Prognostic significance of IgG-Kappa positivity detected by serum immunofixation during daratumumab therapy in multiple myeloma

Background: Daratumumab, an immunoglobulin G kappa (IgG-κ) monoclonal antibody, can co-migrate with endogenous M-protein on serum immunofixation (IF), producing IgG-κ bands that may be misinterpreted as residual disease. We therefore evaluated treatment responses and the prognostic impact of daratumumab-associated IgG-κ IF positivity on progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Methods: We retrospectively analyzed 108 patients with MM treated with daratumumab-containing regimens at any line of therapy between January 2014 and January 2024. Serum IF IgG-κ positivity was assessed both at the first response assessment and during continued treatment. Treatment responses were classified according to the International Myeloma Working Group (IMWG) criteria, and PFS and OS were analyzed using the Kaplan–Meier method, the log-rank test, and multivariable Cox proportional hazards regression. Results: IgG-κ IF positivity was detected in 85 patients (78.7%) at first response, and the overall response rate to daratumumab was 64.8%. Patients positive at first response had longer PFS (14.0 vs. 7.0 months; P = 0.048) and higher very good partial response/complete response rates (65.9% vs. 43.5%; P = 0.058). In non–IgG-κ myeloma, treatment-emergent positivity was associated with a markedly higher deep-response rate (88.5% vs. 44.2%; P < 0.001) and a reduced risk of progression (hazard ratio 0.17; 95% confidence interval 0.03–0.74; P = 0.018). On multivariable analysis, older age independently predicted mortality, whereas persistent IF positivity did not worsen survival. Conclusions: IgG-κ IF positivity during daratumumab therapy should not be interpreted as residual disease in isolation; a substantial proportion likely reflects therapeutic antibody interference. Recognizing this interference is important to avoid overestimating residual disease and misclassifying treatment response, and confirmatory assays should be used where available.