Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens
Menée à partir d'échantillons de moelle osseuse, d'échantillons tumoraux et d'échantillons tissulaires sains prélevés sur des patients atteints d'un myélome multiple diagnostiqué récemment et traité par daratumumab, carfilzomib, lénalidomide et dexaméthasone, cette étude met en évidence une association entre des caractéristiques génétiques acquises par les cellules cancéreuses, les caractéristiques des cellules immunitaires du microenvironnement tumoral et les résultats thérapeutiques
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.
Nature Cancer , résumé, 2023