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.

Introduction: In this paper, we studied the effect over time of agomelatine, an antidepressant drug administered in patient with major depressive disorder, through item response theory (IRT), taking into account a strong placebo effect and missing not at random data. We also assessed the informativeness of the HAMD-17 scale's item. Materials and Methods: The data includes five phase III clinical trials sponsored by Servier Institute, totalling 1549 patients followed during a maximum of 1 year. At each observation, individual scores for the 17 items of the HAMD scale were recorded. The probability for each score was modelled with IRT. A non-linear mixed effects model was used to describe the evolution of the disease and was coupled with a time to event model to predict dropout. Clinical trial simulations were then used to compare placebo and active treatment. Informativeness of each item was evaluated using the Fisher information theory. Results: The best model combined an IRT model, a longitudinal model for underlying depression which describes the remission and then a possible relapse, and a hazard model for dropout depending on the evolution from baseline. The drug effect was best modelled as an effect on the remission and the relapse phases. The median predicted drop in HAMD between baseline and 6 weeks was 8.8 (90% PI, 8.3-9.2) when on placebo and 13.1 (90% PI, 12.8-13.4) when treated. Nine items were found to be the most informative. Conclusion: The IRT framework allowed to characterise the evolution of depression with time and estimate the effect of agomelatine, as well as the link between symptoms and disease.