IRAKLIA Trial Shows Body Weight Doesn’t Alter Outcomes With On-Body Injector Isatuximab

There was no notable impact from isatuximab (Sarclisa; Sanofi) on-body injector (OBI) observed across different body weight groups, said investigators of research presented at the 67^th American Society of Hematology (ASH) Annual Meeting and Exposition. The findings are from the phase 3 IRAKLIA (NCT05405166) clinical trial.^1,2

The IRAKLIA trial is an international, open-label, noninferiority trial that investigated subcutaneous isatuximab compared to intravenous (IV) administration, plus pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma and with different body weights. All enrolled patients were 18 years of age or older and received at least 1 prior line of therapy. They were randomly assigned to receive either isatuximab with an OBI (1400 mg; n = 263) or IV (10 mg/kg; n = 264) weekly in cycle 1, then every 2 weeks with pomalidomide (4 mg/day on days 1–21) and dexamethasone (40 mg weekly, or 20 mg weekly if 75 years or older) in 4-week cycles.^1,2

For this trial, patients were categorized based on body weight. The analysis, according to the investigators, was run by body weight (≤65 kg, >65–≤85 kg, >85 kg), which was a stratification factor, and extreme body weight (≤50 kg, >50–≤100 kg, >100 kg).^1,2

The number of patients per body weight group are as follows¹:

• 50 kg or less: OBI: n = 16; IV: n = 14;
• 65 kg or less: OBI: n = 84; IV: n = 85;
• greater than 65 to 85 kg or less: OBI: n = 117; IV: n = 118;
• greater than 85 kg: OBI: n = 62; IV: n = 65;
• and greater than 100 kg: OBI: n = 22; IV: n = 22.

Generally, baseline demographic and disease characteristics were balanced across body weight groups for OBI isatuximab compared with IV isatuximab, including age (median: 66 years) and prior lines of treatment (median: 2 lines); however, in the 100 kg group, there were more patients receiving OBI isatuximab than IV isatuximab who exhibited poor prognostic characteristics, including plasmacytoma, International Staging System Stage II/III disease, beta 2-microglobulin level of 5.5 mg/L or higher, estimated glomerular filtration rate below 60 mL/min/1.73 m², and a lower very good partial response (VGPR) rate as best overall response at last regimen.¹

Further, flat-dose OBI isatuximab showed adequate exposure for all body weight groups, with geometric means greater than IV isatuximab for the 65 kg or less than (1.628 [90% CI 1.294–2.048]), greater than 65 kg through 85 kg or less (1.303 [90% CI 1.089–1.560]), and greater than 85 kg (1.006 [90% CI 0.817–1.239]) groups. Additionally, OBI isatuximab overall response rates (ORRs) were comparable to IV isatuximab across body weight groups (≤ 65 kg: 66% vs 71% (relative risk [RR]: 0.928); > 65 through ≤ 85 kg: 70% vs 70% (RR: 1.009); and > 85 kg: 81% vs 72% (RR: 1.115). For extreme body weight groups, ORRs were similar between OBI and IV isatuximab for the 50 kg or less group (56% vs 60%) and for greater than 50 kg to 100 kg or less (72% [95% CI 66%–78%] vs 70% [95% CI 63%–76]), but lower in the greater than 100 kg group (68% vs 86%).¹

Of note, an exposure-response analysis showed the impact of body weight on response. For instance, patients receiving OBI isatuximab who weighed 50 kg or less tended to respond less than those weighing greater than 50 kg, despite correct exposure, because they were confounded by baseline disease characteristics (eg, higher proportion of high-risk cytogenetics and plasma cells in the bone marrow) compared with other patients in other body groups.¹

Grade 3 or higher treatment-emergent adverse events (TEAEs) for both OBI and IV isatuximab decreased with increasing body weight. They were similar between treatment arms in the 65 kg or less group (OBI: 87%; IV: 88%). Additionally, a similar trend was observed in extreme body weight groups along with similar incidences between arms in the 50 kg or less group. While treatment-emergent serious adverse events decreased with increasing body weight for IV isatuximab, incidence was stable in OBI isatuximab. Additionally, OBI grade 5 TEAEs were similar between groups and arms, except for a higher incidence in the 65 kg or less group (12% vs 5%) with OBI versus IV that was not reflected in other groups.¹

Treatment discontinuation rates for OBI and IV isatuximab were about 14% and 6% (≤65 kg), 8% and 10% (>65–≤85 kg), and 2% and 10% (>85 kg). A similar incidence of grade 3 or higher laboratory neutropenia was observed across body weight groups for those receiving OBI isatuximab but was higher in the 50 kg or less group (OBI: 93.8%; IV: 71.4%). Finally, the exposure-response analysis revealed no relationship between Isa pharmacokinetic exposure and safety for either the OBI or IV arms.¹

Generally, there was no notable impact from OBI flat dosing observed across body weight groups. Flat-dose OBI isatuximab showed consistent safety and efficacy across different body weight groups, with any observed differences likely linked to baseline disease characteristics, the authors noted.¹

REFERENCES

1. Lu J, Oriol A, Berkovits A, et al. Isatuximab subcutaneous by on-body injector in Relapsed/Refractory multiple myeloma in the Phase 3 iraklia study: Effect of body weight on pharmacokinetics and clinical outcome. Blood. 2025;146:5812. doi:10.1182/blood-2025-5812

2. SC Versus IV Isatuximab in Combination With Pomalidomide and Dexamethasone in RRMM (IRAKLIA). ClinicalTrials.gov identifier: NCT05405166. Updated November 14, 2025. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT05405166