Cast nephropathy is the most common cause of acute kidney injury (AKI) in patients with multiple myeloma (MM). A prompt reversal of renal injury is paramount for improving clinical outcomes. Daratumumab, an anti-CD38 monoclonal antibody, has significant clinical efficacy in MM. We describe the effects of daratumumab-based therapy in 20 patients admitted with a new diagnosis of MM and AKI with a median creatinine of 6.5 mg/dL. All patients (100%) achieved sFLC reduction ≥50% within the first cycle with median time to sFLC reduction ≥50% of 3 days (95% CI 3-7). Fifteen of 17 patients (88%) achieved sFLC reduction ≤500 mg/L after 1 cycle of treatment. Median time to sFLC reduction ≤500 mg/L was 14.5 days (95% CI 9-49). Overall renal response at 3 months was 85% (n=17), with complete, partial, minor responses in 50% (n=10), 10% (n=2), and 25% (n=5), respectively. Out of the 9 patients who required dialysis at presentation, 4 out of 7 (57.1%) and 6 out of 7 (85.7%) were dialysis independent at 3 and 12 months, respectively. Hematologic ORR was 100% with VGPR in 90%. With median follow-up of 25 months, PFS was 46.5 months (95% CI, 11.9-NR) and 2-year OS was 83.7% (95% CI 68.4-100%). These findings highlight the importance of early initiation of daratumumab-based treatment in patients with MM and AKI to induce rapid and significant reductions in sFLC, improve renal outcomes, and provide an approach without plasmapheresis.