Background: Isatuximab (ISA) is an anti-CD38 mAb with potent anti-myeloma effects as monotherapy or together with lenalidomide (Len) + dexamethasone (d) in RRMM. Carfilzomib (K) is a proteasome inhibitor approved for use in RRMM as a single agent or in combination (Kd or LenKd). Objectives: The primary objective was to assess the maximum tolerated dose (MTD) of ISA + K in RRMM. Secondary objectives were assessment of safety, PK, immunogenicity, and efficacy (IMWG response criteria (ORR)). (NCT02332850) Methods: Eligible patients (pts) had disease progression after 2 prior lines, an ECOG < 3, and adequate organ function. A 3+3 dose escalation (DE) design was utilized. 3 dosing levels (DL) were tested: ISA 10 mg/kg Q2W, ISA 10 mg/kg QW x 4 then Q2W and ISA 20 mg/kg QW x 4 then Q2W in combination with K standard dose (27 mg/m2) and schedule. An expansion cohort (EC) of 18 pts was enrolled at DL2. Results: 15 pts were treated in DE and 18 in the EC. The median age (n = 33) was 61 yrs (range 39-79). Pts received a median of 3 (2-8) prior lines. All pts were IMid and PI exposed: 26/29 Len refractory (Refr), 21/29 Vel Refr, 13/29 Pom Refr and 8/11 K Refr. Median follow-up is 6.5m (0.5 – 24m). 29 pts are evaluable for response. ORR = 66% (1 sCR, 7 VGPR, 11 PR) and CBR is 86%. The median progression free survival has not been reached. Disposition: 15 pts have progressed (4 deaths from PD), 1 pt withdrew after 27 cycles and 17 remain on therapy. The median # of cycles given is 3 (range 1-27). No DLT or severe toxicity has been observed. Common adverse events (AEs-all grades, incidence ≥ 15%), were thrombocytopenia (66%), pain (60%), upper respiratory infection (56%), diarrhea (40%), fatigue (40%), anemia (33%), cough (33%), elevated creatinine (30%), nausea (30%), neutropenia (27%), headache (27%), dyspnea (16.7%) and fever (16.7%). Serious AEs occurred in 9pts and < 5% of AEs were Gr 3/4. Infusion reactions (IRs) were the most common ISA-related AE: 17 IRs in 16/32 pts (50%: Gr 1 (9) + Gr 2 (8)). Conclusions: Combining ISA and K appears safe; toxicity is c/w the AEs of the individual agents with few G3/4 AEs. Encouraging anti-MM activity (ORR 66%) was seen at all DLs. ISA 10 mg/Kg QW x 4 then Q2W dosing was selected for an ongoing Phase III trial of ISA + Kd versus Kd (IKEMA: NCT03275285). Clinical trial information: NCT-02332850.