FDA Approves Frontline Daratumumab Regimen for Transplant-Eligible Myeloma

The FDA has approved 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) study, in which the stringent complete response (sCR) rate at post-consolidation therapy was 29% in patients who received the daratumumab regimen compared with 20% in those who received VTd alone following consolidation therapy (odds ratio [OR], 1.60; 95% CI, 1.21-2.12; P = .0010).

"Today’s approval is an important step forward for patients with multiple myeloma. There are now three different treatment combinations that include Darzalex for patients newly diagnosed with multiple myeloma, whether they are eligible for ASCT or not. We are grateful for the efforts of the IMF, HOVON and Janssen that led to the strong data from the CASSIOPEIA trial, which formed the basis of this new approval,” Jan van de Winkel, PhD, chief executive officer of Genmab, stated in a press release.

In the open-label, multicenter, phase III trial (NCT02541383) 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, and 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 progression-free survival (PFS).

In results that were presented at the 2019 ASCO Annual Meeting, at a median follow-up of 18.8 months, the overall response rate (ORR) post-consolidation therapy was 93% with D-VTd and 90% 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 (VGPR) rates were 45% and 52%, respectively. The partial response rates were 9% and 12% for the D-VTd and VTd-alone arms, respectively. Moreover, responses were found to deepen over time.

The median PFS had not yet been reached in either arm at a median follow-up of 18.8 months, and the daratumumab regimen showed a 53% reduction in the risk of disease progression or death (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). 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 for the ASCO abstract, 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 treatment-emergent adverse events (TEAEs) 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. Fourteen percent of patients discontinued treatment on the D-VTd arm compared with 19% on the VTd-alone arm; the most common reason for discontinuation was AEs or serious AEs.

Data from a subgroup analysis of CASSIOPEIA that were presented at the 17th International Myeloma Workshop also showcased an improvement in minimal residual disease (MRD) negativity rates and PFS with D-VTd compared with VTd alone in patients with high-risk multiple myeloma. 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 of del(17p) or t(4;14), 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 (P = .8506) or high-risk cytogenetics (P = .4839).

References

1. Genmab Announces U.S. FDA Approval of DARZALEX® (daratumumab) in Combination with Bortezomib, Thalidomide and Dexamethasone for Frontline Multiple Myeloma. Genmab. Published September 26, 2019. Accessed September 26, 2019. https://bit.ly/2nzRy05.
2. 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.2019;37(suppl; abstr 8003). doi: 10.1200/JCO.2019.37.15_suppl.8003.
3. Sonneveld P, Attal M, Perrot A, et al. Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (NDMM): subgroup analysis of high-risk patients (Pts) in CASSIOPEIA. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract OAB-003.