The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.

3rd Medical Department Paracelsus Medical University Salzburg Salzburg Cancer Research Institute Cancer Cluster Salzburg Salzburg Austria

Clinical R and D Pharma Mar Colmenar Viejo Madrid Spain

Departamento de Hematología Hospital Universitario de Salamanca Paseo de San Vicente 58 182 37007 Salamanca Spain

Department of Blood and Marrow Transplantation Seoul St Mary's Hospital The Catholic University of Korea Seoul South Korea

Department of Clinical Haematology Mater Health Services Brisbane Australia

Department of Clinical Therapeutics Alexandra General Hospital Athens Greece

Department of Haemato Oncology St Bartholomew's Cancer Centre Barts Health NHS Trust London UK

Department of Hematology Canberra Hospital and Health Service Canberra Australia

Department of Hematology Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Hematology Institut Jules Bordet Brussels Belgium

Department of Hematology IRCCS Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genoa Italy

Department of Hematology Oncology Faculty of Medicine University Hospital Ostrava Ostrava Czech Republic

Department of Hematology University Hospital Marqués de Valdecilla IDIVAL University of Cantabria Santander Spain

Department of Hematology University Hospital of Salamanca IBSAL Salamanca Spain

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

Department of Medicine National Taiwan University Hospital Taipei Taiwan

Department of Medicine Royal Perth Hospital Perth Australia

Hematology Division Department of Internal Medicine University of Patras Medical School Patras Greece

Wilhelminen Cancer Research Institute Department of Medicine Center for Oncology Hematology and Palliative Care Wilhelminen Hospital Vienna Austria

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