Waldenström macroglobulinemia: 2026 so far

Comparative and longer follow-up data clarified BTK trade-offs.

In the months covered, the biggest step forward was a clearer picture of how different BTK inhibitors compare, both in response and in side effects. With extended ASPEN phase III follow-up (phase III = a late-stage trial comparing treatments), rates of very good partial or complete response stayed numerically higher with zanubrutinib than with ibrutinib at each reported time point, the median time to reach a very deep response was shorter (6.7 vs 16.6 months), and fewer people stopped zanubrutinib because of side effects. The side-effect patterns also differed: atrial fibrillation/flutter (an irregular heart rhythm) was more common with ibrutinib, while neutropenia (low neutrophil white blood cells) was more common with zanubrutinib. Longer follow-up from a phase 2 acalabrutinib study (phase 2 = a mid-stage trial testing whether a treatment works and is safe) supported sustained disease control out to about 5 years, and it also reported cardiac events and one treatment-related grade 5 intracranial hematoma (bleeding inside the skull). Real-world analyses and cohorts supported that BTK inhibitors can work in routine care, while also showing that infections and other complications during therapy can be a meaningful part of the treatment experience.

Research covered in: February 2026, April 2026, May 2026, July 2026

Retrospective cohorts compared frontline regimens using response and durability.

From January 2026 to September 2026, several retrospective routine-care comparisons (looking back at real-world records) added detail on how common first treatments differ in response rates and how long control lasts. In one newly diagnosed cohort comparison, BTK inhibitor regimens had the highest major response rate and a longer time to next treatment. Overall survival was reported as similar across groups, and differences in WM-related death were not statistically certain. Another real-world cohort reported that rituximab-based combinations tended to have longer disease control, while some other regimens had quicker early responses but shorter control in that dataset. Taken together, these reports mainly highlight which outcomes differed most in routine care (depth/speed of response and time-to-next-treatment), rather than proving one best first regimen for everyone.

Research covered in: August 2026, September 2026

Newer agents and non-BTK regimens showed activity with caveats.

In the months covered, several reports suggested WM can still respond after prior therapies, including after standard covalent BTK inhibitors (BTK drugs that bind permanently to their target). At the same time, safety signals and study-design limits were hard to ignore. In the BRUIN phase 1/2 study (phase 1/2 = early-stage testing of dosing, safety, and early effectiveness), pirtobrutinib led to responses in relapsed/refractory WM (disease that has returned or not responded), including in people previously treated with covalent BTK inhibitors. Serious (grade >=3) side effects were common, and a small number of treatment-emergent deaths were reported. A fixed-duration ibrutinib plus venetoclax study showed deep responses for some people, but it stopped early because of serious heart rhythm problems, including fatal events. Other non-BTK approaches also showed activity in small or single-arm reports (for example, bortezomib-based regimens after BTK inhibitors; obinutuzumab plus bendamustine in a group that included WM), with low blood counts and infections repeatedly showing up as important side effects to plan around.

Research covered in: March 2026, May 2026, June 2026

Reports repeatedly highlighted infections and IgM-driven complications.

Across January 2026 to September 2026 reports, day-to-day complications were often about infections and IgM-related bleeding or hyperviscosity (blood that becomes too thick). Real-world and registry-based reports continued to list infections among major causes of death. A database analysis described invasive fungal infections (serious deep fungal infections) during BTK inhibitor therapy as uncommon, while several single-patient reports described severe fungal infections on BTK inhibitors. Case-based and small-collection evidence also highlighted acquired von Willebrand syndrome (a bleeding problem from low/poor von Willebrand factor) and hyperviscosity presentations. This included one acquired von Willebrand syndrome case in which bleeding worsened after zanubrutinib was added, and individual cases in which therapeutic plasma exchange (a procedure that removes proteins from blood plasma) improved hyperviscosity symptoms. In ICU-level illness, infections were a leading cause of death in a WM ICU cohort, showing how a severe infection episode can become a defining event when it happens.

Research covered in: January 2026, April 2026, July 2026, August 2026, September 2026

Mutation and imaging measures often diverged from IgM on BTK.

In the months covered, several studies looked beyond IgM alone for monitoring, especially to explain why test results can disagree during BTK inhibitor treatment. Exploratory analyses suggested MYD88/CXCR4 mutation levels (DNA changes in common WM genes) -- especially in bone marrow -- may reflect marrow disease burden more closely than IgM changes. Additional assay-development work reported mutation allele frequency patterns (the fraction of DNA carrying a mutation) that were higher in symptomatic WM and fell in samples from people described as responding to ibrutinib, with cell-free DNA (DNA fragments circulating in blood) sometimes very low. Imaging work using 68Ga-pentixafor PET/CT (a PET scan using a specific tracer) matched standard blood-based response categories after chemoimmunotherapy, but it was often inconsistent during BTK inhibitor therapy. This means that in research, and sometimes in complex clinical situations, more than one type of measurement may be needed to interpret response, particularly for people on BTK inhibitors.

Research covered in: January 2026, May 2026, June 2026