Which BTK inhibitor is best for Waldenström’s macroglobulinemia?

By Naveed Saleh, MD, MS | Medically reviewed by Nitin Chandramouli, MD FACP
Published December 1, 2023

Key Takeaways

  • Survival rates for Waldenström’s macroglobulinemia (WM) are on the rise, with younger age at diagnosis predicting better outcomes.

  • Immunoglobulin M monoclonal gammopathy of undetermined significance is a common pre-malignant condition that can lead to WM.

  • In a phase 3 clinical trial, the second-generation BTKi zanubrutinib was safer and more effective than ibrutinib, a first-generation counterpart.

Survival rates for patients with Waldenström’s macroglobulinemia (WM) is ameliorating: the change in median OS from 1991–2000 and 2001–2010 jumped from 6 years to 8 years, respectively, per the SEER database, as noted by WM experts writing in the American Journal of Hematology.[]

Deaths during 2001–2010 also dropped from WM-related and non-WM-related causes. Age of diagnosis predicts survival, with the hazard ratio for death for WM patients age >80 years being 6.99 vs that for a reference group <50.9 years.

Disease background

WM refers to lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features of WM include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy, as well as, more rarely, hyperviscosity.

The existence of a monoclonal IgM protein offers a unique dimension to WM because it can lead to hyperviscosity syndrome, peripheral neuropathy, hemolytic anemia, and immune complex vasculitis. 

The 10-year survival rate for WM is 66%. According to the results of a population-based study of Latin American patients with WM and lymphoplasmacytic lymphoma (LPL), the 5-year relative survival of WM was 81%. Although increasing age was related to decreased survival, survival improvements were observed in all age groups in the study.


Diagnosis of WM is based on the presence of IgM monoclonal protein with ≥10% clonal lymphoplasmacytic cells in bone marrow. The L265P mutation in MYD88 is present in >90% of patients and is present in most patients with IgM MGUS (monoclonal gammopathy of undetermined significance). MYD88 is not necessary for diagnosis. IgM MGUS is a common pre-malignant condition that can lead to WM.[]

The addition of genomic alterations likely occurs during a multistep process of progression, and probably represents a central mechanism mediating the progression of IgM MGUS to WM. The result is higher tumor burden and end-organ damage.

The role of the immune system in this pathology remains to be elucidated.


The NCCN Guidelines Version 1.2022 WM/LPL[] were updated and now include zanubrutinib (Category 1) as a preferred first-line regimen for the primary therapy of WM/LPL.[] Other preferred interventions include bendamustine/rituximab (Category 2A), bortezomib/dexamethasone/rituximab (Category 2A), ibrutinib with or without rituximab (Category 1), and rituximab/cyclophosphamide/dexamethasone (Category 2A). The preferred interventions are related to superior efficacy, safety, and evidence.

The updated guidelines also add zanubrutinib Category 1 as the preferred regimen for previously treated WM/LPL, with other preferred regimens for previously treated WM/LPL the same as the preferred regimens for primary treatment.

The ASPEN study

The majority of studies involving Bruton's tyrosine kinase inhibitor (BTKi) treatment for WM have been single-arm trials, which have demonstrated variations in safety/tolerability due to differences in prior treatment history, study populations, and toxicity associated with individual BTK inhibitors. The phase 3 ASPEN trial was the highest powered randomized controlled trial of BTK-inhibitor monotherapy of WM to date, and the only one to compare outcomes from two different BTKis: ibrutinib vs zanubrutinib.[]

Related: Managing cardiotoxicity of BTKi treatments

“The pharmacokinetics, pharmacodynamics, and selectivity profile of zanubrutinib predict that it has the potential to be more efficacious with a superior safety profile vs ibrutinib. This study established that zanubrutinib is highly effective in the treatment of WM; zanubrutinib is associated with important safety advantages, especially with respect to cardiovascular toxicity,” the investigators concluded.

The adverse event (AE) rate demonstrates the safety advantages of zanubrutinib, per the ASPEN trial. The AE (all grade) percentages for AFib/flutter are 23.5% for ibrutinib vs 8.0% for zanubrutinib.

Researchers also found a trend toward improved disease control for zanubrutinib vs ibrutinib, including higher rates of very good partial response, increased and better sustained IgM reduction, and increased improvement in quality of life. 

What this means for you

Clinicians should take heart in the fact that survival is improving in patients with WM. The BTKi zanubrutinib was elevated to a Category 1 recommendation by the NCCN as first-line treatment for WM. In a major clinical trial, this drug proved safer and more effective than ibrutinib.

Read Next: Looking forward: How far we’ve come with understanding BTKis
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