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Targeting BCL‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma

Kaufman, Jonathan L. ; Gasparetto, Cristina ; Schjesvold, Fredrik H. ; Moreau, Philippe ; Touzeau, Cyrille ; Facon, Thierry ; Boise, Lawrence H. ; Jiang, Yanwen ; Yang, Xiaoqing ; Dunbar, Fengjiao ; Vishwamitra, Deeksha ; Unger, Stefanie ; Macartney, Tammy ; Pesko, John ; Yu, Yao ; Salem, Ahmed Hamed ; Ross, Jeremy A. ; Hong, Wan‐Jen ; Maciag, Paulo C. ; Pauff, James M. ; Kumar, Shaji

American journal of hematology, 2021-04, Vol.96 (4), p.418-427 [Periódico revisado por pares]

Hoboken, USA: John Wiley & Sons, Inc

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Título:
Targeting BCL‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma
Autor: Kaufman, Jonathan L. ; Gasparetto, Cristina ; Schjesvold, Fredrik H. ; Moreau, Philippe ; Touzeau, Cyrille ; Facon, Thierry ; Boise, Lawrence H. ; Jiang, Yanwen ; Yang, Xiaoqing ; Dunbar, Fengjiao ; Vishwamitra, Deeksha ; Unger, Stefanie ; Macartney, Tammy ; Pesko, John ; Yu, Yao ; Salem, Ahmed Hamed ; Ross, Jeremy A. ; Hong, Wan‐Jen ; Maciag, Paulo C. ; Pauff, James M. ; Kumar, Shaji
Assuntos: Adverse events ; Aged ; Antibodies, Monoclonal - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; bcl-X Protein ; Bone Marrow - pathology ; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage ; Bridged Bicyclo Compounds, Heterocyclic - adverse effects ; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Cancer ; Chromosomes, Human, Pair 11 - genetics ; Chromosomes, Human, Pair 14 - genetics ; Combined Modality Therapy ; Cytogenetics ; Dexamethasone ; Dexamethasone - administration & dosage ; Female ; Follow-Up Studies ; Gene expression ; Genes, bcl-2 ; Hematologic Diseases - chemically induced ; Hematology ; Hematopoietic Stem Cell Transplantation ; Humans ; Infections - etiology ; Kaplan-Meier Estimate ; Life Sciences ; Lymphopenia ; Male ; MAP kinase ; Middle Aged ; Multiple myeloma ; Multiple Myeloma - drug therapy ; Multiple Myeloma - genetics ; Multiple Myeloma - therapy ; Mutation ; Neoplasm Proteins - antagonists & inhibitors ; Neutropenia ; Pharmacokinetics ; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors ; Recurrence ; Safety ; Salvage Therapy ; Signal Transduction ; Steroids ; Sulfonamides - administration & dosage ; Sulfonamides - adverse effects ; Sulfonamides - pharmacokinetics ; Sulfonamides - pharmacology ; Thrombocytopenia ; Translocation, Genetic
É parte de: American journal of hematology, 2021-04, Vol.96 (4), p.418-427
Notas: Funding information
AbbVie; Genentech
PMCID: PMC7986778
Funding information AbbVie; Genentech
Descrição: 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.
Editor: Hoboken, USA: John Wiley & Sons, Inc
Idioma: Inglês;Norueguês

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Targeting BCL‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma

Hoboken, USA: John Wiley & Sons, Inc

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