The European Commission has granted marketing authorization for daratumumab in combination with bortezomib, thalidomide, and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.
Philippe Moreau, MD
The European Commission has granted marketing authorization for daratumumab (Darzalex) in combination with bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd) for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).1
The approval is based on results from part 1 of the phase III CASSIOPEIA (MMY3006) trial, which showed that after consolidation therapy, the stringent complete response (sCR) rate was 29% in patients who received daratumumab-VTd compared with 20% for those who received VTd alone (odds ratio [OR], 1.60; 95% CI, 1.21-2.12; P <.0010).2,3 Additionally, the daratumumab-VTd regimen led to a 53% reduction in the risk of disease progression or death (HR, 0.47; 95% CI, 0.33-0.67; P <.0001); the median progression-free survival (PFS) was not reached in either arm.
“The effectiveness of first-line treatment is critical to maximize time until relapse. So, we asked ourselves, can we improve the standard of care that is bortezomib, thalidomide and dexamethasone (VTd) to provide patients with valuable extra time?” principal investigator Philippe Moreau, MD, and head of the Hematology Department at the University Hospital of Nantes, France, stated in a press release. “The CASSIOPEIA study answered that question definitively, demonstrating that the addition of daratumumab in combination with VTd can lead to very deep remissions and also prolong PFS. I’m pleased to see the European Commission have recognized this as well.”
In the open-label, multicenter, phase III CASSIOPEIA trial (NCT02541383), investigators enrolled 1085 patients with newly diagnosed, previously untreated symptomatic multiple myeloma who were eligible for high-dose chemotherapy and ASCT. In part 1 of the trial, patients were first randomized to receive 4 cycles of induction therapy with VTd alone (n = 542) or in combination with daratumumab (n = 543) at 16 mg/kg, high-dose therapy (melphalan), and ASCT, and then consolidation therapy with VTd alone for 2 cycles or combined with daratumumab at 16 mg/kg.
To be eligible for enrollment, patients had to have previously untreated myeloma that is eligible for high-dose chemotherapy and ASCT, as well as an ECOG performance status of 0 to 2. The baseline characteristics were similar between arms. Patients on the trial were aged 18 to 65, the median age was 58.5 years, and most patients had standard-risk disease (84.5%). Moreover, 85% and 81% of patients on the D-VTd and VTd arms, respectively, completed induction and consolidation therapy; a total 90% of patients on the D-VTd arm and 89% of those on the VTd arm underwent ASCT.
The primary endpoint of part 1 of the trial was proportion of patients who achieved sCR. In the second part of CASSIOPEIA, which is ongoing, patients who achieved a partial response or better in part 1 of the trial will then undergo a second randomization to either receive maintenance daratumumab at 16 mg/kg every 8 weeks for up to 2 years or observation. The primary endpoint of this phase is PFS.
At a median follow-up of 18.8 months, the overall response rate post-consolidation therapy was 92.6% with D-VTd and 89.9% with VTd; the ≥complete response (CR) rates were 39% and 26%, respectively. Additionally, the CR rates were 10% and 6%, and the very good partial response rates were 45% and 52%, respectively. The partial response rates were 9% and 12% for the D-VTd and VTd-alone arms, respectively. Responses were also found to deepen over time.
Additionally, the 18-month PFS rate was 93% with the daratumumab regimen and 85% with VTd alone, and the PFS benefit was observed across all patient subgroups. The overall survival data were still immature at the time of data cutoff, with 14 deaths reported for the daratumumab arm compared with 32 deaths for the control arm (HR, 0.43; 95% CI, 0.23-0.80).
In part 1, the most frequently (≥10%) reported grade 3/4 adverse events in the daratumumab arm were neutropenia (28% vs 15% in the VTd arm), lymphopenia (17% vs 10%, respectively) stomatitis (13% vs 16%), and thrombocytopenia (11% vs 7%). Infusion-related reactions were experienced by 35% of patients who received the daratumumab regimen.
Data from a subgroup analysis of CASSIOPEIA that were presented at the 17th International Myeloma Workshop also showcased an improvement in minimal residual disease negativity rates and PFS with D-VTd compared with VTd alone in patients with high-risk multiple myeloma.4 Results showed that D-VTd led to a 34% reduction in the risk of disease progression or death compared with VTd alone in those with International Staging System (ISS) stage III disease (HR, 0.66; 95% CI, 0.32-1.39). In patients with high-risk cytogenetics, the daratumumab regimen reduced the risk of disease progression or death by 33% (HR, 0.67; 95% CI, 0.35-1.30). However, no benefit with sCR was observed with D-VTd over VTD alone in those with ISS stage III disease or high-risk cytogenetics.
“This approval represents our commitment to investigate daratumumab in earlier disease stages of multiple myeloma and to develop more effective frontline treatment options for newly diagnosed patients who are eligible for transplantation,” Craig Tendler, MD, vice president, Clinical Development and Global Medical Affairs, Oncology, of Janssen Research and Development, the developer of daratumumab, concluded in the press release.