Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Multiple myeloma (MM) is an incurable hematologic malignancy with frequent relapses.
• Current treatment strategies necessitate improved methods for monitoring disease progression and treatment response.

Purpose of the Study:

• To develop and validate a circulating tumor DNA (ctDNA) assay for molecular characterization, treatment response monitoring, and early relapse detection in MM.
• To assess the utility of ctDNA in patients undergoing anti-BCMA CAR T-cell therapy.
• To evaluate ctDNA for measurable residual disease (MRD) assessment and prediction of clinical relapse.

Main Methods:

• Sequencing of 412 specimens from 64 patients with newly diagnosed or relapsed/refractory MM.
• Correlation analysis of ctDNA with clinical biomarkers and patient outcomes.
• Simultaneous tracking of ctDNA and CAR-specific cell-free DNA (CAR-cfDNA) in patients receiving BCMA-CAR T-cell therapy.

Main Results:

• ctDNA levels demonstrated correlation with key clinical biomarkers and patient outcomes.
• Post-treatment ctDNA levels inversely correlated with time to progression (TTP) in BCMA-CAR T-cell therapy recipients.
• ctDNA-based measurable residual disease (ctDNA-MRD) assessment was concordant with bone marrow MRD and could anticipate clinical relapse.
• Emergence of therapy-resistant clones was identified through ctDNA analysis.

Conclusions:

• ctDNA analysis provides valuable insights into MM tumor genomics and disease dynamics.
• ctDNA serves as a sensitive tool for monitoring treatment response and detecting MRD.
• ctDNA-based MRD assessment can predict relapse and identify resistance mechanisms, supporting its clinical utility in MM surveillance and management.