July 2026 Research Update

This month added more detail to a familiar WM story: BTK inhibitors can control disease for many people, but infection risk remains a central trade-off. In routine care, patients treated with ibrutinib or acalabrutinib often had tumor and IgM improvements, yet infections and blood count problems were common. In an early phase study of HZ-A-018 (a newer BTK inhibitor) tested across several B-cell cancers including WM, the drug showed clear target engagement and a safety profile that included infections, but WM-specific outcomes were not separated out. [1] [2]

In a single-center Indian cohort of 22 people with WM, the reported overall response rate with ibrutinib or acalabrutinib was 81.8%, with 2-year overall survival of 91% and 2-year progression-free survival of 82% during a median follow-up of 30 months. The study did not find clear differences in overall survival or progression-free survival between ibrutinib and acalabrutinib, or between using a BTK inhibitor first-line versus later, although the numbers were small. This supports the idea that BTK inhibitors can be effective in everyday practice, while also highlighting that results can vary by patient and setting. [1]

Safety signals were prominent in the same cohort: infections were reported in 81.8% of patients, and there were also issues like low neutrophils, low platelets, bleeding, and arrhythmias. Two deaths were reported (septic shock and pneumonia), showing that infections can be serious for some patients receiving these therapies. Because this was a retrospective study without randomization, it cannot prove why infections happened, but it does make the burden of infection during BTK inhibitor treatment hard to ignore. [1]

A first-in-human phase I study tested HZ-A-018 in 31 treated patients with several relapsed or refractory B-cell cancers, including WM, and found no dose-limiting toxicities with strong BTK occupancy in blood cells (>95% at steady state). Across the whole mixed-cancer group, the overall response rate was 44.8%, and side effects included low blood counts, infections, thrombocytopenia, rash, and hypertension, with one pneumonia death considered possibly related. This mainly adds early safety and dosing information, and it shows that new BTK inhibitors continue to move forward, but it does not yet tell WM patients how this drug compares with established options. [2]

For patients and caregivers, the most practical update is that newer and existing BTK inhibitors are still showing disease control in reported groups, but infections remain a major real-world concern to understand and study. The Indian cohort gives a clearer picture of what treatment can look like outside of clinical trials, including both responses and common complications, while the HZ-A-018 study is earlier-stage research focused on safety and how the drug behaves in the body. What remains uncertain from this month is how HZ-A-018 performs specifically in WM (because results were reported across different cancers), and which patients are most likely to have serious infections on BTK inhibitors. [1] [2]

This month strengthened a big-picture point that matters in daily life: WM often sits alongside other health risks, and some complications are driven by the broader immune and protein changes rather than the lymphoma alone. In large datasets, monoclonal proteins and related blood disorders were frequently found in people with severe infections, and WM was among conditions linked to cardiac amyloidosis in hospitalized patients. Several case reports added concrete examples of how infections or amyloid-related kidney disease can become the main problem at a given moment. [3] [4] [5] [6]

A large US inpatient analysis (23,119 hospitalizations with cardiac amyloidosis) reported that Waldenstrom macroglobulinemia was among diagnoses strongly linked to having cardiac amyloidosis (odds ratio 6.99), alongside related conditions like multiple myeloma and MGUS. The same analysis reported higher in-hospital mortality with end-stage kidney disease and older age. For WM readers, this does not mean cardiac amyloidosis is expected, but it reinforces why doctors pay attention to new heart or kidney problems when a monoclonal protein disorder is present. [4]

A Swedish prospective study of invasive pneumococcal disease (IPD) found monoclonal protein (M protein) in 27% of patients during acute infection, compared with 4.7% of controls, and several people were later diagnosed with blood cancers including Waldenstrom macroglobulinemia. Many patients also had low antibody levels or low B-cell counts during recovery, and some started immunoglobulin replacement. This adds evidence that a serious pneumococcal infection can sometimes be a sign of an underlying immune weakness or previously unrecognized blood disorder, rather than just a one-time infection. [3]

Case reports illustrated how infections and organ involvement can dominate the course for individual people with WM. One report described WM-associated kidney AL amyloidosis where bendamustine plus rituximab produced a partial blood response but kidney protein loss improved only slightly, and a severe lung infection occurred during therapy. Another described a culture-negative prosthetic joint infection with spread to multiple joints, where molecular testing identified Mycoplasma pneumoniae and guided antibiotic treatment while surgery was deferred. [5] [6]

