March 2026 Research Update

This month added a clearer but mixed picture for BTK inhibitor-based treatment in Waldenstrom macroglobulinemia: several studies reported meaningful response rates, but safety and patient subgroups mattered a lot. A fixed-duration combination of ibrutinib (a BTK inhibitor) plus venetoclax (a BCL-2 inhibitor) showed deep responses in some people, yet the study stopped early because serious heart rhythm problems occurred. In routine care in Japan, tirabrutinib (a BTK inhibitor) showed response rates that looked similar to prior reports, with side effects that were common but often improved or resolved. [1] [2]

For people whose disease returned or did not respond, a retrospective comparison suggested venetoclax and pirtobrutinib (a newer, non-covalent BTK inhibitor) had broadly similar results when patients were matched as closely as possible. The same report also described that side effects leading to stopping treatment were seen with venetoclax but not with pirtobrutinib in that dataset. It also highlighted that IgM rebound during transitions off a BTK inhibitor was more common when starting venetoclax without overlap than in other transition approaches reported. [3]

Across different B-cell lymphomas (including WM), a meta-analysis comparing BTK inhibitors reported higher complete and overall response rates with zanubrutinib than with acalabrutinib or ibrutinib. The strongest statistically significant differences were reported in specific lymphoma subgroups (not WM-specific), so this result supports a general direction across diseases but does not by itself prove the same size of benefit in WM alone. Still, it reinforces why patients may hear these BTK inhibitor names discussed as not all being identical in how they perform across studies. [4]

For patients and caregivers, these studies mainly add context about what BTK inhibitor-based options can look like in the real world and in trials, rather than changing what any one person should do now. The fixed-duration ibrutinib plus venetoclax study shows that deep responses and time without treatment are possible for some, but it also clearly shows that serious safety events can limit a regimen even when it looks active. The relapsed/refractory comparison helps clarify that different targeted medicines may lead to similar disease control in some matched groups, while certain gene changes (like TP53 or CXCR4) and transition periods between therapies may relate to different outcomes in the reported datasets. What remains uncertain is how best to choose among these options for an individual person, because several results come from non-randomized comparisons and some WM-specific details are limited. [1] [3] [2] [4]

This month, studies looking at chemoimmunotherapy and aggressive transformation of WM reinforced that outcomes can differ widely across treatment approaches and disease situations, but comparisons are hard when groups are small or different at baseline. In one long-term single-center experience, FCR (fludarabine, cyclophosphamide, and rituximab) was reported with the longest overall survival and the highest complete response rate, while rituximab alone looked safer but had poorer outcomes. In a separate small series focused on transformation from WM to diffuse large B-cell lymphoma (a more aggressive lymphoma), BTK inhibitor-based treatment after transformation was linked to longer survival in that dataset. [5] [6]

The chemoimmunotherapy report also described a trade-off between disease control and side effects in routine practice: more intensive regimens had more severe blood count problems and infections, while rituximab alone had fewer severe side effects but lower response rates. Because patients receiving different regimens were not similar at the start, the results cannot show that one regimen caused better survival, but they do illustrate the kind of real-world balancing of effectiveness and tolerability that people with WM often face. Quality-of-life was not measured, which leaves an important gap in understanding what these survival and toxicity differences felt like for patients. [5]

In transformed WM (WM changing into diffuse large B-cell lymphoma), the series described a difficult disease course, yet also reported that BTK inhibitor-based regimens after transformation were associated with longer survival compared with regimens not using a BTK inhibitor in that center's experience. A small subset treated with zanubrutinib plus R-CHOP all reached complete response in the report, but this involved only a few people and may not apply broadly. This study helps clarify that transformation is being studied as its own clinical situation, with targeted agents being explored even after transformation, but stronger evidence is still needed. [6]

For patients, these studies mainly help with expectation-setting about how varied WM treatment situations can be. The chemoimmunotherapy data may matter now as a description of what one center observed over many years, including the idea that more intensive regimens may bring more side effects, while less intensive approaches may be easier to tolerate but may control the disease less well in that dataset. The transformation report may matter later if confirmed, because it points to BTK inhibitor-based approaches as an area of active study for a rare but serious change in the disease, yet the evidence is still early due to the small number of patients and non-randomized comparisons. [5] [6]

