Objectives: Isatuximab (Isa) is an approved IgG1 monoclonal antibody that targets a specific epitope of CD38 and kills multiple myeloma (MM) cells via multiple mechanisms. The Phase 3 IKEMA study (NCT03275285) demonstrated that Isa plus carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed MM (hazard ratio [HR], 0.531; 99% CI, 0.32–0.89; p = 0.0007), leading to the approval of Isa-Kd in the US for adults with MM with 1–3 prior lines and in the EU for those with ≥1 prior therapy. The presence of soft-tissue plasmacytomas is associated with poor prognosis, and newer therapies are urgently needed. In this post hoc analysis, we evaluated the efficacy and safety of Isa-Kd vs Kd in pts with relapsed MM and pre-existing soft-tissue plasmacytomas. Material and methods: Pts (n = 302) were randomized (3:2) to Isa-Kd (n = 179) or Kd (n = 123). Isa (10 mg/kg IV) was given weekly for 4 weeks, then every 2 weeks. K (20 mg/m2 days 1–2, then 56 mg/m2) was given twice-weekly 3 of 4 weeks, and d (20 mg) twice-weekly. The independent review committee assessed response based on central radiology review and central lab M-protein using the International Myeloma Working Group criteria. Results: At study entry, 19 (6.3%) pts had soft-tissue plasmacytomas: 12/179 (6.7%) had Isa-Kd and 7/123 (5.7%) had Kd. Overall median (range) duration of exposure in these pts was 41.9 (2–87) weeks for Isa-Kd vs 29.9 (4–83) for Kd, with 41.7% pts still on treatment at cycle 20 in Isa-Kd vs 14.3% pts in Kd. Baseline characteristics in the plasmacytomas subgroup were similar to those in the overall IKEMA intent-to-treat (ITT) population with the exception of ISS stages II (42.1% vs 31.1%) and III (31.6% vs 15.2%), and renal function impairment (38.9% vs 22.1%) which were more prevalent in the plasmacytomas subgroup vs ITT. PFS was improved with Isa-Kd vs Kd: HR, 0.574; 95% CI, 0.125–2.640. Median PFS was 18.76 (95% CI, 4.435–not calculable [NC]) months with Isa-Kd vs NC (0.986–NC) months with Kd. Overall response rate (50.0% vs 28.6%), very good partial response or better (33.3% vs 14.3%), and complete response (25.0% vs 0%, all with minimal residual disease negativity) rates were also improved with Isa-Kd vs Kd. Grade ≥3 TEAE occurred in 12 (100%) pts with Isa-Kd vs 4 (57.1%) with Kd. Grade 5 TEAEs during study treatment occurred in 2 (16.7%) vs 1 (14.3%) pt; serious TEAEs in 9 (75.0%) vs 4 (57.1%); TEAEs leading to discontinuations were 0 (0%) vs 1 (14.3%). Grade 5 events were pneumonia (1 [8.3%], Isa-Kd) and progressive disease (1 [8.3%], Isa-Kd; 1 [14.3%], Kd). Conclusions: In pts with relapsed MM and soft-tissue plasmacytomas, Isa-Kd improved PFS and depth of response compared with Kd alone, with a manageable safety profile, consistent with the benefit observed in the IKEMA study overall population. Isa-Kd is a new treatment option for pts with relapsed MM and soft-tissue plasmacytomas. Funding: Sanofi.