For patients, these studies add clarity about what can be happening in the background with WM: immune function and abnormal proteins can connect to infection risk and, in some situations, to organ problems like amyloidosis. The large IPD study may matter now in the sense that it documents how often an M protein is found during severe pneumococcal infection and how often immune deficits show up during recovery, although it does not show the best next steps for any one person. The cardiac amyloidosis inpatient analysis and the infection-focused case reports mainly add awareness of patterns that researchers and clinicians are trying to recognize earlier, but they do not predict what will happen for a specific individual. [3] [4] [5] [6]

This month made it clearer that WM can be recognized as a specific biological pattern, but that pattern can also show up in early or atypical presentations that are easy to mislabel. Population screening work suggested that some IgM monoclonal gammopathy cases already look WM-like at the cell and mutation level. Separately, a large WM biology study reported that abnormal WNK2 isoforms were common in MYD88-mutated WM and could activate growth and inflammation-related signaling in lab experiments. Case reports reinforced how diagnosis can hinge on putting together multiple pieces of testing, especially in unusual variants. [7] [8] [9]

In a screening-identified group of 25 asymptomatic people with monoclonal gammopathy, IgM-MGUS cases showed WM-like cell markers and carried MYD88 and/or CXCR4 mutations in both clonal B cells and clonal plasma cells. By contrast, non-IgM monoclonal gammopathy more often showed multiple-myeloma-like features such as t(11;14), and the coexisting B-cell clone was often genetically unrelated. For patients, this supports the idea that the type of M protein (IgM versus non-IgM) can reflect different underlying biology, even before symptoms appear, although this is not yet used as a stand-alone decision tool. [7]

A multi-omics study in 264 untreated WM cases reported that abnormal WNK2 isoforms were very commonly expressed in early-stage WM, especially in plasma cell-like MYD88-mutated WM. In lab and primary WM cell experiments, the most expressed kinase-domain-lacking isoform (WNK2/S-NK1) triggered signaling changes involving ERK1/2 and NF-kB, which are pathways linked to cell survival and inflammation. This is research-stage biology, but it helps explain why WM cells may behave differently from normal cells and points to possible future drug targets if confirmed. [8]

A rare diagnostic case described CD19-negative, non-IgM lymphoplasmacytic lymphoma with an IgG-lambda monoclonal protein and a MYD88 L265P mutation, managed with active surveillance. The report emphasized that unusual immune-marker patterns (like CD19 negativity) can create a diagnostic gray zone between conditions such as MGUS and lymphoma, so multiple testing methods may be needed to classify the illness correctly. For caregivers, the main message is that an IgM monoclonal protein is not the only way these diseases can present, even when the underlying mutation pattern looks WM-like. [9]

For patients, this group of studies mainly matters as background knowledge rather than something that changes care right now. The screening study and the rare diagnostic case help clarify why doctors sometimes order both mutation testing (like MYD88 and CXCR4) and detailed cell testing to sort out whether a monoclonal protein state looks more like WM or something else. The WNK2 findings are laboratory and tumor-profiling research that may matter later if they lead to new treatment ideas, but they do not yet tell an individual person what will happen or which treatment to choose. [7] [8] [9]

This month had several case reports that, when taken together, show how WM care can become complex when multiple conditions overlap. Some cases focused on diagnostic clues (like cold agglutination) or uncommon test findings, while others showed that more than one cancer or infection can be present at the same time. These reports do not tell how common these situations are, but they give real examples of why symptoms and test results sometimes require broader thinking than WM alone. [10] [11] [12] [13]

One WM case highlighted cold agglutination as an important diagnostic clue, and the patient had hyperviscosity symptoms that improved after therapeutic plasma exchange, followed by bortezomib plus dexamethasone. The report described improvements in IgM and kidney-related lab values after treatment, although follow-up was later limited by a serious infection. For patients, it shows how symptom-driven supportive procedures can quickly relieve thick-blood symptoms in some situations, while also reminding that infections can complicate the course. [10]

Another report described a person with MYD88-mutant lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia occurring alongside an IgG-kappa plasma cell cancer with features suggestive of multiple myeloma, raising the possibility of two clones. Treatment with zanubrutinib, bortezomib, and dexamethasone was reported as well tolerated and led to a partial response with reduced clonal populations on flow testing. This case adds an example of how more than one antibody-producing cell disorder can exist together, making diagnosis and tracking more complicated than usual. [11]

A separate case report described WM in which hidden spread of estrogen receptor-positive breast cancer was found in the bone marrow within a lymphoid background, and later treatment with palbociclib plus fulvestrant led to stable disease at 6 months. Another imaging-focused report noted diffuse liver uptake on a bone scan tracer (99mTc-MDP) in a patient with WM. