Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies.

The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs.

A CD38/CD3xCD28 trispecific T-cell engager as a potentially active agent in multiple myeloma patients relapsed and/or refractory to anti-CD38 monoclonal antibodies.

There is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257.

An open-label, first-in-human, single agent, dose escalation study for the evaluation of safety and efficacy of SAR442085 in patients with relapsed or refractory multiple myeloma.

Objectives: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM.

Methods: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion).

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma.

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients.

Ex Vivo Efficacy of SAR442257 Anti-CD38 Trispecific T-cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA-targeted Therapies.

Unlabelled: T cell-engaging antibodies (TCEs) are showing promising efficacy in relapsed/refractory multiple myeloma, even in patients that relapsed after B-cell maturation antigen (BCMA)-targeted therapy. Patients with multiple myeloma may have compromised T-cell health unaccounted for by preclinical models. Here, we use Myeloma Drug Sensitivity Testing (My-DST) for ex vivo measurement of anti-multiple myeloma cytotoxicity for the trispecific CD38/CD28xCD3 TCE SAR442257 through activation of the patients' own endogenous T cells to inform clinical development of the compound in multiple myeloma.

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma.

Background: CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.

Aim: Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38-mediated T-cell activation.

Isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma: A phase 1/2 study.

Background: Given the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti-CD38 monoclonal antibodies via combinations with other potentially synergistic therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti-PD-1) enhances the anti-myeloma activity of isatuximab (anti-CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety.

Methods: Patients received isatuximab 10 mg/kg once weekly for 4 weeks followed by every 2 weeks (Isa), or isatuximab 10 mg/kg plus cemiplimab 250 mg every 2 (Isa + CemiQ2W) or every 4 weeks (Isa + CemiQ4W).

Evaluation of isatuximab in patients with soft-tissue plasmacytomas: An analysis from ICARIA-MM and IKEMA.

The Phase 3 ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) studies demonstrated that isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) or carfilzomib (K) and d (Isa-Kd) improved progression-free survival (PFS) versus Pd or Kd in patients with relapsed and/or refractory multiple myeloma. In this post hoc analysis of patients with soft-tissue plasmacytomas, we evaluated Isa-Pd/Isa-Kd efficacy using central radiology and central laboratory assessments. Given the low incidence of soft-tissue plasmacytomas (7.

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

Introduction: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics.

Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma.

The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10-5 sensitivity level).

Exposure-response analyses for selection/confirmation of optimal isatuximab dosing regimen in combination with pomalidomide/dexamethasone treatment in patients with multiple myeloma.

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).

SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma.

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a).

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study.

Background: The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.

Methods: In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions.

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

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.

Chromosomal 1q21 abnormalities in multiple myeloma: a review of translational, clinical research, and therapeutic strategies.

Multiple myeloma (MM) remains an incurable disease with a median overall survival of approximately 5 years. Gain or amplification of 1q21 (1q21+) occurs in around 40% of patients with MM and generally portends a poor prognosis. Patients with MM who harbor 1q21+ are at increased risk of drug resistance, disease progression, and death.

PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma.

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.

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients.