Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00843989%3A_____%2F25%3AE0111968" target="_blank" >RIV/00843989:_____/25:E0111968 - isvavai.cz</a>
Alternative codes found
RIV/61988987:17110/25:A2603DMN
Result on the web
<a href="https://ashpublications.org/blood/article-abstract/146/13/1575/537722/Biallelic-antigen-escape-is-a-mechanism-of?redirectedFrom=fulltext" target="_blank" >https://ashpublications.org/blood/article-abstract/146/13/1575/537722/Biallelic-antigen-escape-is-a-mechanism-of?redirectedFrom=fulltext</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1182/blood.2024028107" target="_blank" >10.1182/blood.2024028107</a>
Alternative languages
Result language
angličtina
Original language name
Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
—
Continuities
V - Vyzkumna aktivita podporovana z jinych verejnych zdroju
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Blood
ISSN
0006-4971
e-ISSN
1528-0020
Volume of the periodical
146
Issue of the periodical within the volume
13
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
1575-1585
UT code for WoS article
001585772400004
EID of the result in the Scopus database
2-s2.0-105009356793