1. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma
- Author
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Hani Hassoun, Jacob P. Laubach, Jan S. Moreb, Sara Thuresson, Paula Rodriguez-Otero, Marcus Thuresson, Michele Cavo, Albert Oriol, Maria-Victoria Mateos, Joan Bladé, John W. Hiemenz, Adrian Alegre, Amitabha Mazumder, Horizon (Op ) Investigators, Kenneth C. Anderson, Omar Nadeem, Johan Harmenberg, Nicolaas A Bakker, Xavier Leleu, Alessandra Larocca, Christopher Maisel, Paul G. Richardson, Agne Paner, Anastasios Raptis, Cyrille Touzeau, Catriona Byrne, Harvard Medical School [Boston] (HMS), Hospital Universitari Germans Trias I Pujol [Badalona], Università degli studi di Torino = University of Turin (UNITO), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Bologna/Università di Bologna, Clínica Universidad de Navarra [Pamplona], Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Florida [Gainesville] (UF), Memorial Sloane Kettering Cancer Center [New York], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA), Université de Nantes (UN), Site de Recherche Intégrée sur le Cancer [Nantes] (SIRIC), Centre hospitalier universitaire de Nantes (CHU Nantes), SIRIC ILIAD [Angers, Nantes], Hospital Universitario Quironsalud, Rush University Medical Center [Chicago], Baylor Scott & White Charles A. Sammons Cancer Center [Dallas, TX, USA], Oncology Institute of Hope and Innovation [Glendale, CA, USA] (OIHI), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Novant Health Forsyth Medical Center [Winston-Salem, NC, USA] (NHFMC), Oncopeptides AB [Stockholm, Sweden], Instituto de Investigación Biomédica de Salamanca [Salamanca, Spain] (IBSAL/CIC), HORIZON (OP-106) Investigators, Bernardo, Elizabeth, Università degli studi di Torino (UNITO), University of Bologna, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Richardson P.G., Oriol A., Larocca A., Blade J., Cavo M., Rodriguez-Otero P., Leleu X., Nadeem O., Hiemenz J.W., Hassoun H., Touzeau C., Alegre A., Paner A., Maisel C., Mazumder A., Raptis A., Moreb J.S., Anderson K.C., Laubach J.P., Thuresson S., Thuresson M., Byrne C., Harmenberg J., Bakker N.A., and Mateos M.-V.
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Adult ,Male ,Cancer Research ,Time Factors ,Time Factor ,Phenylalanine ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Tumor cells ,Drug resistance ,Dexamethasone ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm ,Progression-free survival ,Melphalan ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Refractory Multiple Myeloma ,Middle Aged ,medicine.disease ,Progression-Free Survival ,United States ,3. Good health ,Europe ,Clinical trial ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Female ,Multiple Myeloma ,business ,Human ,Conjugate ,medicine.drug - Abstract
PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.
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- 2021