Abstract B45: Multiple myeloma: A novel tailor-made therapeutic management.
Authors: Sabna Rajeev Krishnan, Mary Bebawy, Frederick Luk, Ross Duncan Brown, Yiu Lam Kwan
Journal: Clinical Cancer Research (2015)

Abstract Introduction: Multiple Myeloma (MM) is an incurable hematological malignancy affecting plasma cells marked by highly heterogeneous survival rate. Relapse is a significant impediment to the successful treatment of MM clinically. One of the main causes for relapse in MM is the development of multidrug resistance (MDR) to cancer chemotherapy. Currently, risk stratification to MM sub-groups and categorization of complete response to therapy are assessed based on molecular, cytogenetic markers using bone marrow biopsy as available systemic markers are incompetent in this regard. We are exploring the clinical significance of our recent in vitro and in vivo findings of a novel non-genetic basis to MDR whereby tiny vesicles called microparticles (MPs) shed from cancer cell's surface transfer MDR phenotype intercellularly. Microparticles isolated from the peripheral blood of patients who suffer from Multiple Myeloma will be phenotyped for resistance, adhesion and dissemination markers. Subsequently, these parameters will be correlated clinically to assess whether these characteristics are predictive of treatment outcome. Materials and Methods: We have analysed 46 de-identified Multiple Myeloma patients and 18 normal subjects. The platelet free plasma was ultracentrifuged, plasma cell derived microparticles were identified and quantified with flow cytometry using Annexin V450, CD 138 APC, P-glycoprotein (P-gp)-FITC in BD TruCount tubes. Also, platelet derived MPs were identified and excluded using CD41a PE and compared to age-matched normal volunteers. Western blot analysis was conducted on microparticle lysate probing for the presence of Lung-Resistance related Protein (LRP). The morphology and size of the MP fraction from MM patients were compared across distinct clinical state of de novo, remission, relapsed through scanning electron microscopy as well. Results: Plasma cell derived MPs were identified based on the CD138 expression systemically. The number of systemic microparticles was found to be significantly higher in MM patients compared to the healthy volunteers. Multidrug resistance markers (LRP &amp; P-gp) were expressed on MPs. The morphology of MP fraction from relapsed patient was distinct from the remission and de novo patients whereas no difference in the size was observed across the cohort. Conclusions: There are elevated numbers of MPs in the 46 MM subjects (for all stages) compared to the 18 normal subjects, supporting elevated CD138+MP numbers in MM. Overexpression of Lung –Resistance related Protein and P-glycoprotein on CD138+MPs are of prognostic significance in MM. Thus, phenotyping plasma cell derived MPs in MM patients provides a personalized systemic biomarker to predict therapeutic response because the microparticles may be the potential ‘biosignatures’ of the less accessible bone marrow compartment. This would possibly unravel the role of microparticle population in disseminating deleterious messages systemically aiding in the Multiple Myeloma clone survival. Note: This abstract was not presented at the conference. Citation Format: Sabna Rajeev Krishnan, Mary Bebawy, Frederick Luk, Ross Duncan Brown, Yiu Lam Kwan. Multiple myeloma: A novel tailor-made therapeutic management. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B45.