International multicentre evaluation of a new anti-idiotypic anti-daratumumab for resolving pre-transfusion interferences

Background and Objectives: Daratumumab, a therapeutic human anti-CD38 monoclonal antibody, improves multiple myeloma outcomes but interferes with pre-transfusion testing by binding CD38 on reagent red blood cells (RBCs), potentially masking clinically significant alloantibodies. This study aimed to evaluate the effectiveness of a novel high-affinity anti-idiotypic anti-daratumumab reagent in neutralizing daratumumab interference while preserving RBC alloantibody detection and ensuring compatibility with routine transfusion laboratory workflows. Materials and Methods: A non-interventional, multicentre study across 28 transfusion laboratories in 15 countries evaluated a novel anti-idiotypic anti-daratumumab reagent (DaraClear). In total, 443 daratumumab-containing plasma samples and 197 RBC alloantibody–containing samples were tested. All samples were initially tested at 10% (v/v), with stepwise escalation to 20% and 30% only if neutralization was incomplete. Neutralization efficiency, antibody detection, cross-match resolution and workflow integration were assessed, alongside comparisons with dithiothreitol (DTT), papain, trypsin and DaraEx. Results: Daratumumab interference was neutralized in 99.5% of samples, with 86.2% resolved using the 10% protocol. Detection of 190/197 RBC antibodies (96.4%) was preserved, including weak/low-titre antibodies. Neutralization was superior to DTT (93.3%), papain/trypsin (84.9%) and DaraEx (68.4%; all p < 0.0001). Titration studies confirmed efficacy across various ranges of daratumumab titres. The reagent integrated seamlessly into workflows, remained stable over time and avoided RBC modification. Conclusion: Daratumumab interference was efficiently neutralized while preserving alloantibody detection. The robust performance and workflow compatibility provide a practical solution for pre-transfusion testing in daratumumab-treated patients, supporting safe and timely transfusions with reduced laboratory burden.