Pitoy Antoine, Desmée Solène, Riglet François, Thai Hoai-Thu, Klippel Zandra, Semiond Dorothée, Veyrat-Follet Christine, Bertrand Julie
Sanofi Data and Data Sciences, Translational Disease Modeling, Gentilly, France.
INSERM, SPHERE, U1246, Tours University, Nantes University, Tours, France.
CPT Pharmacometrics Syst Pharmacol. 2024 Dec;13(12):2087-2101. doi: 10.1002/psp4.13206. Epub 2024 Nov 28.
This study aimed at leveraging data from phase I/II clinical trials to build a nonlinear joint model of serum M-protein kinetics and progression-free survival (PFS) accounting for the effects of isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex) in patients with relapsed and/or refractory multiple myeloma. Serum M-protein levels and PFS data from 203 evaluable patients, included either in a phase I/II study (n = 173) or in a phase I study (n = 30), were used to build the model. First, we independently developed a longitudinal model and a PFS model. Then, we linked them in a nonlinear joint model by selecting the link function that best captured the association between serum M-protein kinetics and PFS. A Claret tumor growth-inhibition model accounting for the additive effects of Isa, with an E function, Pom, and Dex on serum M-protein elimination was selected to describe serum M-protein kinetics. PFS was best described with a log-logistic model and associations with baseline beta-2 microglobulin level, age, and coadministration of Dex were identified. The instantaneous change in serum M-protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA-MM phase III pivotal study, and validated it using the same phase III pivotal study data.
本研究旨在利用I/II期临床试验数据，建立一个血清M蛋白动力学和无进展生存期（PFS）的非线性联合模型，该模型考虑了isatuximab（Isa）、泊马度胺（Pom）和地塞米松（Dex）对复发和/或难治性多发性骨髓瘤患者的影响。来自203例可评估患者的血清M蛋白水平和PFS数据被用于建立模型，这些患者纳入了一项I/II期研究（n = 173）或一项I期研究（n = 30）。首先，我们独立开发了一个纵向模型和一个PFS模型。然后，通过选择最能捕捉血清M蛋白动力学与PFS之间关联的链接函数，将它们链接成一个非线性联合模型。选择了一个考虑Isa、具有E函数的Pom和Dex对血清M蛋白清除的累加效应的Claret肿瘤生长抑制模型来描述血清M蛋白动力学。PFS用对数逻辑模型进行最佳描述，并确定了与基线β2微球蛋白水平、年龄以及Dex联合使用的关联。在最终的联合模型中，发现血清M蛋白水平的瞬时变化与PFS相关。通过模型模拟，我们回顾性地支持了ICARIA-MM III期关键研究中Isa每周10 mg/kg，共4周，然后每两周一次（QW/Q2W）的给药方案，并使用同一III期关键研究数据对其进行了验证。
