ABSTRACT Project Summary. This research program aims to test the hypothesis that inhibition of interferon regulatory factor-4 (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 multiple myeloma. 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. 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 IRF4, a key B-cell transcription factor and myeloma cell survival factor. 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. This administrative supplement is requested to provide additional salary support for laboratory personnel, equipment, and publication funding intended to offset additional costs incurred as a result of a critical life event for the PI, thus ensuring the continued success of the parent award project in completing the three ongoing research Aims. 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. Supplemental funding will accelerate the PI’s productivity through the supplement period and enable parent award funds to be redirected towards key supplies and reagents as originally budgeted. Together, the proposed research will set the stage for rapid clinical translation of more selective combination therapies for myeloma.