ASH 2025 Updates: What’s New in Waldenström Macroglobulinemia Treatment

Learn how genetics, prior treatments, and newer medicines may affect care decisions for people living with Waldenström macroglobulinemia (WM). These insights come from four WM studies presented at the American Society of Hematology (ASH) meeting in December 2025. 

Genetic changes that signal high-risk WM after prior treatment

Researchers studied people with WM who had already received treatment and had a MYD88 mutation. This is a common genetic change in WM that helps drive cancer cell growth. They focused on TP53 alterations, which are changes in a gene that normally helps control damaged cells.

About 12% of patients had TP53 alterations, and roughly half of these had “double-hit” changes, meaning two separate TP53 problems were present. These double-hit changes were more common in WM patients previously treated with certain chemotherapy combinations. Patients with double-hit TP53 changes had much shorter overall survival compared with those who had one or no TP53 changes.

This study shows that not all TP53 alterations carry the same risk. Identifying double-hit TP53 changes may help doctors recognize patients who need closer monitoring or different treatment approaches earlier. 

Read this abstract: Double-hit alterations of TP53 identify ultra high-risk disease in previously treated, MYD88 mutated Waldenstrom macroglobulinemia. 

A fixed-duration combination shows strong responses in previously treated WM

Another study looked at a combination of two targeted therapies: the newer BTK inhibitor pirtobrutinib (Jaypirca, Eli Lilly) with venetoclax (Venclexta, AbbVie). Unlike many BTK inhibitor-based treatments that are given indefinitely, this combination was given for up to two years. 

Among people with MYD88-mutated WM who had received prior treatment, more than half experienced a very good partial response or complete response to pirtobrutinib within a median time of 5.8 months. Of patients who responded, they also saw positive benefits like improved blood counts, lowered IgM levels, and decreased bone marrow involvement. Side effects were manageable, with low rates of serious complications. 

These findings showcase that a time-limited treatment may reduce long-term side effects and offer flexibility for people with WM, offering a break from continuous therapy. 

Read this abstract: High VGPR/CR rates with pirtobrutinib plus venetoclax in previously treated Waldenström macroglobulinemia: Results from a multicenter phase II study

Up to five years of follow-up with pirtobrutinib alone

Long-term results from the BRUIN study followed people with relapsed or refractory WM treated with pirtobrutinib alone. Most participants had already tried multiple treatments, including other BTK inhibitors.

More than 80% of patients responded, and responses often lasted several years. Importantly, pirtobrutinib worked even in people whose WM had progressed on earlier BTK inhibitors. Side effects such as low blood counts and diarrhea were common but usually manageable, and few people needed to stop treatment.

These insights provide reassurance that pirtobrutinib can remain effective over time, even after other treatments stop working for people with WM. 

Read this abstract: Pirtobrutinib in Relapsed/Refractory (R/R) Waldenström macroglobulinemia (WM): Up to 5 years of follow-up from the Phase 1/2 BRUIN study

Long-term safety and effectiveness of first-line immunochemotherapy

The final study reported long-term results from a large European trial comparing DRC (dexamethasone, rituximab, and cyclophosphamide) with or without bortezomib as a first treatment for WM. Both approaches were given for a fixed number of cycles.

The five-year overall survival was about 90% in both groups. Adding bortezomib led to faster and deeper responses, but it did not improve long-term survival and caused more nerve-related side effects. Researchers also found that outcomes were similar regardless of MYD88 or CXCR4 mutation status.

These results confirm that DRC remains a reliable first treatment option for people with WM, especially for those who prefer a fixed-duration approach. 

Read this abstract: Dexamethasone, Rituximab and Cyclophosphamide with Bortezomib is a rapidly acting and highly efficient first-line treatment in Waldenström’s Macroglobulinemia

Conclusion

Recent ASH 2025 updates show progress in understanding risk and expanding treatment choices for WM. Genetic testing can identify high-risk groups, while newer targeted approaches offer promising responses. Long-term data also reinforce the value of established first-line options, helping people with WM make informed decisions with their care team. 

We need your help! Easily contribute to WM research

If you are living with WM, we need your help improving patient outcomes for all by taking simple, anonymous surveys that contribute to real-world research in HealthTree Cure Hub®. Click the buttons below to get started or see the current impact of this research! 

Make an Impact with Brief Blood Cancer Surveys

See Patients’ Progress: Research Results News