The majority of patients with newly diagnosed multiple myeloma (NDMM) are treated with induction therapy followed by autologous stem cell transplant (ASCT) and consolidation therapy. The combination of bortezomib, thalidomide, and dexamethasone (VTd) is one of the standard induction/consolidation regimens. Daratumumab, a CD38-targeting antibody, is effective as monotherapy and in combinations in relapsed or refractory multiple myeloma. Furthermore, daratumumab is an approved front-line treatment option in combination with bortezomib, melphalan, and prednisone for patients who are not eligible for ASCT. The randomized phase III CASSIOPEIA trial is the first study evaluating the role of daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma. In the first part of the study, daratumumab in combination with VTd (D-VTd) was compared with standard VTd as induction and consolidation therapy in 1085 transplant eligible patients aged less than 66 years with NDMM. The second part of the ongoing study compares maintenance of daratumumab with no maintenance in those patients who achieved at least partial response after consolidation. Results from part 1 of the study were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 8003) and the 24th Congress of the European Hematology Association (EHA, Abstract S145), and were also published in The Lancet.
With a median follow-up of 18.8 months, 90% of patients underwent ASCT and 85% of patients on D-VTd arm and 81% on VTd arm completed induction and consolidation. The overall response rate (ORR) was similar between the two treatment arms (93% vs 90%), but significantly more patients in the D-VTd arm achieved a complete response (CR) or better (39% vs 26%; P<.0001). The primary endpoint was stringent complete response (sCR) postconsolidation and was assessed day 100 post-ASCT. The sCR rate was significantly higher with D-VTd compared to VTd (29% vs 20% P = .0010). The benefit of daratumumab was consistent across all prespecified patient subgroups, with the exception of patients with high-risk cytogenetics and patients with International Staging System (ISS) stage III disease. When evaluating minimal residual disease (MRD) after consolidation, a greater proportion of patients in the D-VTd arm achieved MRD negativity compared to VTd (64% vs 44%; P<.0001). Of note, the addition of daratumumab improved MRD negativity across all patient subgroups, including those with high-risk cytogenetics and ISS stage III disease. Furthermore, responses deepened over time.
The addition of daratumumab to VTd also resulted in a significant improvement in median progression-free survival (HR 0.47, P<.0001). The 18-month progression-free survival (PFS) rate was 93% in the D-VTd arm, compared to 85% in the VTd arm, corresponding to a 53% reduction in the risk of progression or death. D-VTd reduced risk of progression in all patient subgroups, including patients with high-risk cytogenetics and ISS stage III disease. Overall survival (OS) are immature and the median OS has not been reached in either treatment arm. The estimated 2-year OS rates are 97% and 93% for D-VTd and VTd, respectively (HR 0.43).
D-VTd was associated with a manageable adverse event (AE) profile that is consistent with the known safety profile of daratumumab. With the exception of infusion related reactions that occurred in 35% of patients treated with D-VTd, the rates of nonhematologic AEs were similar in both treatment arms. While treatment with D-VTd was associated with higher rates of grade 3/4 neutropenia (28% vs 15%) and lymphopenia (17% vs 10%), these did not translate into higher rates of grade 3/4 infection (22% vs 20%).
The investigators concluded that the addition of daratumumab to standard induction and consolidation therapy in transplant-eligible patients with NDMM is safe and associated with significant and clinically meaningful benefits, including improved depth of response and prolonged PFS, and this combination should be considered as a valid treatment option for these patients.