KT-474, a novel heterobifunctional IRAK4 degrader that targets both IRAK4 and IMiD biology leads to potent cell kill in ABC DLBCL lines harboring MYD88 L265P through down modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. Here, IRAK4 is linked to diffuse large B-cell lymphoma.