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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 (NDMM) treated with daratumumab, an CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole genome (WGS) and microenvironment single-cell RNA sequencing from upfront phase-II trials using carfilzomib, lenalidomide and dexamethasone with/without daratumumab (DKRd) (NCT03290950 and NCT02937571), we show how distinct genomic drivers including high APOBEC mutational activity, deletion of IKFZ3, TENT5C, RPL5, and gain(8q) impact clinical outcomes. Furthermore, the evaluation of paired-marrow profiles, taken before and after eight cycles of DKRd, shows that the NK-cells before treatment, disappearance of sustained immune activation (i.e., B-cell and T-cells), and monocyte expansion over time is predictive of sustained minimal residual disease negativity. Overall, this study shows that there is a complex interplay between tumor cells and immune microenvironment which is predictive of clinical outcome and the depth of treatment response in NDMM treated with CD38-targeted monoclonal antibody.

PROVIDER: EGAS00001007404 | EGA |

REPOSITORIES: EGA

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Project description:Prospective series of 136 clinical monoclonal B lymphocytosis (cMBL) and 216 chronic lymphocytic leukemia (CLL) Rai 0 patients, were investigated in this study. While the distribution of CD38 and ZAP-70 positivity was similar, IGHV-mutated cases were more frequent among cMBL (P = 0.005). A Cox multivariate analysis on the whole patient cohort showed that cMBL condition was predictive of longer PFS, while CD38 expression and IGHV-unmutated status and CD38 expression correlated significantly with a shorter PFS in cMBL and Rai0-CLL, respectively. Trisomy 12, 11q- and 17p- abnormalities were scanty and of no predictive value in both conditions. Notably, gene and miRNA expression profiling showed no significant differences between cMBL and Rai0-CLL. Furthermore, similar gene and miRNA expression signatures were found in cMBL and Rai0-CLL according to the IGHV gene mutational status: that is, unmutated cases had different signatures from mutated cases, irrespectively of the cMBL or CLL condition. Overall, our study based on a prospective series of patients indicates that no major biological differences exist in cMBL compared to Rai0-CLL, suggesting that this two entities mainly differ for the initial size of the monoclonal cell population which may reflect in the longer time for clonal expansion. This series of microarray experiments contains the gene expression profiles of purified B-cell chronic lymphocytic leukemia (B-CLL) cells obtained from 160 patients (Binet stage A) including 45 cMBL and 115 Rai0-CLL. Peripheral blood mononuclear cells from CLL patients were isolated by Ficoll-Hypaque (Seromed, Biochrom KG, Berlin, Germany) density-gradient centrifugation. For gene and miRNA expression profiling experiments CLL cells were enriched by negative selection with the EasySep-Human B cell enrichment kit without CD43 depletion (Stem Cell Technologies) using the fully automated protocol of immunomagnetic cell separation with RoboSepTM (Stem Cell Technologies).

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Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens

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