Subcutaneous Daratumumab Quadruplet Approaches EU Approval for Newly Diagnosed Myeloma

The European Medicines Agency’s Committee for Medicinal Products for Human Use issued a positive opinion supporting the approval of a type II variation for subcutaneous daratumumab (Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) for use in adult patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplant (ASCT).¹

The recommendation is supported by findings from the phase 3 PERSEUS study (NCT03710603).² Data from the primary analysis showed that at a median follow-up of 47.5 months (range, 0-54.4), the estimated 48-months progression-free survival (PFS) rate was 84.3% (95% CI, 79.5%-88.1%) with daratumumab plus VRd induction and consolidation therapy and with maintenance lenalidomide (D-VRd; n = 355) vs 67.7% (95% CI, 62.2%-72.6%) with VRd induction and consolidation therapy and maintenance lenalidomide alone (VRd; n = 354), translating to a 58% reduction in the risk of disease progression or death (HR, 0.42; 95% CI, 0.30-0.59; P < .001).

Deep and durable minimal residual disease (MRD) negativity was achieved with D-VRd. The percentage of patients with MRD-negative status assessed at a sensitivity threshold of 10-5 was 75.2% in the D-VRd arm vs 47.5% in the VRd arm (odds ratio [OR], 3.40; 95% CI, 2.47-4.69; P < .0001). The percentage of patients who had sustained MRD negativity for at least 1 year was 64.8% in the D-VRd arm and 29.7% in the VRd arm (OR, 4.42; 95% CI, 3.22-6.08; P < .0001). The percentage of patients with MRD-negative status assessed at a sensitivity threshold of 10-6 was 65.1% with D-VRd vs 32.2% with VRd (OR, 3.97; 95% CI, 2.90-5.43; P < .0001).

Updated findings were shared at the 2024 ASCO Annual Meeting and showed that responses continued to deepen over time with D-VRd vs VRd.3 Overall, in the intention-to-treat population, the complete response (CR) or better rates in the respective arms were 87.9% and 70.1%, respectively. Rates of deeper MRD negativity at 10-6 were observed with D-VRd vs VRd. In the D-VRd arm, MRD-negativity 10-6 rates at the end of consolidation, up to 1 year, up to 2 years, and up to 3 years were 34.4%, 43.9%, 57.7%, and 63.9%, respectively; in the VRd arm, these respective rates were 16.1%, 20.9%, 27.4%, and 30.8%. Moreover, MRD-negativity 10-5 rates at these respective time points in the D-VRd arm were 57.5%, 65.1%, 72.1%, and 74.6%; in the VRd arm, these rates were 32.5%, 38.7%, 44.9%, and 46.9%.

“Optimising frontline therapy is crucial in disease control and improving long-term outcomes for patients with newly diagnosed multiple myeloma,” Edmond Chan, MBChB, MD (ses), EMEA Therapeutic Area Lead Haematology at Johnson & Johnson Innovative Medicine, stated in a news release.¹ “By incorporating [subcutaneous] daratumumab into this novel quadruplet regimen, we aim to establish a new standard of care for eligible patients, enhancing progression-free survival and transforming the treatment landscape.”

PERSEUS: Design, Treatment, and Objectives

The open-label, multicenter, phase 3 trial enrolled patients with newly diagnosed multiple myeloma who were eligible to receive high-dose therapy and ASCT.^2,3 They were required to be between the ages of 18 years and 70 years with an ECOG performance status ranging from 0 to 2.

Participants were randomly assigned 1:1 to the D-VRd or VRd arms. Those in the D-VRd arm were given 1800 mg of subcutaneous daratumumab weekly for cycles 1 and 2 and every 2 weeks for cycles 3 and 4. Bortezomib was given subcutaneously at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11; oral lenalidomide was given at 25 mg on days 1 to 21; and dexamethasone was administered intravenously at 40 mg on days 1 to 4 and 9 to 12. After transplant, they received consolidation treatment with 1800 mg of subcutaneous daratumumab every 2 weeks plus VRd at the same dose and schedule as in the induction phase. In the maintenance phase, patients received subcutaneous daratumumab at 1800 mg every 4 weeks plus 10 mg of lenalidomide on days 1 to 28 for a minimum of 2 years. Patients who had MRD positivity continued treatment with daratumumab and lenalidomide until disease progression; those with a CR or better and sustained MRD negativity 10^-5 of 12 months stopped daratumumab and continued to receive lenalidomide if they lost CR and did not experience disease progression or MRD recurrence, they were able to restart daratumumab.

Those in the VRd arm received induction treatment with VRd at the same dose and schedule as those in the investigative arm, followed by transplant and subsequent consolidation treatment with VRd. In the maintenance phase, they received 10 mg of lenalidomide for days 1 to 28 until disease progression.

The primary end point of the study was PFS, and key secondary end points were overall CR or better rate, overall MRD negativity rate, and overall survival.

Additional Efficacy Data

Investigators also examined MRD negativity in patients with high-risk disease. MRD negativity 10^-6 was achieved by 57.9% of those given D-VRd (n = 76) vs 30.8% (n = 78) with VRd; 30.3% and 14.1% of patients experienced sustained negativity status of at least 12 months.³ Moreover, MRD negativity 10-5 was achieved by 68.4% and 47.4% of patients in the D-VRd and VRd arms, respectively; sustained negativity status of 12 months or longer was achieved by 48.7% and 25.6% of patients, respectively. PFS was again improved with D-VRd vs VRd in patients with MRD-negative, high-risk disease (HR, 0.62; 95% CI, 0.21-1.84; P = .3853).

During the maintenance phase, a higher proportion of patients in the D-VRd arm (10^-5, n = 88; 10^-6 n = 134) converted to MRD-negative status vs the VRd arm (10^-5, n = 121; 10^-6, n = 155). The respective percentages were 60.2% and 40.5% for MRD negativity 10-5 (P = .0049); for MRD negativity 10-6, these rates were 56.7% and 25.2% (P < .0001). Sustained MRD negativity 10-5 was achieved by 38.6% and 17.4% of patients, respectively (P = .0006); and sustained MRD negativity 10-6 was achieved by 31.3% and 10.3% of patients, respectively (P < .0001).

References

1. DARZALEX (daratumumab)-based quadruplet regimen receives positive CHMP opinion for transplant-eligible patients with newly diagnosed multiple myeloma. News release. Janssen-Cilag International NV. September 20, 2024. Accessed September 20, 2024. https://www.jnj.com/media-center/press-releases/darzalex-daratumumab-based-quadruplet-regimen-receives-positive-chmp-opinion-for-transplant-eligible-patients-with-newly-diagnosed-multiple-myeloma
2. 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
3. Rodríguez-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