Waldenström macroglobulinemia: from frontline choice to sequencing informed by resistance biology

Waldenström macroglobulinemia (WM) causes morbidity through lymphoplasmacytic infiltration and the effects of monoclonal immunoglobulin M. Treatment selection must reconcile disease urgency, molecular context, comorbidity, and the burden of finite or continuous therapy. This review integrates clinical and translational evidence to propose a conditional sequence from frontline treatment to relapse after Bruton tyrosine kinase (BTK) inhibition. Bendamustine–rituximab and selective covalent BTK inhibitors remain central frontline options; genotype modifies their use alongside clinical priorities. At relapse, intolerance, late recurrence after finite therapy, and symptomatic progression on treatment require different decisions. Pirtobrutinib and venetoclax have prospective WM data after covalent BTK inhibitor exposure, but their optimal order has not been tested directly. Resistance variants can inform mechanistic reasoning and trial selection, although mutation-directed treatment algorithms remain unvalidated in WM. Emerging BTK degraders and radiopharmaceuticals have larger disease-specific cohorts than cellular therapy or bispecific antibodies, with comparative efficacy and long-term safety still unresolved. Fatal ventricular arrhythmias with ibrutinib plus venetoclax illustrate the need to assess each combination independently. A clinically useful sequence should preserve subsequent options and measure organ recovery, treatment-free survival, cumulative toxicity, and patient-reported function alongside disease response.