Background: Myeloma patients (pts) with renal insufficiency (RI) have inferior disease outcomes; up to 50% present with acute kidney injury (AKI). AKI results from light chain-induced cast nephropathy; physicochemical properties (self-association, aggregate formation) may determine severity. Daratumumab has extensive data in myeloma, reduces circulating light chains, preserves renal function in AL amyloidosis, and has non-renal clearance. We hypothesized early therapy with daratumumab and VRD normalize myeloma-induced AKI in a population rarely included in trials. Methods: We used a Simon’s two-stage design in newly diagnosed pts with severe AKI (CrCl <30 mL/min) of 4 x 21-D cycles of daratumumab 16mg/kg IV QW x 3 (C1-3, C4D1 only), bortezomib 1.3 mg/m² SQ D1, 4, 8, and 11, and dexamethasone 40mg (reduced to 20mg at C2 for ≥75 yrs.) D1-4 (C1 only, D1 only C2-4), 8, and 15, with add-on lenalidomide at C2 (25mg if CrCl ≥30 mL/min). Standard antiviral, antithrombotic, premedications were used. Eligibility criteria were broad (CrCl <30 mL/min, PS 0-2, ANC>1000/mm³, Hgb>7 g/dL, plt>75,000/mm³) with liberal dose reductions for generalizability. Primary objective: determine proportion with renal recovery (CrCl ≥50 mL/min) after 2 cycles; secondary objectives: best response (IMWG), renal function at end of treatment, dose density/tolerability, adverse events (AE), renal function change by estimates [Cockcroft-Gault (C-G), MDRD, 24-hour urine, CKD-EPI], and daratumumab PK. If ≥7 responses seen in the first 11 pts, 14 more would be accrued. These data are the planned analysis of the initial cohort. Results: Thirteen pts enrolled: 8 male, 7 white/6 black, median age 69 yr (46-82), 11 treated/evaluable for the primary endpoint. Median baseline CrCl 13.8 mL/min (4.9-20.2), median serum creatinine (SCr) 4.92 mg/dL (3.53-9.93). One withdrew consent, 1 was inevaluable (rapid disease progression and death). Seven achieved CrCl of ≥50 mL/min (median C3D1 CrCl 61 mL/min, 22-151) after 2 cycles, all had SCr improvement at C3D1. Lenalidomide dose was 25 mg on C2D1 in 9/11 pts. Median (range) dose density (delivered/planned): daratumumab 100% (40-100), bortezomib 100% (25-100), dexamethasone 80% (67-100), lenalidomide 100% (0-100). The overall response rate was 100%, ≥VGPR rate 82%. Best responses were CR (3), VGPR (6), PR (2). Treatment-emergent grade ¾ hematologic AEs: anemia (90.9%), lymphopenia (81.8%), thrombocytopenia (36.4%), neutropenia (9.1%). Conclusions: Early, aggressive therapy with a daratumumab-based induction regimen in myeloma pts with severe AKI improves renal function, with the majority achieving CrCl ≥50 mL/min after 2 cycles; all responded. AEs seen were consistent with prior experience with the 4-drug regimen. Per protocol, 14 additional patients will be accrued in the second stage. Clinical trial information: NCT04352205.