Although there have been marked improvements in outcomes for patients with multiple myeloma — largely down to the use of CD38-targeted antibodies — 30–50% of people with the disease eventually progress. Understanding why this occurs is thus a priority. Maura et al. took bone marrow samples from 49 patients with newly diagnosed multiple myeloma who had been treated with daratumumab (a monoclonal CD38-targeted antibody), carfilzomib, lenalidomide and dexamethasone (hereafter termed DKRd) as part of the MANHATTAN trial (NCT03290950). Samples were subjected to whole-genome sequencing (tumor cells) and single-cell RNA sequencing (scRNA-seq; microenvironmental cells). The analysis highlighted known genomic drivers such as high APOBEC activity, but also new ones such as loss of IKZF3 and XBP1, which both correlated with treatment resistance. Comparing scRNA-seq data of samples taken before and after treatment implicated low baseline numbers of natural killer cells in failure to achieve sustained minimal residual disease after DKRd treatment. The persistence of activated T cells, with a depleted B cell population, and expanded monocyte populations were also associated with mimical residual disease negativity after treatment. The authors also identified a ‘favorable’ immune microenvironment that was characterized by high numbers of CD14+ cells and low numbers of T cells. This study provides crucial insight into the way immunotherapeutics interact with the tumor ecosystem — and how this crosstalk modulates responses. It is hoped that these findings will help match patients to therapies, which will lead to sustained responses in the future.
Original reference: Nat. Cancer https://doi.org/10.1038/s43018-023-00657-1 (2023)
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