Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma.

Matteo C Da Vià, Oliver Dietrich, Marietta Truger, Panagiota Arampatzi, Johannes Duell, Anke Heidemeier, Xiang Zhou, Sophia Danhof, Sabrina Kraus, Manik Chatterjee, Manja Meggendorfer, Sven Twardziok, Maria-Elisabeth Goebeler, Max S Topp, Michael Hudecek, Sabrina Prommersberger, Kristen Hege, Shari Kaiser, Viktoria Fuhr, Niels Weinhold, Andreas Rosenwald, Florian Erhard, Claudia Haferlach, Hermann Einsele, K Martin Kortüm, Antoine-Emmanuel Saliba, Leo Rasche

Journal: Nature medicine 2021;27(4):616-619

PMID: 33619368

Full Text on Nature Publishing Group View on PubMed

Abstract

B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.

Address: Department of Internal Medicine 2, University Hospital of Würzburg, Würzburg, Germany.; Helmholtz Institute for RNA-based Infection Research, Helmholtz-Center for Infection Research, Würzburg, Germany.; Munich Leukemia Laboratory, Munich, Germany.; Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany.; Department of Radiology, University Hospital of Würzburg, Würzburg, Germany.; Bristol Myers Squibb, San Francisco, CA, USA.; Institute of Pathology, University of Würzburg, Würzburg, Germany.; Medizinische Klinik 5, University Hospital of Heidelberg, Heidelberg, Germany.; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.; Department of Internal Medicine 2, University Hospital of Würzburg, Würzburg, Germany. [email protected].; Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany. [email protected].

DOI: 10.1038/s41591-021-01245-5

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MeSH Terms: Aged, Antigens, Neoplasm, B-Cell Maturation Antigen, DNA Copy Number Variations, Gene Deletion, Homozygote, Humans, Magnetic Resonance Imaging, Male, Multiple Myeloma, Receptors, Chimeric Antigen, T-Lymphocytes