STUDIO DI NUOVI MARCATORI PER LA STRATIFICAZIONE PROGNOSTICA DEI PAZIENTI CON MIELOMA MUTLIPLO

The therapeutic options for the treatment of multiple myeloma (MM) have rapidly evolved starting from the mid ‘90s, leading to a great improvement of the clinical outcome and prolonged survival for this pathology. In addition to the development of novel agents, the identification of new biomarkers and a deeper insight into the biological features of this neoplasia can lead to a further amelioration in patients’ prognosis. In this study we have evaluated several features of this disease in order to identify new factors to allow a better prognostic stratification of MM subjects. We have initially investigated circulating microRNAs as potential biomarkers for multiple myeloma. MiRNAs are small regulatory non coding RNAs that primarily affect the stability of mRNA and/or the initiation and progression of protein translation. It has been demonstrated that circulating miRNAs are stable and can be reliably extracted and assayed in either serum or plasma. The expression profile of circulating miRNAs has therefore been analyzed in newly diagnosed MM patients looking for a correlation with the clinical features of the disease. We have so identified miR-193b as a new possible biomarker of osteolytic lesions, that represent a distinctive feature of multiple myeloma. Furthermore, we have performed an immunophenotypic analysis of bone marrow aspirates and peripheral blood of patients with relapsed/refractory disease that have subsequently received a protein inhibitor or immunomodulant drug based regimen. In this section it has been observed the presence of tiding tumoral clones in the bone marrow of patients being treated after disease relapse. We have also evaluated the potential role of myeloid derived suppressor cells (MDSC) present in the peripheral blood of patients during therapy and we have analyzed their trend during treatment. Our data suggest a possible role of these cells in regulating treatment response to proteasome inhibitor bortezomib. Eventually, it has been studied the presence of tumor initiating cells, whose existence has been demonstrated in several cancer types. This relatively small subpopulation could represent the therapy resistant tumor fraction that prompts its recurrence. In this study we have defined a method for a simple identification of these cells in bone marrow samples from MM patients and have identified a possible immunophenotype for their definition. On the whole, this study has investigated several aspects of this pathology that supply further insights on the biological and clinical features of this complex pathology in order to achieve a more efficient prognostic stratification.