A multi-center, phase 1, open-label, first-in-human study was conducted investigating the safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of AMG 224 in patients with relapsed or refractory (R/R) multiple myeloma (MM) with ≥ 3 lines of prior therapy including an immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).In the dose expansion, patients were divided into groups A (prior anti-CD38 antibody) and B (no prior anti-CD38 antibody) and received i.v. AMG 224 at the preliminary MTD determined during dose escalation, adjusted for body weightIn the dose escalation, patients received i.v. AMG 224 every 3 wk (Q3W) at prespecified doses of 30-300 mg in a 3 + 3 design, with no mandated premedications.Objective responses occurred in 5/21 patients refractory to prior IMiDs, 3/14 refractory to prior PIs, 3/13 refractory to prior IMiDs and PIs, and 1/7 refractory to prior daratumumab.In conclusion, this phase 1 first-in-human study of AMG 224 in patients with R/R MM demonstrated a favorable pharmacokinetic and manageable safety profile and single-agent activity with the achievement of durable responses in some patients.