Subcutaneous daratumumab plus VRd significantly improves PFS in patients with newly-diagnosed, transplant-eligible multiple myeloma
Results of the primary analysis of the phase III PERSEUS study demonstrated that induction with subcutaneous daratumumab in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), followed by autologous stem cell transplantation (ASCT), D-VRd consolidation and D-R maintenance significantly improved progression-free survival versus VRd induction followed by ASCT, VRd consolidation and R maintenance in transplant-eligible patients with newly-diagnosed multiple myeloma.
For transplant-eligible patients with newly-diagnosed multiple myeloma (NDMM), induction with bortezomib, lenalidomide and dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT), VRd consolidation and lenalidomide maintenance is considered the standard of care. In the phase II GRIFFIN study, intravenous daratumumab combined with VRd (D-VRd) induction/consolidation followed by D-R maintenance improved depth of response and progression-free survival (PFS) versus VRd induction/consolidation and R maintenance in transplant-eligible patients with NDMM after >4 years of follow-up. The phase III PERSEUS study is evaluating subcutaneous (SC) daratumumab in combination with VRd induction/consolidation followed by D-R maintenance versus VRd induction/consolidation and R maintenance in transplant-eligible NDMM. The primary results of this study were presented at ASH 2023.
Study design
PERSEUS is a multicentre, randomised, open-label, phase III study. Patients aged 18-70 years with newly diagnosed multiple myeloma who were eligible for high-dose therapy and an autologous stem cell transplant were randomised (1:1) to D-VRd or VRd. All patients received up to six 28-day treatment cycles, of which 4 cycles as induction therapy before the stem cell transplant and 2 cycles as consolidation therapy after the stem cell transplant, of VRd (bortezomib 1.3 mg/m2 SC on days 1, 4, 8 and 11; lenalidomide 25 mg PO on days 1-21; and dexamethasone 40 mg PO or IV on days 1-4 and 9-12). They then received maintenance treatment with lenalidomide (10 mg PO on days 1-28) until disease progression. Patients in the D-VRd arm also received subcutaneous daratumumab (1,800 mg co-formulated with recombinant human hyaluronidase PH20) weekly in cycles 1-2, every 2 weeks in cycles 3-6, and every 4 weeks during maintenance until disease progression. After at least 24 months of maintenance therapy, daratumumab could be discontinued in patients who achieved a complete response or better (≥CR) and sustained minimal residual disease (MRD) negativity for at least 12 months. The primary endpoint was progression-free survival (PFS) and key secondary endpoints include the percentage of patients in whom a ≥CR was achieved, the overall MRD-negativity rate (10-5 threshold) and overall survival (OS).
Results
Out of the 709 patients that were randomised, 698 received at least one dose of the assigned treatment. Median age of the patients was 60.0 years, 58.7% were female, 14.8% had stage III disease and 21.7% had high-risk cytogenetics. At the time of the primary analysis, 314 of 351 patients (89.5%) in the daratumumab group and 299 of 347 patients (86.2%) in the control group had completed all four induction and two consolidation cycles. Furthermore, 89.7% in the D-VRd group and 87.0% in the VRd group had undergone an ASCT and respectively 91.7% and 86.5% entered maintenance.
After a median follow-up of 47.5 months, treatment with D-VRd resulted in significantly longer PFS than treatment with VRd (HR[95% CI]: 0.42[0.30-0.59], p< 0.0001). Median PFS was not reached in either group and the estimated 4-year PFS rates were 84.3% in the D-VRd group and 67.7% in the VRd groups. Prespecified subgroup analyses confirmed that treatment with daratumumab led to an improvement in PFS in clinically relevant subgroups, including patients with stage III disease and patients at high cytogenetic risk. Both the ≥CR rate (87.9% vs. 70.1%; p< 0.0001) and the MRD negativity rate (75.2% vs. 47.5%; p<0.0001) were significantly higher in the daratumumab group. In total, 64% of patients receiving maintenance in the D-VRd group discontinued daratumumab after achieving sustained MRD negativity per protocol. Overall survival data were not mature yet, 78 patients died during the study, including 34 patients (9.6%) in the daratumumab group and 44 patients (12.4%) in the control group (HR: 0.73). The most common grade 3 or 4 treatment-related adverse events (TRAEs) were neutropenia (62.1% vs. 51.0%), thrombocytopenia (29.1% vs. 17.3%), diarrhoea (10.5% vs. 7.8%), pneumonia (10.5% vs. 6.1%) and febrile neutropenia (9.4% vs. 10.1%). Serious AEs occurred in 57.0% of patients in the daratumumab group and 49.3% of patients in the control group. The most common serious AE was pneumonia (11.4% vs. 6.1%). Treatment had to be discontinued due to a TRAE in 8.8% and 21.3% of patients in the D-VRd and VRd arms, respectively.
Conclusion
Subcutaneous daratumumab plus VRd induction, followed by ASCT, D-VRd consolidation, and D-R maintenance significantly improved PFS vs. VRd induction followed by ASCT, VRd consolidation and R maintenance in transplant-eligible patients with NDMM. Furthermore, the D-VRd regimen significantly improved the depth of response and the observed safety profile was consistent with the known safety profiles for subcutaneous daratumumab and VRd.
Reference
Sonneveld P, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplantation (ASCT): primary results of the PERSEUS trial. Presented at ASH 2023; Abstract LBA-1.
