Background: Systemic AL amyloidosis is characterized by disposition of insoluble amyloid fibrils into tissues and organs via clonal expansion of CD38⁺ plasma cells. The safety run-in of DARA SC + CyBorD in ANDROMEDA (NCT03201965) is presented. Methods: Eligible pts had ≥1 involved organs, ECOG score ≤2, absolute neutrophil count ≥1.0 × 10⁹/L; hemoglobin ≥8.0 g/dL; platelet count ≥50 × 10⁹/L; estimated glomerular filtration rate ≥20 mL/min/1.73m², and NT-ProBNP ≤8,500 ng/L. In the safety run-in, pts received a concentrated co-formulation of DARA (1,800 mg in 15 mL) and recombinant human hyaluronidase enzyme (rHuPH20; 30,000 U) in a single, pre-mixed vial, given by manual SC injection qw in Cycles 1-2, q2w in Cycles 3-6, and q4w thereafter ≤2 y. Cy 300 mg/m² PO or IV and Bor 1.3 mg/m² SC were given on Days 1, 8, 15, 22 of each 28-day cycle for ≤6 cycles and D 40 mg was given qw. Dosing was staggered ≥48 hours between pts to assess infusion related reactions (IRRs). Safety was evaluated after ≥10 pts received ≥1 treatment cycle. Results: Pts (n = 15) had a median (range) age of 63 (35-77) y and a median of 58 (15-157) d from diagnosis. Pts had a median of 1 (1-3) involved organ, with kidney involvement affecting 67% of pts and 40% of pts with ≥2 organs involved. At baseline, 73% and 27% of pts were grouped into New York Heart Association class I and II, respectively, and 93% of pts had an ECOG score of ≤1. Pts received a median of 2 (1-4) treatment cycles and a median of 5 (1-10) DARA injections. Most common ( > 2 pts) treatment emergent adverse events (TEAEs) were nausea (47%), diarrhea (33%), fatigue (33%), injection site erythema (20%), anemia (20%), and rash (20%). Dyspnea and peripheral edema were reported in 1 (7%) pt each. One grade 3/4 TEAE (hypertension; unrelated to treatment) and no serious TEAEs occurred. IRRs occurred in 2 (13.3%) pts (all grade 1). Additional data will be presented. Conclusions: DARA-CyBorD is tolerable in pts with AL amyloidosis with a low IRR rate and no new safety signals. The limited incidence of dyspnea and peripheral edema indicate a low risk for volume overload. Randomization into ANDROMEDA has begun. Clinical trial information: NCT03201965