Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients

Abstract This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M‐protein kinetics and its association with p...

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Main Authors: Hoai‐Thu Thai, Kimiko Koiwai, Yoshihisa Shitara, Hirotaka Kazama, Jean‐Baptiste Fau, Dorothée Semiond, Christine Veyrat‐Follet
Format: Article
Language:English
Published: Wiley 2023-12-01
Series:CPT: Pharmacometrics & Systems Pharmacology
Online Access:https://doi.org/10.1002/psp4.12947
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author Hoai‐Thu Thai
Kimiko Koiwai
Yoshihisa Shitara
Hirotaka Kazama
Jean‐Baptiste Fau
Dorothée Semiond
Christine Veyrat‐Follet
author_facet Hoai‐Thu Thai
Kimiko Koiwai
Yoshihisa Shitara
Hirotaka Kazama
Jean‐Baptiste Fau
Dorothée Semiond
Christine Veyrat‐Follet
author_sort Hoai‐Thu Thai
collection DOAJ
description Abstract This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M‐protein kinetics and its association with progression‐free survival (PFS) was developed using data from 201 evaluable Japanese and non‐Japanese patients with RRMM enrolled in two monotherapy phase I/II trials, where Japanese patients (n = 31) received isatuximab at 10 or 20 mg/kg once weekly (qw) for 4 weeks then every 2 weeks (q2w) in subsequent cycles (10 or 20 mg/kg qw–q2w). Among non‐Japanese patients, 38 received isatuximab 20 mg/kg qw–q2w in combination with dexamethasone. Trial simulations were then performed to evaluate the effect of the isatuximab dosing regimens on both serum M‐protein and PFS with and without dexamethasone. The model identified instantaneous changes in serum M‐protein as the best on‐treatment predictor for PFS. Trial simulations demonstrated that 20 mg/kg qw–q2w induced a greater decrease (30% vs. 22%) of serum M‐protein at week 8 and prolonged median PFS by 2.4 weeks compared with 10 mg/kg qw–q2w. Although Japanese patients did not receive isatuximab plus dexamethasone in the phase I/II trial, simulations predicted that isatuximab 20 mg/kg qw–q2w plus dexamethasone would induce a greater decrease (67% vs. 43%) of serum M‐protein and a prolonged median PFS by 7.2 weeks compared with isatuximab alone. Trial simulations support the approved isatuximab 20 mg/kg qw–q2w regimen when administered as a single agent and in combination with dexamethasone in Japanese patients.
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spelling doaj.art-daa28da7c7994013bf748c2247ab74212023-12-16T18:59:25ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-12-0112121846185810.1002/psp4.12947Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patientsHoai‐Thu Thai0Kimiko Koiwai1Yoshihisa Shitara2Hirotaka Kazama3Jean‐Baptiste Fau4Dorothée Semiond5Christine Veyrat‐Follet6Sanofi R&D, Data and Data Science Translational Disease Modeling Chilly‐Mazarin FranceTranslational Medicine and Early Development, Sanofi Chilly‐Mazarin FranceTranslational Medicine and Early Development, Sanofi Tokyo JapanSpecialty Care Oncology Medical, Sanofi Tokyo JapanTranslational Medicine and Early Development, Sanofi Chilly‐Mazarin FranceTranslational Medicine and Early Development, Sanofi Cambridge Massachusetts USASanofi R&D, Data and Data Science Translational Disease Modeling Chilly‐Mazarin FranceAbstract This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M‐protein kinetics and its association with progression‐free survival (PFS) was developed using data from 201 evaluable Japanese and non‐Japanese patients with RRMM enrolled in two monotherapy phase I/II trials, where Japanese patients (n = 31) received isatuximab at 10 or 20 mg/kg once weekly (qw) for 4 weeks then every 2 weeks (q2w) in subsequent cycles (10 or 20 mg/kg qw–q2w). Among non‐Japanese patients, 38 received isatuximab 20 mg/kg qw–q2w in combination with dexamethasone. Trial simulations were then performed to evaluate the effect of the isatuximab dosing regimens on both serum M‐protein and PFS with and without dexamethasone. The model identified instantaneous changes in serum M‐protein as the best on‐treatment predictor for PFS. Trial simulations demonstrated that 20 mg/kg qw–q2w induced a greater decrease (30% vs. 22%) of serum M‐protein at week 8 and prolonged median PFS by 2.4 weeks compared with 10 mg/kg qw–q2w. Although Japanese patients did not receive isatuximab plus dexamethasone in the phase I/II trial, simulations predicted that isatuximab 20 mg/kg qw–q2w plus dexamethasone would induce a greater decrease (67% vs. 43%) of serum M‐protein and a prolonged median PFS by 7.2 weeks compared with isatuximab alone. Trial simulations support the approved isatuximab 20 mg/kg qw–q2w regimen when administered as a single agent and in combination with dexamethasone in Japanese patients.https://doi.org/10.1002/psp4.12947
spellingShingle Hoai‐Thu Thai
Kimiko Koiwai
Yoshihisa Shitara
Hirotaka Kazama
Jean‐Baptiste Fau
Dorothée Semiond
Christine Veyrat‐Follet
Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients
CPT: Pharmacometrics & Systems Pharmacology
title Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients
title_full Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients
title_fullStr Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients
title_full_unstemmed Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients
title_short Model‐based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients
title_sort model based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed refractory multiple myeloma in japanese patients
url https://doi.org/10.1002/psp4.12947
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