Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma Journal Article
| Authors: | Firestone, R. S.; Socci, N. D.; Shekarkhand, T.; Zhu, M.; Qin, W. G.; Hultcrantz, M.; Mailankody, S.; Tan, C. R.; Korde, N.; Lesokhin, A. M.; Hassoun, H.; Shah, U.; Maclachlan, K. H.; Rajeeve, S.; Landau, H. J.; Scordo, M.; Shah, G. L.; Lahoud, O. B.; Giralt, S.; Murata, K.; Usmani, S. Z.; Chung, D. J. |
| Article Title: | Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma |
| Abstract: | B-cell maturation antigen (BCMA)–targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy–naïve patients. Prior therapy–mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA–directed treatments, underscoring the importance of verifying the presence of a target antigen. © 2024 American Society of Hematology |
| Keywords: | immunohistochemistry; cancer chemotherapy; controlled study; human tissue; protein expression; unclassified drug; major clinical study; sequence analysis; gene deletion; cd3 antigen; multiple myeloma; bone marrow; protein depletion; cohort analysis; plasmacytoma; tumor biopsy; cancer resistance; plasma cell; dna; immunoglobulin heavy chain; minimal residual disease; fc receptor; bone marrow cell; parallel design; gamma secretase; syndecan 1; copy number variation; frequency analysis; cell loss; human; article; b cell maturation antigen; whole exome sequencing; chimeric antigen receptor t-cell immunotherapy; belantamab mafodotin; ciltacabtagene autoleucel; teclistamab; antigenic escape; fc receptor homolog 5 |
| Journal Title: | Blood |
| Volume: | 144 |
| Issue: | 4 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2024-07-25 |
| Start Page: | 402 |
| End Page: | 407 |
| Language: | English |
| DOI: | 10.1182/blood.2023023557 |
| PUBMED: | 38728378 |
| PROVIDER: | scopus |
| PMCID: | PMC11302451 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK authors are Ross S. Firestone, Saad Z. Usmani, and David J. Chung -- Source: Scopus |
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