1. Targeting BCL ‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma
- Author
-
Jonathan L. Kaufman, Ahmed Salem, Xiaoqing Yang, James M. Pauff, Paulo Maciag, Cyrille Touzeau, Fredrik Schjesvold, Thierry Facon, Lawrence H. Boise, Shaji Kumar, Yanwen Jiang, Stefanie Unger, Wan-Jen Hong, Deeksha Vishwamitra, John Pesko, Fengjiao Dunbar, Yao Yu, Jeremy A. Ross, Cristina Gasparetto, Philippe Moreau, R. N. Tammy Macartney, Emory University [Atlanta, GA], Duke University [Durham], University of Oslo (UiO), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Université d'Angers (UA), Université de Nantes (UN), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), CHU Lille, Hôpital Claude Huriez [Lille], Genentech, Inc. [San Francisco], Abbvie Inc. [North Chicago], AbbVie Deutschland GmbH & Co KG, Abbott GmbH & Co KG, Mayo Clinic [Rochester], 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), and Bernardo, Elizabeth
- Subjects
Male ,medicine.medical_treatment ,Salvage therapy ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,Gastroenterology ,Dexamethasone ,Translocation, Genetic ,chemistry.chemical_compound ,0302 clinical medicine ,Bone Marrow ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Research Articles ,Multiple myeloma ,Sulfonamides ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Combined Modality Therapy ,Neoplasm Proteins ,3. Good health ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,Female ,Multiple Myeloma ,Signal Transduction ,Research Article ,medicine.drug ,medicine.medical_specialty ,bcl-X Protein ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Neutropenia ,Infections ,03 medical and health sciences ,Refractory ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Humans ,Aged ,Chromosomes, Human, Pair 14 ,Salvage Therapy ,business.industry ,Venetoclax ,Chromosomes, Human, Pair 11 ,Daratumumab ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Hematologic Diseases ,Genes, bcl-2 ,chemistry ,business ,Follow-Up Studies ,030215 immunology - Abstract
International audience; Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.
- Published
- 2021
- Full Text
- View/download PDF