Timing Genomic Antigen Loss in Multiple Myeloma Treated with T Cell-Redirecting Immunotherapies

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Genomic antigen loss is a known resistance mechanism to chimeric antigen receptor T-cell (CAR-T) and T-cell engager (TCE) therapies in relapsed/refractory multiple myeloma (RRMM).
• It is uncertain whether these resistance events are acquired during treatment or selected from pre-existing, undetectable clones.

Purpose of the Study:

• To determine the timing of genomic antigen escape in RRMM patients undergoing CAR-T/TCE therapy.
• To assess the prevalence of antigen loss mutations at baseline and their emergence during treatment.

Main Methods:

• Whole genome sequencing (WGS) utilizing chemotherapy mutational signatures as temporal barcodes to time genomic events.
• Analysis of 11 RRMM patients treated with BCMA- and GPRC5D-targeted CAR-T/TCE.
• Longitudinal digital PCR (dPCR) to track resistance mutations from therapy initiation to relapse.

Main Results:

• Genomic antigen escape was timed in 4 out of 11 RRMM patients, with biallelic loss acquired after CAR-T/TCE exposure.
• Resistance mutations were undetectable at baseline and therapy initiation, emerging before clinical relapse.
• In a cohort of 752 newly diagnosed patients, only a small fraction had monoallelic inactivation of TNFRSF17 (2.7%) or GPRC5D (9%), with no biallelic loss.

Conclusions:

• Genomic antigen loss in RRMM is acquired under treatment, not pre-existing, highlighting treatment-induced resistance.
• Pre-treatment mutational screening for antigen loss has limited utility for predicting CAR-T/TCE efficacy.
• Continuous monitoring of antigen expression during therapy is essential for managing resistance in RRMM.