KEY TAKEAWAYS
- A phase 3 PERSIUS study compared subcutaneous DARA with VRd to VRd alone in transplant-eligible NDMM.
- The primary results showed that combining DARA SC with VRd in transplant-eligible NDMM patients significantly improved PFS and response depth, with consistent benefits across subgroups.
The DARA plus bortezomib, thalidomide, and dexamethasone (D-VTd) quadruplet therapy demonstrates clinical benefit over VTd alone and is approved for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM).
In the GRIFFIN study, DARA combined with VRd (D-VRd) showed improved responses and progression-free survival (PFS) compared to standard VRd induction/consolidation with lenalidomide maintenance after >4 years of follow-up.
For the ongoing PERSEUS study, researchers aimed to assess subcutaneous DARA (DARA SC) with VRd induction/consolidation and D-R maintenance to provide insights into its efficacy for transplant-eligible NDMM patients.
Patients aged 18-70 with NDMM, eligible for high-dose therapy and autologous stem cell transplant (ASCT), were randomized 1:1 to receive D-VRd or VRd. All patients underwent up to six 28-day cycles of VRd, followed by lenalidomide maintenance.
The D-VRd arm received daratumumab subcutaneously (DARA SC) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks during maintenance until progressive disease.
The primary endpoint was progression-free survival, and the key secondary endpoints included overall complete response or better rate, overall minimal residual disease–negativity rate (10–5 threshold), and overall survival.
A total of 709 patients participated in the randomized trial (D-VRd, n=355; VRd, n=354), with a median age of 60. Notably, 14.8% had ISS stage III disease, and 21.7% had high cytogenetic risk.
At the clinical cutoff, 314 D-VRd arm patients and 299 VRd arm patients completed induction and consolidation cycles, with 309 and 294 undergoing ASCT. Median follow-up at 47.5 months demonstrated significantly improved progression-free survival (PFS) with D-VRd versus VRd (HR, 0.42; 95% CI, 0.30-0.59; P <0.0001), exceeding prespecified stopping boundaries.
Median PFS was unreached; 48-month rates were 84.3% (D-VRd) versus 67.7% (VRd). Subgroup analyses consistently favored D-VRd. Rates of ≥CR (87.9% vs 70.1%; P <0.0001) and MRD negativity (75.2% vs 47.5%; P <0.0001) were significantly higher with D-VRd. Overall survival data were immature, with 78 deaths, including 7 from COVID-19 (D-VRd, 4; VRd, 3).
The most common grade 3/4 treatment-emergent adverse events (TEAEs) for D-VRd/VRd were neutropenia (62.1%/51.0%), thrombocytopenia (29.1%/17.3%), diarrhea (10.5%/7.8%), pneumonia (10.5%/6.1%), and febrile neutropenia (9.4%/10.1%). Serious TEAEs occurred in 57.0% (D-VRd) versus 49.3% (VRd) of patients, with TEAEs leading to treatment discontinuation in 8.8% (D-VRd) versus 21.3% (VRd).
DARA SC with VRd in transplant-eligible patients with NDMM markedly enhanced PFS and depth of response, including CR and MRD negativity. The benefits, consistent across key subgroups, align with known safety profiles for DARA SC and VRd.
These primary findings, alongside GRIFFIN study results, establish the robust and clinically significant advantages of the DARA plus VRd regimen followed by D-R maintenance, positioning it as a new standard of care for transplant-eligible NDMM.
Source: https://ash.confex.com/ash/2023/webprogram/Paper191911.html
Clinical Trials: https://clinicaltrials.gov/study/NCT02874742
https://clinicaltrials.gov/study/NCT04458051
Sonneveld, P., Dimopoulos, M. A., Boccadoro, M., et al. (2023). “1 Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus VRd Alone in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Eligible for Autologous Stem Cell Transplantation (ASCT): Primary Results of the Perseus Trial.” Presented at the ASH 2023 – 65th American Society of Hematology Annual Meeting and Exposition, December 9-12, 2023, San Diego, CA, US.
