Related Experiment Video
Updated: Oct 15, 2025
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Joint modelling and simulation of M-protein dynamics and progression-free survival for alternative isatuximab dosing
Hoai-Thu Thai1, Nadia Gaudel2, Marc Cerou1
1Translational Disease Modeling, Data and Data Science, Sanofi, France.
Aims:
Addition of isatuximab (Isa) to pomalidomide/dexamethasone (Pd) significantly improved progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (RRMM). We aimed to characterize the relationship between serum M-protein kinetics and PFS in the phase 3 ICARIA-MM trial (NCT02990338), and to evaluate an alternative dosing regimen of Isa by simulation.
Methods:
Data from the ICARIA-MM trial comparing Isa 10 mg/kg weekly for 4 weeks then every 2 weeks (QW-Q2W) in combination with Pd versus Pd in 256 evaluable RRMM patients were used. A joint model of serum M-protein dynamics and PFS was developed. Trial simulations were then performed to evaluate whether efficacy is maintained after switching to a monthly dosing regimen.
Results:
The model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and baseline patient characteristics impacting serum M-protein kinetics (albumin and β2-microglobulin on baseline levels, non-IgG type on growth rate) and PFS (presence of plasmacytomas). Trial simulations demonstrated that switching to a monthly Isa regimen at 6 months would shorten median PFS by 2.3 weeks and induce 42.3% patients to progress earlier.
Conclusions:
Trial simulations supported selection of the approved Isa 10 mg/kg QW-Q2W regimen and showed that switching to a monthly regimen after 6 months may reduce clinical benefit in the overall population. However, patients with good prognostic characteristics and with a stable, very good partial response may switch to a monthly regimen after 6 months without compromising the risk of disease progression. This hypothesis will be tested in a prospective clinical trial.
Insights
Adding isatuximab to pomalidomide/dexamethasone improves progression-free survival in multiple myeloma. Serum M-protein changes predict survival, and simulations suggest a monthly isatuximab dose may reduce benefits.
Area of Science:
- Hematology
- Clinical Pharmacology
- Biostatistics
Background:
- Relapsed/refractory multiple myeloma (RRMM) remains a challenge.
- Isatuximab combined with pomalidomide/dexamethasone (Pd) demonstrated improved progression-free survival (PFS) in the ICARIA-MM trial.
- Understanding M-protein kinetics is crucial for predicting treatment outcomes.
Purpose of the Study:
- To analyze the relationship between serum M-protein kinetics and PFS in RRMM patients treated with isatuximab plus Pd.
- To evaluate a potential alternative monthly dosing regimen for isatuximab via simulation.
Main Methods:
- Utilized data from 256 RRMM patients in the ICARIA-MM trial comparing isatuximab (Isa) plus Pd versus Pd alone.
- Developed a joint model to analyze serum M-protein dynamics and PFS.
- Conducted trial simulations to assess efficacy of a modified Isa dosing schedule.
Main Results:
- Serum M-protein slope was the strongest on-treatment predictor of PFS.
- Baseline factors like albumin, beta2-microglobulin, and non-IgG myeloma type influenced M-protein kinetics.
- Simulations indicated a monthly Isa regimen after 6 months could shorten median PFS by 2.3 weeks and lead to earlier progression in 42.3% of patients.
Conclusions:
- The approved weekly-then-biweekly isatuximab regimen is supported by simulations.
- Switching to a monthly isatuximab dose after 6 months may decrease overall clinical benefit.
- Selected patients with favorable prognosis and stable response might tolerate a monthly regimen without increased progression risk, warranting further investigation.
More Related Videos
10:27Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
12:41Multiparametric Tumor Organoid Drug Screening Using Widefield Live-Cell Imaging for Bulk and Single-Organoid Analysis
Published on: December 23, 2022
Related Concept Videos
01:21Cancer Survival Analysis
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...