On November 19, the U.S. Food and Drug Administration (FDA) granted traditional approval to daratumumab and hyaluronidase-fihj (Darzalex Faspro) with bortezomib, cyclophosphamide, and dexamethasone (VCd) for newly diagnosed light chain (AL) amyloidosis. The FDA granted accelerated approval to the regimen for this indication in 2021.
ANDROMEDA
Efficacy was evaluated in ANDROMEDA (ClinicalTrials.gov identifier NCT03201965), an open-label, randomized, active-controlled trial in 388 patients with newly diagnosed AL amyloidosis with measurable disease and at least one affected organ according to consensus criteria. Patients were randomly assigned to receive VCd alone or VCd in combination with daratumumab hyaluronidase-fihj (D-VCd).
The approval was based on major organ deterioration progression–free survival (MOD-PFS; defined as the duration from the date of randomization to either hematologic progression, major organ deterioration, or death—whichever occurred first), and overall survival. After a median follow-up of 61.4 months, the trial demonstrated an improvement in MOD-PFS in the D-VCd arm as compared to the VCd arm (hazard ratio [HR] = 0.47; 95% confidence interval [CI] = 0.33–0.67; P < .0001). The median MOD-PFS was not reached in the D-VCd arm vs 30.2 months in the VCd arm. The trial also demonstrated an improvement in overall survival in the D-VCd arm as compared to the VCd arm (HR = 0.62; 95% CI = 0.42–0.90; P = .0121). The median overall survival had not been reached in either arm.
The prescribing information includes a Warnings and Precaution for cardiac toxicity, stating that serious or fatal cardiac adverse reactions occurred in patients with AL amyloidosis who received daratumumab and hyaluronidase-fihj in combination with VCd, along with Warnings and Precautions for hypersensitivity and other administrative reactions, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interference with cross-matching and red blood cell antibody screening. Daratumumab and hyaluronidase-fihj is not indicated and is not recommended for the treatment of patients with AL amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.
The recommended dose is 1,800 mg daratumumab and 30,000 units hyaluronidase-fihj administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to the recommended schedule in combination with VCd.
