In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse. Display omitted •Myeloma progenitors are enriched in protective niches and with IRF4 overexpression•IRF4 antisense agents impair myeloma cell survival through cell cycle disruption•Selective IRF4 inhibition reduces myeloma regeneration in pre-clinical models•IRF4 inhibitors sensitize myeloma cells to clinical drugs and spare normal immune cells Crews and colleagues demonstrate that selective antisense oligonucleotides targeting the plasma cell transcription factor, IRF4, reduce disease burden and myeloma regeneration in human-relevant pre-clinical models. Mechanistically, IRF4 overexpression expands a myeloma progenitor population, while IRF4 inhibition impairs cell survival via cell cycle arrest and sensitization to clinical myeloma drugs.