Background: Residual therapeutic mAbs can be detected by assays intended to monitor clonal myeloma protein (M-protein). Daratumumab, a human anti-CD38 IgG1k mAb in MM clinical trials, has been detected on serum protein electrophoresis (SPE) and immunofixation (IFE) gels, interfering with IMWG response criteria requiring negative SPE/IFE for CR/sCR. As new therapeutics emerge that induce very deep responses a method is needed to confirm CR/sCR. Validation and use in clinical studies of an assay that distinguishes daratumumab from M-protein is presented. Methods: Mouse anti-daratumumab antibody is used to shift daratumumab’s IFE migration away from M-protein. Commercial and daratumumab-treated MM patient samples were evaluated to assess specificity, reproducibility and concordance. Detection of M-protein depletion by DIRA triggered additional clinical testing to confirm CR/sCR. Results: Daratumumab was identified on IFE in 10/10 samples when added to commercial MM serum in a 1:1 ratio with anti-daratumumab. Reproducibility was tested in 3 independent DIRA runs on 10 samples from daratumumab treated patients (16 mg/kg). 2 independent reviewers assessed daratumumab and M-protein levels and observed 100% concordance. Specificity was evaluated in commercial (n = 16) and daratumumab-treated patient samples (n = 36) by scoring whether the malignant M-protein was shifted with the anti-idiotype antibody. 94.4% (34/36) of samples had no shift in M-protein with anti-daratumumab. 33 daratumumab patient samples (from single-agent or combination studies) were DIRA tested and clinical responses assessed; 13 (39%) had no M-protein (DIRA -ve) and 10 were confirmed as CR. 20 patients had malignant M-protein remaining (DIRA +ve) and monitoring continued. Conclusions: DIRA, a robust and reproducible tool, determines if residual IgGk on IFE is caused by the mAb daratumumab or actual M-protein. DIRA results can trigger further assessments to confirm clinical CR. This first approach to distinguish therapeutic mAb from M-protein in MM will be needed for clinical research and eventually MM treatment.