Microparticles isolated from multiple myeloma patients are indicative of tumor burden, disease progression and treatment unresponsiveness

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Multiple Myeloma (MM) is a progressive malignancy of bone-marrow plasma cells. Treatment typically involves combination chemotherapy, which forms part of a continuing cycle of treatment, remission and relapse corresponding to the evolution multiple drug resistance (MDR). There are currently no procedures available that allow for a direct, non-invasive, real time monitoring of the development of MDR in MM. Although bone marrow biopsy can directly test for the presence MDR markers on malignant plasma cells, this procedure is highly invasive, does not allow for routine assessment and fails to capture the patchy, multi-site tumor infiltrates characteristic of MM. An ideal test would directly measure markers of MDR expressed in MM cells during routine follow up, be non-invasive and representative of multi-site tumors as well allow for simultaneous comparative analysis of tumor burden. Microparticles (MPs) are 0.1- to 1.0-μm membrane vesicles, and contain the cellular substances of their originating cell. Microparticles, are spontaneously shed from tumor cells; they carry resistance proteins and nucleic acids from their originating cell; and (iii) can confer MDR within cancer cell populations. The overarching aim of this study was to investigate the prognostic potential of MPs in MM patients. For this purpose, we characterized the morphology, phenotype and quantitated the level of non-platelet derived MPs in the peripheral blood of MM patients across all clinical states and healthy volunteers after informed consent. MPs were isolated from patient blood samples by ultracentrifugation and phenotyped for the presence of the plasma cell marker CD138, the MDR protein P-glycoprotein (P-gp), the stem cell marker, CD34 and for phosphatidylserine (PS) exposure and quantitated using BD TruCount™ beads. We observed significantly greater levels of total MP and CD138⁺ MP counts in MM patients relative to healthy volunteers. The levels of these MPs were shown to correspond to tumor burden in MM patients. We also detected the presence of P-gp on MPs isolated from MM patients. Specifically, we identified a number of MP subtypes including a ‘dual positive’ (CD138⁻ CD34⁺ P-gp⁺) population, the levels of which corresponded to aggressive and active disease (N=1). We also identified an evolving shift in the dominance of MP subtypes with disease progression. This research describes a simple blood test where by the presence of MDR can be serially monitored through ‘liquid biopsy’. This thesis introduces new insights into the utility of biomarkers and the molecular mechanisms contributing to disease progression, MDR and treatment failure in MM.
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