Skip to main content
IMS Events Main banner
Back

    Myeloma Genomics and Microenvironment and immune profiling

    Immunomodulatory Effects of Daratumumab on the Bone Marrow Microenvironment in Multiple Myeloma: Insights from Single-Cell Analyses

    P-198: Immunomodulatory Effects of Daratumumab on the Bone Marrow Microenvironment in Multiple Myeloma: Insights from Single-Cell Analyses

    Thursday, September 26, 2024
    Introduction: Daratumumab (Dara), a monoclonal antibody targeting CD38, is approved for treating multiple myeloma (MM). Its impact on the cellular immune compartment and the relation to response/resistance are not fully understood. Understanding Dara's effects on the immune landscape and its therapeutic mechanisms is crucial for identifying synergistic immunotherapeutic approaches and informing therapy sequencing for long-term efficacy.

    Methods: Mass cytometry (CyTOF) and single-cell RNA sequencing (scRNA-seq) were used to comprehensively characterize the immune microenvironment in MM patients undergoing Dara therapy, either as monotherapy or in combination regimens. CD138-negative fractions of bone marrow mononuclear cells (BMMCs) collected from MM patients at pre-treatment (pre-Dara, n=37), on-treatment (on-Dara; in remission, n=10), and post-treatment (post-Dara; relapsed, n=32) timepoints were analyzed to focus on the non-malignant immune compartment.

    Results: CyTOF and scRNA-seq analyses revealed a consistent decrease in the frequency of CD4+ T cells, B cells, plasma cells, and NK cells by up to 50%, on- and post-Dara compared to pre-Dara, while CD8+ T cells showed a 30% increase. CD38 expression was markedly reduced on- and post-Dara across most immune cell types, confirming the antibody's on-target effects and previously published results. On-Dara samples exhibited increased expression of cell surface markers associated with T cell activation and migration (HLA-DR and CXCR3), compared to pre-Dara samples. This was accompanied by a concomitant downregulation of inflammatory pathways, including TNFα and IL-2 gene signatures, potentially enhancing anti-tumor immune responses during treatment. When comparing patients in remission to relapsed patients, a significant upregulation of a senescence marker (CD57), and immune checkpoint molecules (ICOS, PD-1 and TIGIT) was observed in the T cell compartment, with the highest fold change (FC=1.98) on regulatory T cells in relapsed patients. Additionally, TIM-3 expression was significantly elevated in dendritic cells (FC=2.08) and monocytes (FC=1.44) in relapsed patients, suggesting a potential restraint of anti-tumor immunity. Moreover, interferon-stimulated gene (ISG) pathways were downregulated in NK cells and monocytes in remission but upregulated in relapsed patients, implying a potential pro-tumoral role in disease progression.

    Conclusions: Our comprehensive single-cell analyses unveil distinct immunomodulatory effects of Dara on the bone marrow immune microenvironment, including alterations in immune cell frequencies, activation states, and functional pathways. The observed upregulation of senescence markers, immune checkpoints, and pro-tumoral pathways in relapsed patients highlights potential resistance mechanisms and suggests avenues for therapy combination and sequencing strategies to enhance efficacy, overcome resistance, and improve patient outcomes in MM.