Daratumumab Plus VRd Improves Progression Free Survival in Newly Diagnosed Multiple Myeloma

Patients with newly-diagnosed multiple myeloma may experience significantly improved progression-free survival and depth of response, as well as consistent progression-free survival benefits in certain subgroups, according to the results of a late-breaking abstract presented at the 65th American Society of Hematology Annual Meeting and Exposition.¹

The meeting was held December 9 to 12, 2023, in San Diego, California.

Currently, daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) quadruplet therapy has a demonstrated clinical benefit vs VTd alone for transplant-eligible patients with newly-diagnosed multiple myeloma. Bortezomib, lenalidomide, and dexamethasone (VRd) induction, followed by autologous stem cell transplant, VRd consolidation, and lenalidomide (R) maintenance is also standard of care for this patient population.

Results of the phase 2 GRIFFIN clinical trial (NCT02874742) showed that intravenous daratumumab plus VRd induction/consolidation, followed by daratumumab-lenalidomide (D-R) maintenance, “improved depth of response and progression free survival” vs VRd induction/consolidation and R maintenance in transplant-eligible patients with NDMM after 4 years of follow up. Researchers for the phase 3 PERSEUS clinical trial (NCT03710603) evaluated subcutaneous daratumumab plus VRd induction consolidation followed by D-R maintenance vs VRd induction/consolidation and R maintenance in this patient population.

Adults with newly-diagnosed multiple myeloma who were eligible to receive high-dose therapy and autologous stem cell transplant were randomly assigned 1:1 to receive either D-VRd or VRd, stratified by International Staging System stage and cytogenic risk. Patients were administered up to six 28-day cycles of VRd followed by R maintenance therapy; those in the D-VRd arm also received daratumumab weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks during maintenance until progressive disease.

The primary study endpoint was progression free survival. Key secondary endpoints included overall complete response or better rate, overall minimal residual disease-negativity rate, and overall survival.

A total of 709 patients were included in the study cohort (D-VRd n=355, VRd n=354); median age was 60 years (range, 31-70 years). A total of 14.8% of patients had stage 3 disease, and 21.7% had high cytogenic risk. At the time of the clinical cutoff, 314 and 299 patients in the D-VRd and VRd arms, respectively, completed all 4 induction and 2 consolidation cycles; 309 and 294 patients underwent ACST, and 322 and 300 patients entered the maintenance phase. At a median follow-up of 47.5 months, progression free survival was “significantly improved” in the D-VRd arm vs VRd (HR, 0.42; 95% CI, 0.30-0.59); however, median progression free survival was not reached in either arm, with estimated 48-month progression-free survival rates of 84.3% and 67.7% in each arm.

Prespecified subgroup analyses demonstrated a consistent improvement in progression-free survival in the D-VRd group across clinically relevant subgroups, including those with stage 3 disease and high cytogenic risk. Overall rates of overall complete response or better rate and MRD negativity were significantly higher in the D-VRd group as well (87.9% vs 70.1% and 75.2% vs 47.5%, respectively).

Seventy-eight deaths were noted during the study (34 and 44 patients in each group), with 7 deaths due to COVID-19. Neutropenia, thrombocytopenia, diarrhea, pneumonia, and febrile neutropenia were the most common grade 3/4 treatment-emergent adverse events across both arms, with slightly higher rates of serious treatment-emergent adverse events in the D-VRd group. Treatment discontinuation occurred in 8.8% and 21.3% of patients in the D-VRd and VRd groups, respectively.

“These data, together with results of the phase 3 GRIFFIN study, demonstrate the consistent and clinically meaningful benefit of quadruplet DARA plus VRd followed by D-R maintenance vs triplet VRd followed by R maintenance and support the combination of DARA plus VRd followed by D-R maintenance as a new standard of care for transplant eligible [newly-diagnosed multiple myeloma],” the researchers concluded.

For a full list of author disclosures, see the full text of the abstract online.

Reference

1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. 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: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract LBA-1.