Prosurvival signaling triggered by mutated MYD88 in WM and its interaction with BTK. BTK, a protein that is uniquely positioned in the B-cell receptor (BCR) signal transduction pathway, upon phosphorylation, interacts with myeloid differentiation primary response protein (MYD88), a Toll-like receptor (TLR) signaling protein, leading to an adaptive immune response, with IgM formation. BTK inhibition reduces MYD88-BTK complexing, with resultant downregulation of NFκB and apoptosis of WM cells. Both ibrutinib and zanubrutinib irreversibly attach via covalent bonding to Cys481 residue within the BTK pocket, permanently shutting off its signaling capability by disrupting ATP binding. In addition, both ibrutinib and zanubrutinib target HCK, a SRC family member responsible for activating BTK in response to mutated MYD88. Two other irreversible BTK inhibitors, acalabrutinib and tirabrutinib, have demonstrated efficacy in WM. In addition, reversible BTK inhibitors, including vecabrutinib, LOXO-305, and ARQ 531, which can bind noncovalently to BTK, are under evaluation, given their potential to dually inhibit wild-type BTK and Cys481S-mutated BTK. Ulocuplumab, a monoclonal antibody against CXC chemokine receptor 4 (CXCR4) and mavorixafor, a CXCR4 allosteric inhibitor, are being evaluated in partnership with ibrutinib, to overcome CXCR4-mediated resistance.