Immunofixation electrophoresis (IF) is the standard method used to confirm the presence of monoclonal proteins (M-protein) at diagnosis of Multiple Myeloma (MM) or at assessment of complete response (CR) during treatment. However, IF results may differ according to the IF systems applied, due to changes in resolution and the influence of anti-CD38 therapy. The HYDRASYS system has a high resolution that identified both IgD and kappa M-proteins in rare IgD kappa type MM patients and was also capable of detecting serum monoclonal kappa free light chain (FLC). These results were in concordance with high serum IgD and kappa FLC values. For patients under daratumumab treatment, the HYDRASHIFT 2/4 Daratumumab assay on the HYDRASYS system successfully shifted the daratumumab interference, allowing precise CR assessment and preventing a false positive diagnosis. HYDRASYS system provides accurate and valuable diagnostic information for MM therapeutic decisions.