SC Daratumumab Plus VRd Earns EU Approval in Newly Diagnosed, Transplant-Eligible Myeloma

The subcutaneous (SC) formulation of daratumumab (Darzalex) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) has been approved by the European Commission (EC) for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).¹

The indication extension was supported by findings from the phase 3PERSEUS study (NCT03710603), which showed that at a median follow-up of 47.5 months, patients who received D-VRd followed by maintenance therapy with SC daratumumab and lenalidomide (n = 355) experienced a 58% reduction in the risk of disease progression or death compared with those who received VRd alone followed by lenalidomide maintenance (n = 354; HR, 0.42; 95% CI, 0.30-0.59; P < .0001). The 48-month progression-free survival (PFS) rates were 84.3% vs 67.7%, respectively.²

The minimal residual disease (MRD)–negativity rates at a threshold of 10-5 were 75.2% vs 47.5% in the investigational and control arms, respectively (odds ratio [OR], 3.40; 95% CI, 2.47-4.69; P < .0001). At a threshold of 10-6, these rates were 65.1% vs 32.2%, respectively (OR, 3.97; 95% CI, 2.90-5.43; P < .0001). Patients sustained MRD negativity (10-5) for at least 12 months at rates of 64.8% vs 29.7%, respectively (OR, 4.42; 95% CI, 3.22-6.08; P < .0001).

“Multiple myeloma is a complex and highly varied disease, which reinforces the need for continuous innovation in first-line treatment strategies to deepen responses, reduce relapse and ultimately improve long-term outcomes,” Paula Rodriguez-Otero, MD, associate clinical professor, Department of Hematology, and deputy director, Expert Degree in Immuno-Oncology, Cancer Center Clínica Universidad de Navarra, in Pamplona, Spain, stated in a news release.¹ “The EC’s approval of this daratumumab SC–based quadruplet regimen offers a practice-changing new option, that has shown the potential to significantly improve PFS, complete response [CR] rates, and MRD-negativity status compared to the current standard of care.”

PERSEUS enrolled patients 18 to 70 years of age with newly diagnosed multiple myeloma and an ECOG performance status of 2 or less.²

Eligible patients were randomly assigned 1:1 to receive SC daratumumab at 1800 mg weekly for the first 2 cycles and once every 2 weeks for cycles 3 and 4, plus SC bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, lenalidomide at 25 mg on days 1 through 21, and dexamethasone at 40 mg on days 1 through 4 and 9 through 12. Patients in the control arm received VRd at the same dosing schedule; both arms underwent ASCT then received D-VRd or VRd consolidation therapy for 2 additional cycles.²

Patients in the control arm received lenalidomide at 10 mg on days 1 through 28 until disease progression as maintenance therapy. In the investigational arm, patients received SC daratumumab at 1800 mg every 4 weeks plus lenalidomide at 10 mg on days 1 through 28 as maintenance therapy for a minimum of 2 years. If patients were MRD positive after 2 years, they continued with daratumumab plus lenalidomide until disease progression. If patients achieved MRD negativity after 2 years, they stopped daratumumab and continued with lenalidomide after at least 24 months of maintenance therapy with the combination if they achieved a CR or better and 12 months of sustained MRD negativity at a threshold of 10-5. Daratumumab treatment was restarted upon the confirmed loss of CR without disease progression or recurrence of MRD.

The primary end point was PFS. Overall CR or better rate, overall survival (OS), and MRD-negativity rate at 10-5 represented key secondary end points.

Additional findings from PERSEUS demonstrated that the CR or better rate was 87.9% in the investigational arm, including a 69.3% stringent CR rate and an 18.6% CR rate; patients also experienced a very good partial response (VGPR; 7.3%), partial response (PR; 1.4%), and stable disease, disease progression, or were not evaluable (3.4%). In the control arm, patients achieved a CR or better (70.1%), stringent CR (44.6%), CR (25.4%), VGPR (19.2%), PR (4.5%), or stable disease, disease progression, or were not evaluable (6.2%).

At a threshold of 10-5, the sustained MRD negativity rates for at least 18 months were 59.4% vs 25.1% for the D-VRd and VRd arms, respectively.

In terms of safety, any-grade adverse effects (AEs) were reported in the D-VRd (n = 351) and VRd (n = 347) arms at rates of 99.4% and 99.1%, respectively. The most common any-grade AEs included infections (86.9% for D-VRd vs 76.7% for VRd), neutropenia (69.2% vs 58.8%), and diarrhea (61.0% vs 54.2%). Serious AEs (57.0% vs 49.3%), AEs leading to treatment discontinuation (8.8% vs 21.3%), and AEs leading to death (3.7% vs 4.6%) were reported in both arms.³

“The EC’s approval of this daratumumab quadruplet regimen marks a pivotal step forward in the treatment of newly diagnosed multiple myeloma,” Edmond Chan, MD, MBChB, senior director, EMEA Therapeutic Area Lead Hematology, Innovative Medicine, Johnson & Johnson, added in the news release.1 “By incorporating daratumumab SC into this regimen we are further optimizing frontline therapy for patients, building on our aim to transform outcomes, and establish new standards of care for eligible patients from induction through to maintenance.”

References

1. Darzalex (daratumumab)-SC based quadruplet regimen approved by the European Commission for patients with newly diagnosed multiple myeloma who are transplant-eligible. News release. Janssen-Cilag International NV. October 23, 2024. Accessed October 23, 2024. https://innovativemedicine.jnj.com/newsroom/oncology/darzalex-daratumumab-sc-based-quadruplet-regimen-approved-by-the-european-commission-for-patients-with-newly-diagnosed-multiple-myeloma-who-are-transplant-eligible
2. Rodriguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial. J Clin Oncol. 2024;42(suppl 16):7502. doi:10.1200/JCO.2024.42.16_suppl.7502
3. 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