Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma

Simple Summary In Multiple Myeloma (MM) malignant cells accumulate in the bone marrow (BM), where they interact with various cell populations. These complex interactions impose mechanisms of tumor growth and proliferation, immune surveillance and immune evasion. The aim of the present study was a detailed immune characterization of MM during the course of the disease, in order to highlight signatures which are clinically relevant. Analyses of both BM and peripheral blood (PB) in matched patients’ samples, we showed that PB cannot representatively reflect the BM microenvironment. Particular immune signatures in BM and PB significantly correlated with established prognostic features and could independently associate with distinct responses to the same induction therapy. Moreover, our data provide evidence of a diverse immune profile according to patients’ MRD status post treatment. Finally, we provide insights that unique PB immune profiles may be used for the prediction of MRD status through a simple non-invasive approach. Abstract Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients’ variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles; most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.