Background Acute kidney injury (AKI) occurs in 12-20% of multiple myeloma (MM) patients. Several studies have shown a reduction of free light chains (FLC) using hemodialysis with High-Cut-Off membranes. However, this technique entails albumin loss. Hemodiafiltration with ultrafiltrate regeneration is a technique that includes a process of adsorption. The aim of this study was to evaluate the effectiveness of hemodiafiltration with ultrafiltrate regeneration in reducing FLC levels without causing albumin loss. Methods This is an observational study (2012 to 2018) including eleven patients with MM (6 kappa, 5 lambda) and AKI. All patients were treated with chemotherapy and hemodiafiltration with ultrafiltrate regeneration. Blood Samples (pre and post-dialysis) and ultrafiltrate were collected pre and post-resin at 5 minutes after initiation of the session and 5 minutes before the end of the procedure. Results The serum levels of kappa and lambda were reduced by a 53±14% and 33±22% respectively. Serum albumin concentration remained unchanged after the procedure. In the ultrafiltrate, the mean FLC reduction ratio shortly after initiation of the dialysis procedure was: 99.2% and 97.06% for kappa and lambda respectively, and only 0.7% for albumin; and at the end of the session the percent reduction was: 63.7% and 33.62% for kappa and lambda respectively, and 0.015% for albumin. Patients clinical outcome was: 36.4% recovered renal function, 18.2% died during the first year and 45.45% required maintenance dialysis. Conclusions Hemodiafiltration with ultrafiltrate regeneration reduces FLC levels without producing a significant loss of albumin; and, FLC removal is maintained throughout the session. Therefore, hemodiafiltration with ultrafiltrate regeneration may be considered an effective adjunctive therapy in patients with MM.