Immune Profiling of Plasma Cell Dyscrasias Reveals a Therapy Related T-Cell Modulation in Multiple Myeloma Patients

Multiple Myeloma (MM) is a hematological malignancy always preceded by a not malignant precursor state defined monoclonal gammopathy of undetermined significance (MGUS) and by a asymptomatic MM (smouldering MM, sMM). Immune dysfunction plays a key role in the pathogenesis of the disease, as demonstrated by the prognostic role of immunoparesis in the progression of MGUS and sMM into active MM (aMM). The aim of this study is to analyze the immune subsets distribution into plasma cells dyscrasias. A total amount of 895 bone marrow samples (170 MGUS, 188 sMM, 586 aMM) of 714 patients affected by plasma cells dyscrasias were studies at the different time point by flow cytometry for CD3, CD4, CD8, CD16, CD19, CD56, CD57, HLA-DR and Tgd antigens. In aMM cases, no differences were found in total T and NK cells percentages towards sMM (73.2±12.5 vs 72.4±10.3, p=0.6717 and 14.8±8.9 vs 14.1±7.9, p=0.5676) and MGUS cases (73.2±12.5 vs 71.9±9.0 p=0.3336 and 14.8±8.9 vs 13.3±7.3, p=0.1205) while CD19+ B cells were usually lower in aMM, even if statistically significant only towards MGUS (9.8±9.1 vs 10.7±5.9, p=0.2955 and 9.8±9.1 vs 12.3±7.1, p=0.001). A more detailed analysis of T cell subsets showed that aMM patients were also characterized by lower percentages of CD4+ T cells (32.9±12.9 vs 39.9±9.5, p=0.0001 and 32.91±12.9 vs 38.4±8.6, p=0.0001) and higher percentages of CD8+ cells (45.1±14.1 vs 38.8±10.0, p=0.0001 and 45.1±14.1 vs 38.7±9.9, p=0.0001), CD8+/DR+ cells (9.7±13.1 vs 4.1±4.7, p=0.0001 and 9.7±13.1 vs 3.8±4.5, p=0.0001) and CD3+/CD57+ cells (18.9±12.7 vs 14.5±9.2, p=0.0001 and 18.9±12.7 vs 13.6±8.8, p=0.0001) while no differences were found in Tgd cells in the different groups (3.6±4.0 vs 4.2±3.6, p=0.2872 and 3.6±4.0 vs 4.2±3.2, p=0.2638). Interestingly, all these differences were mostly attributed to treated patients towards newly diagnosed MM (CD4+ cells= 27.0±12.1 vs 39.5±10.3, p<0.0001, CD8+ cells=50.5±14.6 vs 39.0±10.5, p<0.0001, CD8+/DR+ cells =14.1±15.8 vs 4.5±4.7, p<0.0001 and CD3+/CD57+ cells =21.7±13.5 vs 15.8±10.9, p<0.0001). In 60 treated patients, a bone marrow evaluation was performed within 3 months from autologous stem cell transplantation (ASCT). These cases displayed towards other treated patients higher percentage of CD8+ cells (59.3±13.8 vs 48.2±13.9, p<0.0001), CD8/DR+ cells (24.2±19.1 vs 10.8±13.1, p<0.0001) and CD3+/CD57+ cells (33.2±12.2 vs 18.6±12.1, p<0.0001) and lower percentages of CD4+ cells (16.6 ±7.7 vs 29.8±11.4, p<0.0001), NK cells (11.3±6.2 vs 16.4±10.0, p=0.0006) and Tgd cells (2.0±3.2 vs 4.4±5.6, p=0.0016).