Novel therapeutic targets in Waldenstrom macroglobulinemia

Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging “WM-relevant” targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA. New drugs for established targets are also discussed. Lastly, we spotlight 3 highly innovative WM-specific therapies: MYD88 peptide inhibitors, MYD88L265P-directed immune activation and CD19-directed chimeric antigen receptor T-cell therapy, which are in various stages of development. Indeed, treatment of WM is poised to undergo a paradigm shift in the coming years towards highly disease-driven and more personalized therapeutic modalities with curative intent.