Background: Cast nephropathy is the most common cause of acute kidney injury (AKI) in patients with multiple myeloma (MM), where light chain accumulation in the distal nephron leads to obstruction and injury of the distal and collecting tubules. A prompt reversal of renal injury is paramount to improve outcomes. Daratumumab (dara), an anti-CD38 monoclonal antibody, has significant clinical efficacy in MM. We report the effects of early initiation of dara-based therapy on sFLC reduction and renal recovery in pts admitted with a new diagnosis of MM and AKI. Methods: Between April 2016 and Dec 2023, pts admitted with newly diagnosed MM (NDMM) with AKI (sCr ≥2 mg/dL and/or eGFR <30 mL/min/1.73 m² by CKD-EPI) and involved sFLC ≥500 mg/L who started dara-based therapy were identified and retrospectively reviewed. We studied pts who started treatment ≤14 days of presentation. Outcomes included sFLC kinetics and renal outcomes per IMWG criteria at 3 months. Results: We identified 20 NDMM pts. Median age was 65 (range 44-87). Median peak sCr at admission was 6.5 mg/dL (range 3.1-17.8) with median eGFR of 8 mL/min/1.73 m² (range 2-16). Nine pts started hemodialysis (HD). The median peak sFLC at diagnosis was 6603 mg/L (range 1839-26,023). Initial dara regimens included cyclophosphamide, bortezomib, and dexamethasone in 11 pts (55%) and with bortezomib and dexamethasone in 9 pts (45%). Median time between presentation and dara start was 3 days (range 0-10). No pts underwent plasmapheresis. Within 1 cycle of therapy, all 20 pts achieved sFLC reduction ≥50% at a median of 3 days (95% CI, 3-7 days). Median time to sFLC ≤500 mg/L was 13 days (95% CI, 9-33 days), and this was in 15 out of 16 pts (94%) assessable for response after 1 cycle of treatment. At 3 m, the overall renal response (≥minor response) was 85% (N=17), with complete, partial, and minor responses in 50% (N=10), 10% (N=2), and 25% (N=5), respectively. Twelve pts (60%) recovered renal function with eGFR ≥40 mL/min. Of 9 pts who required HD, 4 and 6 pts were free of HD at 3 m and 12 m, respectively. Two pts on HD died within 3 m (age 86, from aspiration pneumonia; age 87, from progressive disease); and 1 continued on HD at 12 months. Fourteen pts (70%) later added lenalidomide, and 3 pts (15%) underwent autologous stem cell transplant. The IMWG ORR was 100% with VGPR 90%. With a median follow up of 25 m, median PFS was 47 m (95% CI 12-not reached) and 2-year OS was 84% (95% CI 68-100%). Conclusions: This is the largest reported cohort of NDMM pts hospitalized with AKI treated with dara-based induction therapy. Treatment with dara combinations shows rapid and deep reductions in sFLC, improving renal recovery outcomes. These findings highlight the efficacy of early use of dara in pts with MM-induced AKI and provide an approach without plasmapheresis.