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

Abstract

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.

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

“…Several links between serum M‐protein dynamics and PFS were evaluated in the joint model and the instantaneous change of serum M‐protein (slope) was found to be the best link, consistent with the IMWG criteria in which the decrease in serum M‐protein in response to treatment is the main component directly impacting PFS. This finding is similar to previous findings using data from the ICARIA‐MM phase III trial 15 . However, the coefficient effect of slope was less important, at half the estimated value in the ICARIA joint model (6.65 vs. 11.9).…”

“…In patients still on treatment, simulations of a hypothetical discontinuation of dexamethasone co‐administration at 6 months predicted progression to occur 1.9 weeks earlier versus the sustained use of dexamethasone, with 51.7% of patients having their serum M‐protein regrow faster. Patients with no risk of earlier progression tended to have lower tumor burden and better prognostic characteristics at baseline, with a stable, very good partial response or better at 6 months, which was similar to our previous monthly dosing regimen evaluation using ICARIA‐MM trial data 15 . Short‐duration dexamethasone plus isatuximab remains beneficial for a subgroup of patients with lower tumor burden and better prognostics.…”

“…Claret's TGI model was used, which accounts for the dynamics of tumor growth, antitumor drug effect, and resistance to drug effect 20 . This model was successfully applied to describe serum M‐protein data as a surrogate of tumor growth in patients with MM 15,21–24 . In this analysis, the mechanism‐based TGI model was extended from the Thai et al 15 model to describe the underlying disease progression and exposure‐driven drug effect of isatuximab and dexamethasone on the time‐course of serum M‐protein by increasing tumor shrinkage rate.…”

“…This provided support for phase II/III dosing regimen selection in patients with MM. This framework and modeling approach has been applied to the phase III ICARIA trial, allowing to well‐characterize the relationship between serum M‐protein kinetics and risk of progression‐free survival (PFS) and identify the impact of baseline covariates (e.g., albumin, β2‐microglobulin [B2MG], presence of plasmacytoma) in patients with RRMM receiving isatuximab plus Pd 15 . The present study evaluated isatuximab treatment as monotherapy or in combination with dexamethasone in both Japanese and non‐Japanese patients to support submission in Japan using a similar framework.…”

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

“…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.…”