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Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma

B. Diamond, L. Baughn, M. Poorebrahim, AM. Poos, H. Lee, M. Kaddoura, JE. Wiedmeier-Nutor, M. Durante, G. Otteson, D. Jevremovic, H. Tang, S. Fröhling, MA. Baertsch, M. Papadimitriou, B. Ziccheddu, T. Jelinek, C. Lemoine, A. Rak, DJ. Green, O....

. 2025 ; 146 (13) : 1575-1585. [pub] 20250925

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25021538

Grantová podpora
K12 CA226330 NCI NIH HHS - United States
P30 CA008748 NCI NIH HHS - United States
P30 CA240139 NCI NIH HHS - United States
U01 CA271410 NCI NIH HHS - United States

Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.

Clinical Cooperation Unit Molecular Hematology Oncology Department of Internal Medicine 5 Heidelberg University Hospital Heidelberg University and German Cancer Research Center Heidelberg Germany

Department of Bio Structure and Biophysics Integrated Drug Discovery Sanofi R and D Vitry sur Seine France

Department of eBiology Large Molecule Research Sanofi R and D Vitry sur Seine France

Department of Hematooncology Faculty of Medicine University Hospital Ostrava University of Ostrava Ostrava Czech Republic

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN

Department of Medicine Mayo Clinic Phoenix AZ

Department of Medicine Mayo Clinic Rochester MN

Department of Oncology Arnie Charbonneau Cancer Institute University of Calgary Calgary AB Canada

Division of Translational Medical Oncology German Cancer Consortium Heidelberg Germany

Division of Translational Medical Oncology German Cancer Research Center Heidelberg Germany

Division of Translational Medical Oncology National Center for Tumor Diseases Heidelberg a partnership between German Cancer Research Center and Heidelberg University Hospital Heidelberg Germany

Division of Translational Precision Medicine Institute of Human Genetics Heidelberg University Heidelberg Germany

Heidelberg Myeloma Center Department of Internal Medicine 5 Medical Faculty Heidelberg University Hospital Heidelberg University Heidelberg Germany

Myeloma Division Sylvester Comprehensive Cancer Center University of Miami Miami FL

Myeloma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Transplantation and Cellular Therapy Division Sylvester Comprehensive Cancer Center University of Miami Miami FL

Citace poskytuje Crossref.org

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