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Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma

Belantamab mafodotin is an antibody–drug conjugate comprising a humanized anti‐B‐cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease‐resistant maleimidocaproyl linker. Single‐agent belantamab mafodotin showed clinically meaningful activity a...

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Autores principales: Ferron‐Brady, Geraldine, Rathi, Chetan, Collins, Jon, Struemper, Herbert, Opalinska, Joanna, Visser, Sandra, Jewell, Roxanne C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293327/
https://www.ncbi.nlm.nih.gov/pubmed/34468979
http://dx.doi.org/10.1002/cpt.2409
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author Ferron‐Brady, Geraldine
Rathi, Chetan
Collins, Jon
Struemper, Herbert
Opalinska, Joanna
Visser, Sandra
Jewell, Roxanne C.
author_facet Ferron‐Brady, Geraldine
Rathi, Chetan
Collins, Jon
Struemper, Herbert
Opalinska, Joanna
Visser, Sandra
Jewell, Roxanne C.
author_sort Ferron‐Brady, Geraldine
collection PubMed
description Belantamab mafodotin is an antibody–drug conjugate comprising a humanized anti‐B‐cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease‐resistant maleimidocaproyl linker. Single‐agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM‐1 and phase II DREAMM‐2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM‐2, efficacy end points (probability of response (PoR) and progression‐free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, ß(2)‐microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM‐1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM‐2). Higher cys‐mcMMAF maximum plasma drug concentration (C(max)) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM‐1 and DREAMM ‐2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies.
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spelling pubmed-92933272022-07-20 Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma Ferron‐Brady, Geraldine Rathi, Chetan Collins, Jon Struemper, Herbert Opalinska, Joanna Visser, Sandra Jewell, Roxanne C. Clin Pharmacol Ther Research Belantamab mafodotin is an antibody–drug conjugate comprising a humanized anti‐B‐cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease‐resistant maleimidocaproyl linker. Single‐agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM‐1 and phase II DREAMM‐2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM‐2, efficacy end points (probability of response (PoR) and progression‐free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, ß(2)‐microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM‐1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM‐2). Higher cys‐mcMMAF maximum plasma drug concentration (C(max)) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM‐1 and DREAMM ‐2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies. John Wiley and Sons Inc. 2021-10-04 2021-11 /pmc/articles/PMC9293327/ /pubmed/34468979 http://dx.doi.org/10.1002/cpt.2409 Text en © 2021 Glaxo Group Limited. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Ferron‐Brady, Geraldine
Rathi, Chetan
Collins, Jon
Struemper, Herbert
Opalinska, Joanna
Visser, Sandra
Jewell, Roxanne C.
Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma
title Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma
title_full Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma
title_fullStr Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma
title_full_unstemmed Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma
title_short Exposure–Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma
title_sort exposure–response analyses for therapeutic dose selection of belantamab mafodotin in patients with relapsed/refractory multiple myeloma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293327/
https://www.ncbi.nlm.nih.gov/pubmed/34468979
http://dx.doi.org/10.1002/cpt.2409
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