<b><i>Introduction:</i></b> Polymethylmethacrylate (PMMA) membranes can adsorb a wide variety of uremic toxins including serum free light chains (sFLC). However, limited data are available regarding the clinical use of PMMA in multiple myeloma patients and its maximum adsorption capacity in this setting. <b><i>Aim:</i></b> This study aimed to measure the capacity of PMMA to adsorb sFLC and identify strategies to improve its efficiency in clinical practice. <b><i>Methods:</i></b> Ten patients with dialysis-dependent renal failure and high levels of sFLC were included in the study. Five patients received standard PMMA hemodialysis (HD; n = 18), while in the other 5 patients a new technique called enhanced adsorption dialysis (EAD) was used, which involves PMMA dialyzer replacement after 2 h (n = 19). In all patients, sFLC were measured at the beginning and at the end of each dialysis session to calculate the difference between start and end of treatment and the percentage removal. <b><i>Results:</i></b> PMMA membranes reduced sFLC in both the PMMA HD and EAD groups. PMMA HD showed similar efficiency on κ and &#x03BB; percentage removal (22.3 and 21.0%, respectively, n.s.) but, in contrast, had a significantly greater effect on the delta of sFLC in κ [1,555 mg/l (-511 to +6,027)] versus &#x03BB; [390 mg/l (120-650)] treatments (p = 0.007). EAD treatments only partially increased percentage removal of κ sFLC (22.3-31.0%, p = 0.38), while they had a significantly great effect on &#x03BB; (21.0-53.1%, p = 0.003). A positive linear correlation was found between delta sFLC and pre-HD sFLC concentrations in PMMA HD κ treatments (r = 0.68, p < 0.02) but not for &#x03BB; treatments (r = 0.54, p = 0.21), while the analysis of patients receiving EAD demonstrated a strong positive correlation for both κ and &#x03BB; subtypes (r = 0.81 and r = 0.85, respectively, p < 0.008). In EAD sessions, a positive linear correlation was shown between blood flow during treatment and percentage removal of sFLC (r = 0.58, p = 0.02); however, with PMMA HD such a correlation was not observed (r = 0.28, p = 0.25). <b><i>Conclusions:</i></b> PMMA membranes can efficiently adsorb sFLC, but the process is limited by membrane saturation and is different between κ and &#x03BB; sFLC. The new EAD technique can greatly improve &#x03BB; removal but only partially act on κ sFLC. Therefore, EAD should be considered a valid economic treatment option without side effects in particular subsets of patients for the removal of sFLC.