PURPOSE: 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). METHODS: 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 Ctrough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority. RESULTS: 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 Ctrough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The Ctrough 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. CONCLUSION: 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.

1st Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Czech Republic

Department of Clinical Therapeutics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacký University and University Hospital Olomouc Olomouc Czech Republic

Department of Hematology and Oncology Clínica São Germano São Paulo Brazil

Department of Hematology Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan China

Department of Hematooncology and Bone Marrow Medical University of Lublin Lublin Poland

Department of Internal Medicine 5 University Hospital Heidelberg Heidelberg Germany

Department of Internal Medicine Istanbul Medical Faculty Istanbul University Istanbul Turkey

Department of Medicine Korea University Seoul South Korea

Division of Hematology Oncology Mayo Clinic Jacksonville FL

Faculty of Health Sciences Institute of Diagnostics University of Pécs Pécs Hungary

Haematology Unit Norfolk and Norwich University Hospitals NHS Foundation Trust Norwich United Kingdom

Hematology AOU Federico 2 Naples Italy

Hematology Department CHU Nantes Nantes France

Hematology Oncology and Cell Therapy University Institute Hôpital Maisonneuve Rosemont Research Center Université de Montréal Montréal QC Canada

Hospital Universitario de Salamanca Instituto Biosanitario de Salamanca Salamanca Spain

Human Institute ShanghaiTech University Shanghai China

Illawarra Cancer Care Centre Wollongong NSW Australia

Inmunocel Las Condes Santiago Chile

Institut Català d'Oncologia and Josep Carreras Research Institute Hospital Germans Trias i Pujol Barcelona Spain

Japanese Red Cross Medical Center Tokyo Japan

Malignant Haematology and Stem Cell Transplantation Service Alfred Health Monash University Melbourne VIC Australia

Mór Kaposi Teaching Hospital Department of Hematology Kaposvár Hungary

Oslo Myeloma Center Department of Hematology Oslo University Hospital Oslo Norway

Peking University People's Hospital Peking University Institute of Hematology National Clinical Research Center for Hematologic Disease Beijing China

Sanofi Bridgewater NJ

Sanofi Cambridge MA

Sanofi R and D Vitry sur Seine France

Service d'Hématologie et Thérapie Cellulaire CHU and CIC Inserm 1402 Poitiers Cedex France

Servicio de Hematología y Trasplante Hematopoyético Instituto Alexander Fleming Buenos Aires Argentina

Spartanburg Medical Center Center for Hematology Oncology Spartanburg SC

Sydney Adventist Hospital Wahroonga NSW Australia

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ClinicalTrials.gov
NCT05405166