Bone marrow immune cell composition reflects multiple myeloma progression and affects treatment response Open Access

• A higher granulocyte-to-T lymphocyte ratio improves daratumumab response and prolongs progression-free survival in multiple myeloma patients.

• Bone marrow-derived granulocytes are involved in the therapeutic activity of daratumumab

The progression of multiple myeloma (MM) is characterized by intricate interactions between clonal plasma cells and the bone marrow (BM) microenvironment. In this study, we conducted a comprehensive analysis of BM immune cell composition spanning from premalignant stages to MM, utilizing FlowCT, a semi-automated workspace empowered to analyze large data sets. Our cohort comprised 159 patients, covering monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM, with the majority undergoing treatment with a daratumumab-based regimen. The evolving disease showed alterations in immune cell populations, including a reduction in the granulocyte-to-lymphocyte (GLR) and -to-T lymphocyte (GTL) ratios, alongside an increase in T lymphocytes. Higher baseline levels of BM GLR and GTL ratios were associated with extended progression-free survival (PFS). Moreover, improved outcomes were observed in patients treated with daratumumab-based regimens with a higher GTL ratio. Furthermore, autologous BM-derived granulocytes enhance daratumumab-mediated cytotoxicity against primary autologous neoplastic plasma cells, unveiling a novel BM-granulocytes-dependent mechanism of action for daratumumab in MM patients. These findings emphasize the dynamic nature of the BM immune compartment during MM progression and underscore the prognostic significance of immune cell composition in guiding therapeutic approaches and enhancing patient outcomes.