Highlights
- Subcutaneous isatuximab administered by on-body injector demonstrated noninferior efficacy to intravenous isatuximab in relapsed/refractory multiple myeloma.
- Pharmacokinetic exposure was higher with the on-body injector, meeting noninferiority criteria.
- Infusion-related reactions were dramatically reduced with the subcutaneous on-body injector formulation.
- Local tolerability was excellent and practice efficiency may be improved by the on-body injector.
Study Background and Disease Burden
Multiple myeloma (MM) remains a challenging hematologic malignancy with significant morbidity and mortality. Despite advances, patients with relapsed or refractory MM (RRMM) often exhaust standard therapeutic options, necessitating innovative approaches to treatment delivery and patient convenience. Isatuximab, an anti-CD38 monoclonal antibody, has established efficacy in RRMM when combined with pomalidomide and dexamethasone. However, intravenous (IV) administration requires prolonged clinic visits and exposes patients to infusion-related reactions, impacting quality of life and healthcare resource utilization. The development of a subcutaneous (SC) formulation delivered by an on-body injector (OBI) offers the potential to improve patient experience and practice efficiency, yet robust randomized data were previously lacking.
Study Design
The IRAKLIA trial (ClinicalTrials.gov: NCT05405166) was a multicenter, open-label, phase III study directly comparing isatuximab SC via OBI to conventional IV administration, both in combination with pomalidomide and dexamethasone, in patients with RRMM who had received at least one prior line of therapy. A total of 531 patients were randomized 1:1 to receive either Isa OBI (1,400 mg) or Isa IV (10 mg/kg) once weekly in the first cycle, then every two weeks thereafter. Pomalidomide (4 mg daily, days 1–21) and dexamethasone (40 mg weekly, reduced to 20 mg for age ≥75) were administered until disease progression, unacceptable toxicity, or patient withdrawal.
Coprimary endpoints were: 1) overall response rate (ORR) with a noninferiority margin of 0.839 and 2) isatuximab trough concentration (Ctrough) at cycle 6, day 1 (C6D1 predose), with a noninferiority margin of 0.8. Noninferiority required that both endpoints met predefined criteria. Secondary endpoints included safety, incidence of infusion/injection reactions, and local tolerability.
Key Findings
Following a median follow-up of 12 months, the trial enrolled 263 patients to the OBI arm and 268 to the IV arm. The ORR was 71.1% for Isa OBI and 70.5% for Isa IV (relative risk 1.008, 95% CI: 0.903–1.126), demonstrating noninferiority. The mean Ctrough at C6D1 was 499 μg/mL (SD 259) for OBI, compared to 340 μg/mL (SD 169) for IV, with a geometric mean ratio of 1.532 (90% CI: 1.316–1.784), also exceeding the noninferiority threshold.
Safety profiles were consistent across groups. Grade ≥3 treatment-emergent adverse events occurred in 81.7% of OBI patients and 76.1% of IV patients. Importantly, infusion-related reactions were notably less frequent in the OBI arm (1.5%) versus the IV arm (25.0%). Local injection site reactions with OBI were rare (0.4% of injections, all grade 1-2), and 99.9% of OBI injections completed without interruption.
Comparison with prior studies (e.g., ICARIA-MM) suggests similar efficacy and safety for Isa OBI, with the additional benefit of markedly reduced infusion reaction rates. These attributes are likely to be highly relevant for both patients and healthcare providers seeking to minimize treatment-associated morbidity and streamline clinic workflows.
Expert Commentary
The IRAKLIA study represents a pivotal advancement in MM therapeutics by demonstrating that subcutaneous administration via OBI is not only efficacious but also offers tangible advantages in terms of safety and patient convenience. Lower rates of infusion reactions may translate to improved patient adherence and reduced emergency interventions. The pharmacokinetic data confirm that adequate systemic exposure is achieved with the OBI device, supporting its interchangeability with IV administration. However, the slightly higher rate of grade ≥3 adverse events in the OBI arm warrants ongoing surveillance. As highlighted by current opinion leaders, the shift toward SC delivery in oncology is driven by both patient-centric and health system imperatives; the IRAKLIA results align with this paradigm. Limitations include the open-label design and the need for longer-term data to assess durability of response and cumulative toxicity.
Conclusion
The IRAKLIA phase III trial provides compelling evidence that isatuximab SC via on-body injector is noninferior to IV administration for RRMM, with similar efficacy and safety, and substantially fewer infusion-related reactions. The device offers excellent local tolerability and may improve practice efficiency. These findings support the adoption of Isa OBI as a new standard option for RRMM patients, addressing both clinical and operational needs. Further research should clarify long-term outcomes and patient preferences in real-world settings.
References
Ailawadhi S, Špička I, Spencer A, Lu J, Oriol A, Ling S, Schjesvold F, Berkovits A, Hus M, Li C, Dimopoulos MA, Rajnics P, Beşışık SK, Hungria V, Custidiano MDR, Parmar G, Leleu X, Li F, Cerchione C, Gomez C, Ishida T, Mateos MV, Buck TT, LeBlanc R, Minařík J, Goldschmidt H, Zhang R, Sémiond D, Suzan F, Stefanova-Urena M, Koch V, Moreau P. Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. J Clin Oncol. 2025 Aug;43(22):2527-2537. doi: 10.1200/JCO-25-00744.