and 11.0% (n = 39/354) in each respective arm.

With a median follow-up of 47.5 months, the 48-month PFS rate was 84.3% with D-VRd vs 67.7% with VRd (HR, 0.42; 95% CI, 0.30-0.59; P <.0001). At a threshold of 10^–5, the MRD-negative status rate was 75.2% vs 47.5% in each arm (OR, 3.40; 95% CI, 2.47-4.69). The MRD-negative rates at a threshold of 10^–6 were 65.1% vs 32.2% (OR, 3.97; 95% CI, 2.90-5.43; P <.0001).

In the D-VRd and VRd arms, respectively, sustained MRD-negative status with a complete response (CR) or better for at least 12 months occurred in 64.8% vs 29.7% of patients at a threshold of 10^–5 (OR, 4.42; 95% CI, 3.22-6.08; P <.0001). Sustained MRD-negative status with a CR or better for at least 24 months was reported in 55.8% and 22.6% of patients, respectively (OR, 4.36; 95% CI, 3.15-6.05).

Of note, the rates of sustained and nonsustained MRD negativity with a CR or better for at least 12 months in the D-VRd arm, respectively, were 55.7% and 46.4% for patients with International Staging System stage I disease, 79.6% and 64.8% for those with standard cytogenetic risk, and 16.1% and 31.2% for those with high-risk cytogenetics. Treatment with D-VRd produced higher rates of sustained MRD-negative status with CRs or better across patient subgroups.

Among patients with sustained MRD-negative status with a CR or better for at least 12 months, the 48-month PFS rates were 95.3% with D-VRd vs 94.2% with VRd (HR, 0.83; 0.3-2.3). Regarding patients with sustained MRD negativity with CRs or better for at least 24 months, the 48-month PFS rates were 97.8% vs 98.8% in each treatment arm.

“Higher rates of sustained MRD negativity were achieved with [D-VRd] vs VRd alone, with nearly two-thirds of patients achieving sustained MRD negativity for more than 12 months, and more than half achieving sustained MRD negativity for more than 24 months,” presenting study author Philippe Moreau, MD, head of the Hematology Department at the University Hospital of Nantes, France, stated.¹ “Sustained MRD negativity was associated with a PFS benefit, with more than 95% with [at least] 12- or 24-month sustained MRD negativity remaining progression free at 48 months.”

Investigators of this post hoc analysis of the PERSEUS trial aimed to determine whether D-VRd plus daratumumab/lenalidomide maintenance could reduce the number of patients with functionally high-risk status while evaluating the impact of sustained MRD negativity with CR or better on PFS.

A total of 709 patients were randomly assigned 1:1 to receive induction therapy with VRd or D-VRd as part of four 28-day cycles followed by single transplant. Patients then received consolidation therapy with VRd or D-VRd for two 28-day cycles; maintenance therapy in the control arm consisted of lenalidomide alone.

Patients in the experimental arm received maintenance therapy with daratumumab/lenalidomide for a minimum of 2 years. Those with MRD-positive status during this period continued maintenance until progressive disease, while those with sustained MRD negativity for at least 12 months discontinued daratumumab/lenalidomide and restarted treatment per trial protocol.

Investigators defined the MRD-negative rate as the proportion of patients with MRD-negative status and a CR or better in the intent-to-treat (ITT) population. Those with indeterminate results were considered to have MRD-positive disease. The analysis included an evaluation of MRD status following consolidation therapy at the time of suspected CR or stringent CR; at 12, 18, 24, 30, and 36 months following day 1 of cycle 1; and every year thereafter.

The trial’s primary end point was PFS.² Secondary end points included overall MRD-negative rate, objective response rate, overall survival, time to response, duration of response, and time to engraftment following autologous stem cell transplantation.

Of note, among patients with functionally high-risk disease (n = 35) and the ITT population (n = 709), 25.7% and 14.8% had ISS stage III disease. Additionally, 57.1% vs 21.7% had high cytogenetic risk, and 91.4% vs 83.1% had symptoms consistent with calcium, renal, anemia, and bone (CRAB) criteria.

References

1. Moreau P, Sonneveld P, Einsele H, et al. Subcutaneous daratumumab (Dara) + bortezomib/lenalidomide/dexamethasone (VRd) with Dara + lenalidomide (DR) maintenance in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM): analysis of sustained minimal residual disease negativity in the phase 3 PERSEUS trial. J Clin Oncol. 2025;43(suppl 16):7501. doi:10.1200/JCO.2025.43.16_suppl.7501
2. Daratumumab, VELCADE (bortezomib), lenalidomide and dexamethasone compared to VELCADE, lenalidomide and dexamethasone in subjects with previously untreated multiple myeloma (Perseus). ClinicalTrials.gov. Updated December 12, 2024. Accessed June 3, 2025. https://tinyurl.com/yvxnbfd8