Jerina Hoxha
21.2.25
Study provides insights into clonal evolution following CAR T and bispecific antibody treatment in multiple myeloma
A recent study published in Nature Medicine reports a rare but significant case of a patient developing peripheral T cell lymphoma following immunotherapy for multiple myeloma. The paper, "Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody ", co-authored by CERTAINTY collaborators from University Hospital Leipzig and Fraunhofer IZI, applies comprehensive multiomic analysis to trace the cellular origins and progression of this unexpected event.
Background
A 63-year-old male patient received BCMA-targeted CAR T-cell therapy (ciltacabtagene autoleucel) followed by a GPRC5D × CD3 bispecific antibody (talquetamab) to treat early relapse of multiple myeloma. Nine months after CAR T cell treatment, the patient developed symptomatic leukemic peripheral T cell lymphoma involving the skin and intestine.
Key Findings
Detection of CAR-positive lymphoma
Longitudinal single-cell RNA and T cell receptor sequencing identified two hyperexpanded CAR-carrying T cell clones in blood and bone marrow. These cells showed an exhausted effector-memory T cell transcriptional profile and were sensitive to dexamethasone.
Spatial and genomic confirmation
Aberrant CAR-expressing T cells were confirmed in skin lesions through spatial transcriptomics. Whole-genome sequencing revealed three distinct integration sites in ZGPAT, KPNA4, and polycomb-associated noncoding RNAs.
Evidence of clonal evolution
The lymphoma appeared to arise from a TET2-mutated precursor cell, which had acquired additional mutations including subclone-specific loss of heterozygosity and secondary events.
Conclusion
This case study highlights the value of advanced sequencing technologies in identifying and understanding rare outcomes following T cell–redirecting immunotherapy. It demonstrates that both genetic modifications and pre-existing vulnerabilities can contribute to secondary tumour development. The findings offer critical insights into the biology of CAR-positive T cell lymphomas and underscore the importance of vigilant molecular monitoring.
Access the Publication
Read the article in Nature Medicine: https://www.nature.com/articles/s41591-025-03499-9