Background: Renal impairment is a frequent and severe complication of multiple myeloma, most commonly caused by light-chain cast nephropathy. Therapeutic plasma exchange (TPE) has been proposed as an adjunctive approach to rapidly reduce circulating free light chains; however, its clinical benefit remains controversial. Methods: We retrospectively analyzed 71 patients treated between 2013 and 2023, of whom 30 received TPE in addition to anti-myeloma therapy and 41 received anti-myeloma therapy alone. Renal outcomes were assessed within a predefined early treatment window encompassing the first 4–6 cycles of therapy. Renal response was defined as a ≥50% reduction in serum creatinine and/or dialysis independence. Multivariable logistic regression and sensitivity analyses were performed to adjust for baseline imbalances, including renal function and anti-myeloma backbone therapy. Results: Although renal function improved significantly over time in both groups, renal response rates were comparable between patients treated with and without TPE (40% vs. 36.6%). In multivariable analysis, TPE was not independently associated with renal response. Importantly, in a sensitivity analyses restricted to patients receiving bortezomib-based regimens, the addition of TPE remained unassociated with improved renal outcomes. Conclusions: In this real-world cohort, adjunctive TPE did not confer a significant advantage in renal recovery or dialysis independence beyond contemporary anti-myeloma therapy. These findings indicate that renal recovery is predominantly driven by effective anti-myeloma treatment rather than extracorporeal light-chain removal.