In a study conducted at three institutions, ibrutinib was associated with major responses in 73% of patients with Waldenström's macroglobulinemia who had received at least one previous treatment. Toxic effects of grade 2 or higher included neutropenia in 22% of the patients. Waldenström’s macroglobulinemia is a malignant B-cell lymphoma that is associated with an accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion. 1 Despite advances in treatment, the disease eventually progresses in most patients, and new treatment options are needed. Whole-genome sequencing has revealed a single activating somatic mutation in MYD88 (resulting in a predicted protein change from leucine to proline at amino acid position 265) and multiple activating mutations in the C-terminal domain of CXCR4 in patients with Waldenström’s macroglobulinemia. 2 , 3 In tumor cells, MYD88L265P triggers activation of nuclear factor κB (NF-κB) through two divergent pathways involving Bruton’s tyrosine kinase (BTK) . . .