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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 E max 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., (© 2024 Sanofi and The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In this multi-center, Phase-1 study (NCT03733717), we characterized the pharmacokinetics (PK) of the anti-CD38 antibody isatuximab (Isa) after IV administration (primary objective), and evaluated safety, immunogenicity, and preliminary anti-myeloma activity in Chinese patients with relapsed/refractory multiple myeloma (RRMM). Isa 20-mg/kg was administered weekly (QW) in cycle 1, then biweekly (Q2W). Twenty-one extensively pretreated RRMM patients (median 4 prior lines; 95.2% refractory to last regimen), received ≥ 1 dose of Isa. After first IV-infusion, mean maximum observed concentration was 402 μg/mL and mean area-under-the-concentration-versus-time curve (first 1-week dosing interval) 37,000 μg·h/mL. After repeated administration, exposure (C trough ) increased 3.11-folds (day 1/cycle 2) versus first administration (day 8/cycle 1). Safety findings were consistent with the known Isa safety profile, with no new safety signals. Any-causality, grade ≥ 3 treatment-emergent adverse events (TEAEs) were reported in 47.6% of patients. Serious, treatment-related AEs occurred in 2 patients. Isa treatment was generally well tolerated; only 1 patient discontinued due to TEAE. Preliminary efficacy results showed a 19.0% overall response rate (clinical benefit, 33.3%). Our results demonstrate a PK profile for Isa comparable to prior findings in Western and other East-Asian populations, as well as safety and tolerability of treatment with IV Isa 20-mg/kg QW-Q2W in Chinese RRMM patients.Trial registration: The trial was registered with ClinicalTrials.gov; NCT03733717. Date of first trial registration: 07/11/2018., Competing Interests: Competing interests MS, HJ, XQ, FD, and JQ: nothing to disclose. YL, ZF, SZ-L, DS, and LL are employed by Sanofi and may hold stock and/or stock options. LQ: consulting for AstraZeneca, Beigene, Xi'an Janssen, Pfizer; Speaker Bureau participation for AstraZeneca, Beigene, Xi'an Janssen, Pfizer, Roche, and Sanofi., (© 2024. The Author(s).)

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., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Isatuximab is an approved anti-CD38 monoclonal antibody with multiple antitumor modes of action. An exposure-response (E-R) analysis using data from patients with relapsed/refractory multiple myeloma (RRMM) enrolled in a phase Ib clinical study who received isatuximab at doses from 5 to 20 mg/kg weekly for 1 cycle (4 weeks) followed by every 2 weeks thereafter (qw/q2w) in combination with pomalidomide/dexamethasone (n = 44) was first used to determine the optimal dose/schedule for the phase III ICARIA-MM study. It was complemented by an E-R analysis from a second phase Ib study of patients who received isatuximab at doses from 3 to 10 mg/kg q2w or 10 or 20 mg/kg qw/q2w in combination with lenalidomide/dexamethasone (n = 52). Plasma trough concentration at week 4 (CT4W) was the best predictor for response, and the benefit of the initial 4-weekly administration was confirmed. Although the predicted overall response rate (ORR) was higher at 20 mg/kg vs. 10 mg/kg, the 95% confidence intervals were overlapping. Considering the high probability of success to reach the targeted ORR of greater than or equal to 60%, 10 mg/kg qw/q2w was selected. Results of the E-R analysis from the lenalidomide/dexamethasone study and published disease modeling using data from both phase Ib clinical studies reinforced 10 mg/kg qw/q2w as the optimal dose/schedule for the phase III ICARIA-MM study. E-R analysis showed that higher CT4W was associated with higher ORR. Developed models supported the phase III isatuximab dosing regimen selection/confirmation of 10 mg/kg qw/q2w for use in combination with pomalidomide/dexamethasone in patients with RRMM., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., (© 2021 Sanofi R&D. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This analysis describes the pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that supported selection of the isatuximab (anti-CD38 monoclonal antibody) dosing regimen alongside its early clinical development in patients with relapsed/refractory multiple myeloma (RRMM). The PK/PD mathematical model characterized the variations of patient serum M-protein concentrations, the primary marker of tumor burden in multiple myeloma (MM). Three separate PK/PD models were built sequentially as data became available from phase I clinical trials. The primary PK/PD analysis was initiated using monotherapy phase I study data (n = 122), followed by analysis of data collected from phase Ib combination studies with lenalidomide and dexamethasone (Rd, n = 40) and then with pomalidomide and dexamethasone (Pd, n = 31). Using the PK/PD model, abnormal "myeloma" protein (M-protein) profiles under different isatuximab dosing regimens were simulated. Overall, simulations revealed that regimens which included a loading period of four weekly administrations followed by administration every 2 weeks thereafter (QW4-Q2W), reduced M-protein levels more than a Q2W regimen without a loading period. For isatuximab monotherapy, a 20 mg/kg dose induced greater reduction in serum M-protein levels compared with doses equal or lower than 10 mg/kg. For isatuximab in combination with either Rd or Pd, simulations yielded no substantial benefit in terms of M-protein reduction between isatuximab 10 mg/kg and 20 mg/kg. These PK/PD analyses supported the use of isatuximab 10 mg/kg QW4-Q2W in combination with Pd in the phase III trial., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Isatuximab, a monoclonal antibody (mAb) of immunoglobulin G (IgG) isotype, specifically targets the cluster of differentiation 38 antigen overexpressed in malignant plasma cells. Isatuximab is used to treat multiple myeloma (MM), characterized by the excessive production of abnormal "myeloma proteins" (M-proteins) that may interact with therapeutic IgG mAb on the neonatal Fc receptor (FcRn)-mediated recycling pathway. The clinical pharmacology profile of isatuximab was investigated by population pharmacokinetics (PKs) modeling in 476 patients with MM who received 1-20 mg/kg isatuximab either as single agent or in combination with pomalidomide-dexamethasone in 4 clinical trials. Isatuximab PKs were characterized by a two-compartment model with parallel time-varying linear clearance (CL) and nonlinear elimination. Due to a mechanism-based drug-disease interaction, patients secreting IgG M-protein exhibited a twofold lower drug exposure compared with patients with non-IgG MM. No dose adjustment was required based on MM immunoglobulin type because efficacy and safety profiles were comparable between IgG and non-IgG MM subpopulations. β2-microglobulin, body weight, sex, drug material, and race have a limited effect on drug exposure and do not require any dose adjustment. A typical 50% decrease in linear CL from initial treatment to steady-state was predicted, and this decrease correlated with the best overall response rate and was slower for patients with IgG MM. These findings suggest that the time-dependent effect of isatuximab is likely mediated by a combined factor of both disease state evolution and the perturbation of the FcRn-mediated recycling pathway., (© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775., (© 2019 by The American Society of Hematology.)