Daratumumab in combination with standard of care, bortezomib, thalidomide, and dexamethasone (VTd) before and after autologous stem-cell transplantation (ASCT) improved depth of response and progression-free survival (PFS) with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. The results were presented at 2019 ASCO Annual Meeting and published simultaneously in The Lancet.
Philippe Moreau of the Hematology, University Hospital Hôtel-Dieu, Nantes, France and colleagues wrote in the study background thatVTd plus ASCT is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. Daratumumab plus standard of care is an effective regimen approved for transplant-ineligible patients with newly diagnosed multiple myeloma. The efficacy and safety of daratumumab as induction and consolidation therapy for transplant-eligible patients with newly diagnosed multiple myeloma was unknown and the CASSIOPEIA is the first phase III study to evaluate daratumumab in that setting.
In this two-part, randomised, open-label, phase III study, the CASSIOPEIA researchers recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned 1:1 to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone or in combination with daratumumab.
The primary endpoint of part 1 was stringent complete response (sCR) assessed 100 days after transplantation. Part 2 (maintenance) is ongoing.
Between 22 September 2015 and 1 August 2017, in total 1085 patients were enrolled; 543 patients were randomly assigned to daratumumab combination with VTd (D-VTd group) and 542 patients to the VTd group.
At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a sCR (odds ratio 1.60, p = 0.0010). In total, 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response (CR) or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease (MRD) negativity (both p < 0.0001).
Median PFS from first randomisation was not reached in either group (hazard ratio 0.47, p < 0.0001).
In the study 46 deaths were observed (14 vs 32, 0.43).
The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%).
D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favourable benefit-risk profile supports the use of D-VTd in transplant-eligible newly diagnosed multiple myeloma.
Overall, D-VTd therapy resulted in a robust clinical benefit that was both statistically significant and clinically meaningful compared with VTd alone. The combination was well tolerated, consistent with the known safety profiles of daratumumab and VTd. The authors cloncluded that D-VTd should be considered a valid treatment option for newly diagnosed multiple myeloma patients who are eligible for ASCT.
The study was funded by The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet; Published online 3 June 2019. pii: S0140-6736(19)31240-1. doi: 10.1016/S0140-6736(19)31240-1.
Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results. J Clin Oncol 37, 2019 (suppl; abstr 8003).