Joint modelling and simulation of M‐protein dynamics and progression‐free survival for alternative isatuximab dosing with pomalidomide/dexamethasone

Self Cite

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.

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Thai

Koiwai

Shitara

et al. 2023

Self Cite

“…The analysis confirmed and quantified the characteristics of the M‐protein response to ixazomib treatment, as well as the relationships between drug exposure and various safety end points. By integrating M‐protein biomarker modeling 42 with DTMM models of safety end points, the joint framework described here represents a unified simulation tool to more fully understand ixazomib clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic/pharmacodynamic joint modeling of ixazomib efficacy and safety using data from the pivotal phase III TOURMALINE‐MM1 study in multiple myeloma patients

Srimani

Diderichsen

Hanley

et al. 2022

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE‐MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time‐to‐event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M‐protein] and progression‐free survival [PFS]) outcomes observed in TOURMALINE‐MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M‐protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M‐protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens.

Isatuximab–dexamethasone–pomalidomide combination effects on serum M protein and PFS in myeloma: Development of a joint model using phase I/II data

Pitoy,

Desmée,

Riglet

et al. 2024

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 Emax 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.