This month made prognosis in WM feel more specific: several large studies reported that certain health factors at diagnosis and certain gene changes can help sort people into different risk groups, but the usefulness of older risk scores may depend on the type of treatment used. Kidney function at diagnosis stood out as a meaningful marker, with worse survival reported in people who started out with reduced kidney filtering. Separately, a large cohort suggested that common clinical scoring systems predicted outcomes in patients not treated with BTK inhibitors, but did not predict as well among those receiving BTK inhibitor-based therapy. [7] [8]

The kidney study reported that reduced kidney filtering was present in about 3 out of 10 symptomatic patients at diagnosis, and it was linked with shorter overall survival and progression-free survival. This matters because kidney problems in WM can reflect disease effects, other health conditions, or both, and this study supports kidney function as a factor that relates to the course of disease over time. The report also noted renal biopsies were done in some cases, reflecting that kidney issues in WM can have different causes that may need clarification in research and care settings. [7]

Two studies focused on genetics and measurements in the bone marrow as ways to refine prognosis across WM and related IgM conditions. One WM study reported that MYD88 mutation status related to better outcomes mainly in people receiving first-line BTK inhibitor therapy, while CXCR4 and TP53 mutations were linked with worse outcomes in both BTK inhibitor and non-BTK inhibitor groups. Another multicenter study across symptomatic WM, asymptomatic WM, and IgM-MGUS reported that a higher MYD88 mutation ratio in the marrow together with higher abnormal cell levels measured by flow cytometry could separate people into groups with different overall survival and time to first treatment. [8] [9]

For patients and caregivers, these studies add understanding about why prognosis conversations in WM often include both general health measures (like kidney function) and disease biology (like TP53 or CXCR4). Some of this may matter now because kidney function and basic bloodwork are already part of routine evaluation, and these data support that they are not just numbers but can relate to long-term outcomes. Some may matter more in the future, such as using more detailed bone marrow measurements (like a quantitative MYD88 ratio plus flow cytometry levels) to better estimate the chance of needing treatment or the expected course, especially across the IgM spectrum. Important uncertainty remains because these are retrospective datasets, and one study suggests that traditional risk scores may not work the same way once BTK inhibitor-based therapy is used. [7] [8] [9]

This month's case reports highlighted that WM can overlap with other conditions and can sometimes present through unexpected problems, especially involving the skin, lungs, or bone marrow. One report described a serious-appearing skin infection in a person on zanubrutinib that improved with prompt biopsy, antibiotics, and surgery. Other reports described rare overlaps, including WM with an unusual lymphoma affecting lung blood vessels, and WM appearing alongside severe aplastic anemia (very low blood cell production). [10] [11] [12]

One skin-focused case described eosinophilic annular erythema in a woman with IgM-MGUS; her doctors considered WM unlikely, although a very early stage could not be entirely ruled out. The rash improved with topical steroid treatment. This case does not show that the rash predicts WM, but it does add to the list of ways IgM-related conditions may appear outside the blood and marrow. Taken together, these reports mainly broaden awareness of possible presentations rather than defining what most people with WM will experience. [13]

A separate observational report in people with osteoporosis and MGUS treated with teriparatide described that a small number later developed blood cancers, including one case of Waldenstrom macroglobulinemia during follow-up. Because there was no control group and numbers were small, it cannot show that teriparatide caused these outcomes, but it documents what was observed when this bone medication was used in a higher-risk population. It also reported improvements in spine bone density, showing why this question is being studied in the first place. [14]

For patients, these reports may matter now mainly as awareness that unusual symptoms can sometimes be linked to WM, treatment effects, or related immune problems, even though they are not common. The infection case especially reinforces that some skin lesions in immunocompromised settings can be caused by specific bacteria found on tissue testing, and in that report the person improved with targeted care. The overlap-condition cases may matter later by encouraging more research into why certain disorders appear together, but single-patient reports cannot predict risk for any individual. The teriparatide report is best viewed as early safety signal monitoring in a small MGUS group, with uncertainty about causality. [10] [11] [12] [13] [14]