The addition of subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction/consolidation followed by daratumumab plus lenalidomide (DR) maintenance continued to improve progression-free survival (PFS) and produce deeper, more durable minimal residual disease (MRD)–negative responses compared with VRd followed by lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma, according to long-term data from the phase 3 PERSEUS trial (NCT03710603) presented at the 23rd International Myeloma Society (IMS) Annual Meeting & Exposition.¹ The benefit was maintained after protocol-defined, MRD-guided discontinuation of daratumumab, with most eligible patients stopping the agent during maintenance.
At a median follow-up of 81.3 months, the 72-month PFS rate was 81.1% among patients treated with daratumumab plus VRd followed by DR maintenance (D-VRd-DR; n = 355) vs 56.1% among those treated with VRd followed by lenalidomide maintenance (VRd-R; n = 354), translating to a 65% reduction in the risk of disease progression or death (HR, 0.35; 95% CI, 0.26-0.46; P < .0001). The median PFS was not reached in the D-VRd-DR arm vs 81.45 months in the VRd-R arm. The rate of sustained MRD negativity (10⁻⁵) with complete response or better (≥CR) lasting at least 12 months was 70.4% vs 36.2%, respectively (OR, 4.29; 95% CI, 3.13-5.89; P < .0001).
PERSEUS Long-Term Takeaways
- At a median follow-up of 81.3 months, D-VRd-DR maintained a PFS benefit over VRd-R in transplant-eligible newly diagnosed multiple myeloma, including in standard- and high-risk cytogenetic subgroups.
- Sustained MRD-negativity rates remained roughly double with the daratumumab-based regimen.
- Nearly 3 of 4 patients receiving DR maintenance stopped daratumumab per MRD-guided protocol criteria, and most remained off therapy.
- PFS2 favored D-VRd-DR despite most VRd-R–treated patients receiving an anti-CD38 antibody at relapse.
"After approximately 7 years of median follow-up, the PERSEUS regimen confirmed deep and durable benefit of daratumumab-based treatment across induction/consolidation and maintenance settings,” said lead study author Pieter Sonneveld, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, the Netherlands, who presented the data.
How was PERSEUS designed?
PERSEUS enrolled patients aged 18 to 70 years with transplant-eligible newly diagnosed multiple myeloma and an ECOG performance status of 0 to 2. Patients were randomly assigned 1:1 to receive 4 cycles of D-VRd induction, autologous stem cell transplant (ASCT), 2 cycles of D-VRd consolidation, and DR maintenance, or the same schedule with VRd and lenalidomide maintenance. Daratumumab was given subcutaneously at 1800 mg co-formulated with recombinant human hyaluronidase PH20. Per protocol, daratumumab was stopped in patients who had received at least 24 months of DR maintenance and achieved ≥CR with at least 12 months of sustained MRD negativity at 10⁻⁵; it could be restarted upon confirmed loss of ≥CR or MRD negativity without progressive disease.
The primary end point was PFS; key secondary end points included overall rate of ≥CR, overall MRD-negativity rate, and overall survival (OS).
In the primary analysis, published in the New England Journal of Medicine, D-VRd-DR reduced the risk of progression or death by 58% vs VRd-R at a median follow-up of 47.5 months, establishing the quadruplet as a standard of care in this setting.² The current analysis adds approximately 34 months of additional follow-up.1
At data cutoff, 61.5% of patients in the D-VRd-DR arm vs 25.4% in the VRd-R arm remained on treatment. The median total treatment duration was 68.7 months (range, 0.49-86.25) vs 42.2 months, and the median duration of maintenance was 63.0 months vs 39.8 months, respectively.
What did additional efficacy analyses show?
The PFS benefit favored D-VRd-DR across prespecified subgroups, including sex, age, International Staging System stage, myeloma type, and baseline ECOG performance status. Among patients with standard-risk cytogenetics, the 72-month PFS rate was 88.3% with D-VRd-DR vs 62.8% with VRd-R (HR, 0.27; 95% CI, 0.18-0.39). Among patients with high-risk cytogenetics—defined as the presence of del(17p), t(4;14), or t(14;16)—the 72-month PFS rates were 55.0% vs 33.4%, respectively (HR, 0.55; 95% CI, 0.34-0.89).
The overall MRD-negativity ≥CR rate at 10⁻⁵ was 77.2% in the D-VRd-DR arm vs 50.3% in the VRd-R arm (OR, 3.41; 95% CI, 2.46-4.73; P < .0001); at 10⁻⁶, the rates were 68.7% vs 36.7% (OR, 3.88; 95% CI, 2.83-5.31; P < .0001). Among patients who were not MRD negative with ≥CR at the end of consolidation, 64.2% of those receiving DR maintenance vs 39.3% of those receiving lenalidomide maintenance converted to MRD negativity (10⁻⁶) with ≥CR during maintenance (OR, 2.76; 95% CI, 1.86-4.10; P < .0001).
Of the 322 patients (91.7%) in the D-VRd-DR arm who received maintenance, 236 (73.3%) stopped daratumumab per protocol after achieving sustained MRD negativity; 175 of these patients (74.2%) had not restarted the agent at data cutoff. The median duration of maintenance before daratumumab discontinuation was 26.83 months (range, 24.5-68.5), and the median time from discontinuation to clinical cutoff was 44.06 months (range, 1.3-52.9).
PFS on the next line of therapy (PFS2) also favored D-VRd-DR (HR, 0.50; 95% CI, 0.37-0.68; P < .0001), with the median not reached in either arm. Fewer patients in the D-VRd-DR arm required second-line therapy (14.2% vs 39.2%), and 72.8% of patients in the VRd-R arm who received second-line therapy were treated with an anti-CD38 antibody.
OS remains immature, with the median not reached in either arm. The 72-month OS rates were 85.9% with D-VRd-DR vs 78.6% with VRd-R (HR, 0.57; 95% CI, 0.40-0.81; P = .0018); 51 and 84 deaths occurred, respectively.
What did the safety analysis show?
No new safety signals were observed with the additional 34 months of follow-up. Treatment discontinuation due to adverse effects (AEs) occurred in 13.4% of patients in the D-VRd-DR arm vs 31.4% in the VRd-R arm, and discontinuation due to progressive disease occurred in 12.3% vs 27.1%, respectively.
References
- 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 (IMS) Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland. Abstract LBA-07.
- 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
