The U.S. Food and Drug Administration has issued a complete response letter (CRL) to Johnson & Johnson regarding the supplemental biologics license application for Darzalex Faspro (daratumumab and hyaluronidase-fihj) in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) for treating newly diagnosed multiple myeloma patients who are ineligible for or have deferred autologous stem cell transplant.
According to Johnson & Johnson's announcement on August 1, the CRL cited observations from facility inspections and was not related to safety and efficacy data for the D-VRd regimen. Importantly, the FDA did not request any additional clinical studies, and there has been no impact on the product supply or commercial availability of Darzalex Faspro in the United States.
Regulatory Context and Company Response
"We are working closely with the FDA and are confident in our ability to promptly resolve the matter," stated Dr. Yusri Elsayed, Global Therapeutic area head, Oncology, Innovative Medicine at Johnson & Johnson. "Healthcare professionals and patients can be assured of no impact to the current use or supply of Darzalex and Darzalex Faspro, which are foundational therapies for treating multiple myeloma."
Darzalex Faspro remains approved in the United States for all nine multiple myeloma indications. The European Commission recently approved its use in newly diagnosed patients who are eligible for stem cell transplant, based on results from the phase 3 CEPHEUS study, and regulatory reviews in other countries are ongoing.
CEPHEUS Trial Results Support Application
The supplemental biologics license application was supported by findings from the phase 3 CEPHEUS trial, which demonstrated significant clinical benefits for the D-VRd quadruplet regimen compared to standard VRd treatment in newly diagnosed multiple myeloma patients ineligible for or who had deferred autologous stem cell transplant.
In the CEPHEUS study, patients receiving D-VRd (n = 197) achieved a minimal residual disease (MRD) negativity rate of 60.9% at 10⁻⁵ sensitivity compared with 39.4% in the VRd-alone arm (n = 198; OR, 2.37; 95% CI, 1.58-3.55; P < .0001). The quadruplet regimen also led to deeper clinical responses, with a complete response or better rate of 81.2% versus 61.6% with VRd alone (OR, 2.73; 95% CI, 1.71-4.34; P < .0001).
Additional efficacy outcomes showed MRD negativity at 10⁻⁶ sensitivity was achieved in 46.2% of D-VRd patients versus 27.3% of VRd patients (OR, 2.24; P = .0001). Sustained MRD-negativity lasting at least 12 months at 10⁻⁵ sensitivity was reported in 48.7% of the D-VRd group compared with 26.3% in the VRd group (OR, 2.63; P < .0001).
Progression-Free Survival Benefits
The median progression-free survival was not reached in the D-VRd group compared with 52.6 months for VRd alone (HR, 0.57; P = .0005). The 54-month progression-free survival rates were 68.1% versus 49.5%, respectively. Overall survival data were not yet mature, but showed a trend favoring D-VRd (HR, 0.85), which strengthened when censoring for COVID-19-related deaths (HR, 0.69).
Safety Profile
Grade 3/4 treatment-emergent adverse effects were observed in 92.4% of patients receiving D-VRd and 85.6% of those receiving VRd alone. Discontinuation of all study drugs due to adverse events occurred in 7.6% of D-VRd-treated patients and 15.9% of patients in the VRd group. Grade 5 non-COVID-19 treatment-emergent adverse effects occurred in 10.7% of patients in the D-VRd arm versus 7.7% in the VRd arm.
Common adverse events in the D-VRd versus VRd arms included blood/lymphatic disorders (82.7% vs 64.6%), neutropenia (55.8% vs 39.0%), thrombocytopenia (46.7% vs 33.8%), and peripheral sensory neuropathy (55.8% vs 61.0%). Most peripheral neuropathy cases were low grade, with grade 3/4 neuropathy rates of 8.1% versus 8.2%, respectively.
About Darzalex Faspro
Darzalex Faspro was approved in the United States in May 2020 and is the only CD38-targeted antibody available as a subcutaneous injection for treating multiple myeloma. The treatment combines daratumumab with hyaluronidase to facilitate subcutaneous delivery. Treatment combinations that include Darzalex have been administered to nearly 650,000 patients worldwide.
