Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens Journal Article
| Authors: | Maura, F.; Boyle, E. M.; Coffey, D.; Maclachlan, K.; Gagler, D.; Diamond, B.; Ghamlouch, H.; Blaney, P.; Ziccheddu, B.; Cirrincione, A.; Chojnacka, M.; Wang, Y.; Siegel, A.; Hoffman, J. E.; Kazandjian, D.; Hassoun, H.; Guzman, E.; Mailankody, S.; Shah, U. A.; Tan, C.; Hultcrantz, M.; Scordo, M.; Shah, G. L.; Landau, H.; Chung, D. J.; Giralt, S.; Zhang, Y.; Arbini, A.; Gao, Q.; Roshal, M.; Dogan, A.; Lesokhin, A. M.; Davies, F. E.; Usmani, S. Z.; Korde, N.; Morgan, G. J.; Landgren, O. |
| Article Title: | Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens |
| Abstract: | Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab (NCT03290950), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | adult; clinical article; treatment response; gene mutation; overall survival; gene deletion; lenalidomide; flow cytometry; outcome assessment; follow up; genetic analysis; polymerase chain reaction; reproducibility; quality control; progression free survival; multiple myeloma; phase 2 clinical trial; gene expression; bone marrow; prevalence; transcription factor; dexamethasone; enzyme activity; b lymphocyte; monoclonal antibody; t lymphocyte receptor; immunotherapy; minimal residual disease; tumor cell; genomics; natural killer cell; monocyte; macrophage; bioinformatics; dna extraction; cd45ra antigen; ribosome protein; carfilzomib; rna sequence; syndecan 1; tumor microenvironment; principal component analysis; clinical outcome; human; male; female; article; differential gene expression; daratumumab; receptor type tyrosine protein phosphatase c; single cell rna seq; multiomics; immunosignature |
| Journal Title: | Nature Cancer |
| Volume: | 4 |
| Issue: | 12 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2023-12-01 |
| Start Page: | 1660 |
| End Page: | 1674 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00657-1 |
| PUBMED: | 37945755 |
| PROVIDER: | scopus |
| PMCID: | PMC12065606 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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