Genomic-based treatment algorithm for patients with symptomatic, treatment-naïve WM. Clinicians should consult local regulatory approvals and guidelines for BTKi status and use in WM. Algorithm represents the recommendations of the authors based on clinical trial data summarized in the text, consensus recommendations (as previously published⁶²), and their practice experiences with patients with WM. Recommendations are intended for educational purposes. Rituximab should be held if chemoimmunotherapy is chosen until the sIgM levels are <4000 mg/dL to avoid triggering or exacerbating a hyperviscosity crisis. Benda-R can be considered for patients with bulky adenopathy or extramedullary disease. PI-based therapy or Benda-R can be considered for symptomatic amyloidosis with autologous stem cell transplantation as consolidation in select patients (as discussed elsewhere⁶⁶). Rituximab alone, or with ibrutinib for MYD88^Mut or Benda-R are options for patients with IgM demyelinating peripheral neuropathy depending on severity and pace of progression. Maintenance rituximab may be considered in patients aged >65 years responding to chemoimmunotherapy with rituximab (as discussed elsewhere⁶²). Rituximab, cyclophosphamide, and dexamethasone (RCD) is an option for chemoimmunotherapy if Benda-R is not accessible (as discussed elsewhere⁶²). ∗Zanubrutinib may also be prioritized for those with TP53 alterations (as previously reported³⁵). Clinical trial options should always be considered. Benda, bendamustine; CAGG, cold agglutinins; CRYOS, cryoglobulinemia; HV, hyperviscosity; PN, peripheral neuropathy; R, rituximab.