May 2026 Research Update

This month added two different pieces to the BTK inhibitor story in Waldenstrom macroglobulinemia (WM): a newer BTK drug showed strong anti-lymphoma activity in relapsed disease, and a large real-world comparison suggested one commonly used BTK drug may have fewer heart rhythm and bleeding problems than another. Together, these studies move the picture forward on both sides that patients care about: how well treatment can work after prior therapies, and what kinds of side effects may differ between BTK inhibitor options. [1] [2]

In the BRUIN phase 1/2 study, pirtobrutinib (a non-covalent BTK inhibitor, meaning it binds BTK differently than older BTK drugs) produced responses in many people with relapsed or refractory WM. The objective response rate by standard WM criteria was 82.5%, and responses looked similar whether or not someone had previously taken a covalent BTK inhibitor. This matters because it suggests pirtobrutinib may remain active even when WM has already been exposed to earlier BTK inhibitor treatment. [1]

Safety signals were also clearly described for pirtobrutinib: many participants had serious (grade 3 or higher) side effects, and treatment-emergent deaths were reported in a small number of patients. In a different kind of evidence, a large database study across several B-cell cancers (including WM) compared people starting zanubrutinib versus ibrutinib and found lower risks of new atrial fibrillation or flutter, major bleeding, and death within 12 months for zanubrutinib, while several other cardiovascular outcomes were similar between groups. Because this was not a randomized trial and it included multiple diseases, it is best read as a real-world safety comparison rather than proof that one drug causes better outcomes. [1] [2]

For patients, these studies mainly add clarity about what researchers are seeing with BTK inhibitors rather than changing anything immediately. The pirtobrutinib trial offers moderate-strength evidence that this newer BTK inhibitor can produce responses in relapsed WM, including in people previously treated with older BTK inhibitors, while also documenting that serious side effects can occur. The real-world zanubrutinib versus ibrutinib comparison suggests differences in certain risks (especially atrial fibrillation or flutter and major bleeding), but it cannot fully separate drug effects from differences in who received each treatment; it still helps patients understand why safety discussions often focus on heart rhythm and bleeding with this drug class. [1] [2]

This month, studies on testing and imaging showed a mixed picture: some tools lined up well with current WM response measures in certain treatment settings, while others did not, and several newer lab approaches looked promising but are still early. The overall message is that how WM is measured can depend strongly on the treatment type and the testing platform, so results from one method may not translate cleanly to another. These studies help explain why response tracking and incidental detection can sometimes feel confusing or inconsistent to patients. [3] [4]

For response assessment, a 68Ga-pentixafor PET/CT scan agreed with standard monoclonal-protein based IWWM response criteria in patients treated with chemoimmunotherapy, but it was often inconsistent in patients treated with BTK inhibitors. In the BTK inhibitor group, changes on the scan did not track with changes in M-protein or IgM, suggesting that the usual blood-based response categories may not describe what this scan is seeing during BTK inhibitor treatment. For patients, this helps explain why different tests may tell different stories about response, especially when treatment is a BTK inhibitor. [3]

Several studies looked at lab-based ways to detect or classify WM without relying only on traditional workflows. A pilot study reported a single-tube PCR test that could detect MYD88 L265P and CXCR4 S338 mutations with 0.1% sensitivity in 12 WM specimens, aiming to make mutation testing faster and more practical. Another exploratory study used serum Raman spectroscopy (a way of reading patterns in blood using laser light) and reported that patients with lymphoplasmacytic lymphoma or WM had different serum patterns than healthy controls, and that LPL could be distinguished from diffuse large B-cell lymphoma in this small dataset. [5] [6]

