Treatment sequencing in Waldenström macroglobulinemia guided by resistance biology

Waldenström macroglobulinemia, a rare lymphoplasmacytic lymphoma, causes illness through the infiltration of lymphoplasmacytic cells and through the effects of the monoclonal immunoglobulin M it produces. A new open-access review published in Clinical and Experimental Medicine on 29 October 2026 brings together clinical and translational evidence to propose a conditional treatment sequence, from frontline therapy through relapse after Bruton tyrosine kinase (BTK) inhibition, with an emphasis on preserving future options.

According to the review, treatment selection in Waldenström macroglobulinemia must reconcile several competing considerations: the urgency of disease control, the molecular context of the individual patient, comorbid conditions, and the burden imposed by either finite or continuous therapy. Bendamustine–rituximab and selective covalent BTK inhibitors remain central frontline options, and the authors note that genotype modifies how these choices are applied alongside clinical priorities.

The review distinguishes between different relapse scenarios that demand different decisions: intolerance of a prior treatment, late recurrence after a finite regimen, and symptomatic progression while still on treatment. For patients who have already received a covalent BTK inhibitor, the authors highlight two agents with prospective data in Waldenström macroglobulinemia, the non-covalent BTK inhibitor pirtobrutinib and the BCL-2 inhibitor venetoclax. However, they stress that the optimal order of these two options has not been tested directly in head-to-head studies.

Resistance variants, the authors write, can inform mechanistic reasoning and the selection of clinical trials, but they caution that mutation-directed treatment algorithms remain unvalidated in this disease. The review also surveys newer modalities: BTK degraders and radiopharmaceuticals currently have larger disease-specific cohorts than cellular therapies or bispecific antibodies, yet their comparative efficacy and long-term safety are still unresolved. Among safety concerns, the authors point to fatal ventricular arrhythmias observed with the combination of ibrutinib and venetoclax as an illustration of why each drug combination must be assessed independently rather than extrapolated from class-level assumptions.

Beyond drug selection, the review argues that a clinically useful treatment sequence should be judged by more than disease response alone. The authors propose that organ recovery, treatment-free survival, cumulative toxicity, and patient-reported function should be measured alongside conventional response endpoints. As an early-access, peer-reviewed accepted article, the publication is citable and carries a permanent DOI, though the version released is subject to further editorial edits before the final Version of Record replaces it. The overall message is that sequencing decisions in Waldenström macroglobulinemia should be conditional and individualized, shaped by molecular findings where validated, and designed so that effective subsequent therapies remain available as the disease evolves.

Subject of Research: Treatment sequencing in Waldenström macroglobulinemia from frontline therapy to relapse after BTK inhibition

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

Article References: Wang, Y., Yang, Y., Wu, J., & Xiao, Y. (2026). Waldenström macroglobulinemia: from frontline choice to sequencing informed by resistance biology. Clinical and Experimental Medicine. https://doi.org/10.1007/s10238-026-02372-4

Image Credits: AI Generated

DOI: 10.1007/s10238-026-02372-4

Keywords: Waldenström macroglobulinemia, BTK inhibitors, pirtobrutinib, venetoclax, bendamustine-rituximab, resistance variants, BTK degraders, radiopharmaceuticals, treatment sequencing, lymphoplasmacytic lymphoma, monoclonal IgM, drug safety