Multiple Myeloma from Bench-to-Bedside: Targeting the Mechanisms of Malignancy and Evaluating the Role of Immunotherapy

Abstract

Multiple Myeloma is a heterogeneous plasma cell malignancy that arises from a combination of genetic abnormalities and aberrant signaling networks in the bone marrow. The mechanisms that direct disease progression transform normal antibody-secreting plasma cells into angiogenesis- and bone resorption- promoting machines, capable of forming bone lesions throughout the body. Treatment for the disease has progressed as understanding of disease pathogenesis has improved, moving forward rapidly with the recent introduction of proteasome inhibitors and immunomodulatory agents. Novel targeted cytotoxic therapies are currently proceeding through the bench-to-bedside framework for agent development. Meanwhile, new immune-based approaches are realizing the concept of treating patients with their own immune systems, but the overwhelming employment of cytotoxic agents indicates that the role of immunotherapy is far from clear. This thesis presents a comprehensive exploration of plasma cell development, myeloma pathogenesis, and myeloma therapy, while analyzing the bench-to-bedside approach that leads to new-agent approval. Examination of the molecular mechanisms underlying the various agents alongside disease pathogenesis allows for analysis regarding the strengths and weaknesses of the therapeutic repertoire. Establishing a scientific rationale for targeted cytotoxic- and immune-based therapies will hopefully move multiple myeloma treatment closer to that elusive cure.