ABSTRACT Multiple myeloma is a fatal plasma cell neoplasm that is characterized by the malignant expansion of abnormal antibody-producing cells. Despite recent therapeutic advances, most patients eventually relapse. Such high- risk patients typically have an overall survival rate of less than one year. These poor clinical outcomes occur as a result of uncontrolled regeneration of malignant stem-like cells in protective, inflammatory microenvironments. However, the precise transcriptional determinants of myeloma stemness in the bone marrow niche remain poorly understood. One intriguing candidate is a key B-cell transcription factor and myeloma cell survival factor, interferon response factor-4 (IRF4). IRF4 also governs normal plasma cell development and immune responses to inflammation, however the extent to which IRF4 promotes malignant progenitor generation in lymphoid or plasma cell neoplasms is unknown. A 50% reduction in IRF4 expression can disrupt myeloma cell survival, but IRF4 remains undeveloped as a therapeutic target because transcription factors are difficult to inhibit using traditional small molecule strategies. To overcome this challenge, proof-of- concept studies were performed to evaluate novel RNA-targeted therapeutic agents that directly inhibit human IRF4 RNA expression and protein translation. Based on extensive preliminary data that characterized IRF4 expression and activity in clinically-relevant in vitro and in vivo models, the central hypothesis of this project is that inhibition of IRF4 will disrupt stem cell pathway activation in multiple myeloma and synergize with standard-of-care drugs to reduce overall disease burden and prevent malignant stem cell generation. In the context of three independent yet conceptually interrelated aims, this hypothesis will be tested in comprehensive molecular and cellular assays through a rigorous scientific approach. Aim 1: Interrogating the role of IRF4 in functional myeloma stem cell generation. This aim will determine the cell-intrinsic mechanisms that link IRF4 to myeloma regeneration. Aim 2: IRF4 inhibitor monotherapy and combination drug treatment in pre-clinical models of multiple myeloma. This aim will develop combination drug treatment and biomarker detection strategies that leverage selective IRF4 inhibition. Aim 3: Elucidating the bone marrow microenvironment-derived signals that promote IRF4 pathway activation in myeloma regeneration. This aim will elucidate the paracrine mechanisms underlying myeloma regeneration and the activity of a novel cancer therapeutic. The proposed research will set the stage for rapid clinical translation of more selective combination therapies for myeloma. The research team unites cancer and stem cell biology experts, myeloma clinicians, and collaborators who are highly experienced in the translation of novel therapeutics for cancer. Together, this project is positioned to advance the rapid clinical translation of IRF4 inhibitor therapy for myeloma....