LAUSR

Despite significant recent advances in therapeutic options, multiple myeloma (MM) remains an incurable disease, and novel agents targeting novel molecular pathways with activity in advanced patients are urgently needed. Interferon Regulatory Factor 4 (IRF4) is a transcription factor involved in immune responses in normal B and T cells, and is strongly implicated in the development of hematological malignancies, especially MM. Although recent publications have pointed to IRF4 as a driver oncogene in the progression of MM, it is considered an intractable target by conventional therapeutic approaches. Here we describe an antisense oligonucleotide (ASO) approach to selectively target IRF4. Administration of next generation human IRF4 ASOs via 9free-uptake9 (without transfection) to a large panel of human MM cell lines resulted in a dose-dependent IRF4 reduction with concomitant induction of apoptosis. ASO-mediated IRF4 depletion also decreased the levels of c-Myc, another key oncogene in MM. MM cells were sensitive to even modest depletion of IRF4 ( Disclosures Zhou: Ionis Pharmaceuticals: Employment, Equity Ownership. Schmidt: Ionis Pharmaceuticals: Employment. Kim: Ionis Pharmaceuticals: Employment. MacLeod: Ionis Pharmaceuticals: Employment.