Joint modeling and simulation of M-protein dynamics and progression-free survival for alternative isatuximab dosing with pomalidomide/dexamethasone.

Aims Addition of isatuximab 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 isatuximab by simulation. Methods Data from the ICARIA-MM trial comparing isatuximab 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 isatuximab 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 isatuximab 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.