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

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 im...

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Main Authors: Diamond, Benjamin (Author) , Baughn, Linda (Author) , Poorebrahim, Mansour (Author) , Poos, Alexandra (Author) , Lee, Holly (Author) , Kaddoura, Marcella (Author) , Wiedmeier-Nutor, J. Erin (Author) , Durante, Michael (Author) , Otteson, Gregory (Author) , Jevremovic, Dragan (Author) , Tang, Hongwei (Author) , Fröhling, Stefan (Author) , Bärtsch, Marc-Andrea (Author) , Papadimitriou, Marios (Author) , Ziccheddu, Bachisio (Author) , Jelinek, Tomas (Author) , Lemoine, Cendrine (Author) , Rak, Alexey (Author) , Green, Damian J. (Author) , Landgren, Ola (Author) , Neri, Paola (Author) , Bergsagel, Leif (Author) , Braggio, Esteban (Author) , Kumar, Shaji (Author) , Raab, Marc-Steffen (Author) , Fonseca, Rafael (Author) , Bahlis, Nizar (Author) , Weinhold, Niels (Author) , Maura, Francesco (Author)
Format: Article (Journal)
Language:English
Published: 16 June 2025
In: Blood
Year: 2025, Volume: 146, Issue: 13, Pages: 1575-1585
ISSN:1528-0020
DOI:10.1182/blood.2024028107
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2024028107
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0006497125014223
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Author Notes:Benjamin Diamond, Linda Baughn, Mansour Poorebrahim, Alexandra M. Poos, Holly Lee, Marcella Kaddoura, J. Erin Wiedmeier-Nutor, Michael Durante, Gregory Otteson, Dragan Jevremovic, Hongwei Tang, Stefan Fröhling, Marc A. Baertsch, Marios Papadimitriou, Bachisio Ziccheddu, Tomas Jelinek, Cendrine Lemoine, Alexey Rak, Damian J. Green, Ola Landgren, Paola Neri, Leif Bergsagel, Esteban Braggio, Shaji Kumar, Marc S. Raab, Rafael Fonseca, Nizar Bahlis, Niels Weinhold, and Francesco Maura
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Summary: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.
Item Description:Gesehen am TT.MM.JJJ
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2024028107

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