FDA Grants Frontline Daratumumab Regimen Priority Review in Transplant-Eligible Myeloma

Jan van de Winkel, PhD

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) 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).

The sBLA is based on findings from part 1 of the phase III CASSIOPEIA (MMY3006) trial, in which the stringent complete response (sCR) rate at day 100 post-ASCT was 28.9% in patients who received the daratumumab regimen compared with 20.3% in those who received VTd alone following induction and consolidation therapy (odds ratio [OR], 1.60; 95% CI, 1.21-2.12; P ≤.001).

Topline results from CASSIOPEIA are scheduled to be presented in an oral abstract session at the 2019 ASCO Annual Meeting. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sBLA on or before September 26, 2019.

“Thanks to the strong collaborative effort of IFM, HOVON and Janssen, should the US FDA approve this sBLA, patients in the United States newly diagnosed with multiple myeloma who are eligible candidates for ASCT may one day also be able to include Darzalex in combination with VTd in their treatment regimen,” said Jan van de Winkel, PhD, chief executive officer of Genmab, which partners with Janssen on the development of daratumumab.

Some of the data from the CASSIOPEIA trial were shared in an abstract made available ahead of the ASCO annual meeting. 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. Patients on the trial were aged 18 to 65.

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).

Part 1 data showed that at day 100 post-ASCT, 38.9% of patients receiving the daratumumab regimen had a CR or higher compared with 26.0% with VTd alone (OR, 1.82; 95% CI, 1.40-2.36; P <.0001). The rates of patients experiencing a very good partial response or higher were 83.4% versus 78.0% (OR, 1.41; 95% CI, 1.04-1.92; P <.0239), respectively. The MRD-negative rate was 63.7% in the daratumumab arm compared with 43.5% in the VTd arm (OR, 2.27; 95% CI, 1.78-2.90; P <.0001). The rates of patients achieving both a CR or better, as well as MRD negativity, were 33.7% versus 19.9% (OR, 2.06; 95% CI, 1.56-2.72; P <.0001), respectively.

The median PFS had not yet been reached in either arm at a median follow-up of 18.8 months, but showed a benefit in favor of the daratumumab arm (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). The 18-month PFS rate was 92.7% with the daratumumab regimen and 84.6% with VTd alone. 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 (27.6% vs 14.7% in the VTd arm), lymphopenia (17.0% vs 9.7%, respectively) stomatitis (12.7% vs 16.4%), and thrombocytopenia (11.0% vs 7.4%). Infusion-related reactions were experienced by 35.4% of patients who received the daratumumab regimen.

In March, Janssen submitted an sBLA to the FDA for the approval of daratumumab in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT.

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).