Ailawadhi Sikander, Špička Ivan, Spencer Andrew, Lu Jin, Oriol Albert, Ling Silvia, Schjesvold Fredrik, Berkovits Alejandro, Hus Marek, Li Chunrui, Dimopoulos Meletios-Athanasios, Rajnics Péter, Beşışık Sevgi Kalayoğlu, Hungria Vania, Custidiano Maria Del Rosario, Parmar Gurdeep, Leleu Xavier, Li Fei, Cerchione Claudio, Gomez Cesar, Ishida Tadao, Mateos Maria Victoria, Buck Tondre T, LeBlanc Richard, Minařík Jiří, Goldschmidt Hartmut, Zhang Rick, Sémiond Dorothée, Suzan Florence, Stefanova-Urena Maya, Koch Victorine, Moreau Philippe
Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL.
1st Department of Medicine-Department of Hematology, First Faculty of Medicine, Charles University and General Hospital, Prague, Czech Republic.
J Clin Oncol. 2025 Aug;43(22):2527-2537. doi: 10.1200/JCO-25-00744. Epub 2025 Jun 3.
To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI).
Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa C (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority.
IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 C was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The C geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption.
IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.
报告多中心、开放标签的IRAKLIA试验（ClinicalTrials.gov标识符：NCT05405166）的结果，该试验比较了皮下注射（SC）与静脉注射（IV）isatuximab联合泊马度胺和地塞米松治疗复发/难治性多发性骨髓瘤（MM）的疗效，据我们所知，这是首个使用体内注射器（OBI）的III期MM试验。
接受过≥1线既往治疗的患者按1:1随机分配，在第1周期（C1）每周1次接受Isa OBI（1400mg）或IV（10mg/kg）治疗，之后每2周1次，同时联合泊马度胺（每日4mg，第1 - 21天）和地塞米松（每周40mg [年龄≥75岁：20mg]），治疗直至疾病进展、出现不可接受的毒性或患者要求停药。共同主要终点为总缓解率（ORR；非劣效性界值为0.839）和Isa C（C6D1给药前；非劣效性界值为0.8）。如果两个共同主要终点均达到非劣效性，则证明OBI相对于IV具有非劣效性。
IRAKLIA试验随机分配了531例患者（OBI组n = 263；IV组n = 268）。中位随访12个月后，ORR分别为71.1%（OBI组）和70.5%（IV组；相对风险，1.008 [95% CI，0.9至1.126]；下限CI超过非劣效性界值）。C6D1时Isa的平均（标准差）血药浓度在OBI组为499（259）μg/mL，IV组为340（169）μg/mL。血药浓度几何平均比值（90% CI）为1.532（1.316至1.784）；下限CI超过非劣效性界值。≥3级治疗中出现的不良事件发生率在OBI组为81.7%，IV组为76.1%；输液反应发生率分别为1.5%和25.0%。OBI注射部位反应发生率为0.4%（均为1 - 2级）；99.9%的注射未中断完成。
IRAKLIA试验证明了Isa OBI与IV在疗效和药代动力学方面具有非劣效性。未观察到意外的安全信号，Isa OBI具有良好的局部耐受性。除OBI输液反应率较低外，其疗效和安全性与ICARIA - MM试验中Isa IV相当。这些结果支持了旨在提高治疗效率的OBI的潜在应用。