A separate real-world laboratory study suggested that an elevated lipemia index (a routine chemistry analyzer flag) in visually clear blood samples often coincided with an M-protein, frequently IgM, and it identified 5 newly diagnosed WM cases among newly detected M-proteins. At the same time, cross-platform checks showed the signal was inconsistent and sometimes absent on other instruments, meaning this cannot be treated as a standardized WM screening tool. For patients, this is a reminder that some "incidental" lab flags may prompt follow-up testing, but the same flag may not appear reliably across different labs. [4]

For patients and caregivers, these studies mainly matter as background for understanding why WM testing can vary by situation. The PET/CT study suggests that during chemoimmunotherapy, scan changes may match traditional blood-based response categories, but during BTK inhibitor therapy the scan and blood markers may not move together, which could affect how response is interpreted in future research. The mutation PCR test and Raman spectroscopy results are early and based on small numbers, so they are better viewed as research steps that could eventually support quicker or less invasive testing if validated. The lipemia index work may matter now only in specific lab settings because it was platform-dependent and not standardized, but it helps clarify how IgM proteins can interfere with routine lab measurements and sometimes lead to an unexpected WM workup. [3] [5] [6] [4]

This month added reassurance in one common worry and cautionary detail in several uncommon ones. In a larger group of patients, having bone involvement at diagnosis did not appear to predict worse survival or faster progression. In contrast, individual case reports showed that WM can sometimes overlap with other diseases or cause organ-specific problems that only become clear after targeted testing, which can change how the situation is understood for that one person. [7] [8]

In a single-center review of 112 adults with lymphoplasmacytic lymphoma or WM, osseous (bone) involvement at diagnosis was seen in 18% of patients and did not meaningfully change the time to first treatment, first-line response, progression-free survival, or overall survival compared with patients without bone involvement. For patients who learn they have bone lesions or bone uptake on imaging, this study supports the idea that bone involvement alone may not automatically signal a worse outlook, although individual risk still depends on many factors not addressed here. [7]

Several case reports focused on organ involvement that required biopsy to identify what was really happening. One person with WM was diagnosed with hepatic AL amyloidosis only after a repeat endoscopic ultrasound-guided liver biopsy produced adequate tissue, and later treatment was followed by lower free light chains and modest improvement in liver tests. Another report described cholestatic liver injury that progressed despite multiple interventions; a liver biopsy showed sinusoidal infiltration by lymphoplasmacytic cells, supporting WM-related liver involvement in that patient. [9] [8]

Kidney amyloidosis and other overlapping conditions were also highlighted as rare but high-impact situations. One case described AL-type lambda light-chain amyloid nephropathy in WM, where multiple lines of evidence suggested the light chain (not the IgM itself) was driving the amyloid damage; chemotherapy was followed by temporary improvement before later rapid decline. Another case described WM occurring alongside alveolar echinococcosis (a parasitic liver infection) with a chylothorax, where zanubrutinib for WM coincided with resolution of the recurrent chylothorax while albendazole was used for the infection. [10] [11]

A separate case report described sudden hearing loss in both ears in a person with presumed WM, linked to hyperviscosity (blood being too thick from very high IgM). Hearing did not improve after several weeks of systemic zanubrutinib in that report, but improved within days after steroid medicine was injected into the ears. For patients, this case illustrates that some WM-related symptoms can be urgent and may involve targeted symptom-focused treatments alongside WM-directed therapy, though a single case cannot predict what will happen for others. [12]

For patients, this group of studies mostly adds understanding about prognosis and about rare complications that may require specialized evaluation. The bone involvement cohort study provides moderate-strength evidence that bone involvement at diagnosis did not worsen key outcomes in that center, which may reduce fear when bone findings are discovered. The case reports are not generalizable, but they clarify that when symptoms involve the liver, kidneys, lungs, or hearing, identifying the exact cause can require specific tests such as biopsy, and the cause may be WM infiltration, amyloidosis, infection, or hyperviscosity depending on the person. What remains uncertain is how often these situations occur and which patients are at highest risk, because single cases cannot provide reliable rates or predictions. [7] [9] [8] [10] [11] [12]