Targeting Myd88-Mutant Dlbcl With Irakimids: A Comparison To Irak4 Kinase Inhibition And Evaluation Of Synergy With Rational Combinations

Introduction: MYD88 mutations are found in 25% of DLBCL and are associated with an inferior survival. MYD88 is an adapter molecule, forming the core of the Myddosome complex. MYD88 mutations constitutively activate pathways such as NFқB, leading to lymphomagenesis. Essential to the Myddosome-dependent signaling pathway is the recruitment of IRAK4 which complexes with MYD88 to activate downstream effects. Targeting IRAK4 is therefore a rational therapeutic approach in MYD88-mutant lymphomas. First-in-class IRAKIMiDs, novel heterobifunctional degraders that target IRAK4 as well as the IMiD substrates Ikaros and Aiolos to enable the inhibition of both the NFkB and IRF4 pathways activated by MYD88 mutations, demonstrate potent efficacy in MYD88-mutant lymphomas (KTX-475, KTX-582, Walker D et al. AACR 2020). Herein, we compare the activity of IRAKIMiDs to IRAK4 kinase inhibitors and IMiDs alone in MYD88-mutant DLBCL, and evaluate rational combinations of IRAKIMiDs and other active agents in DLBCL for synergy.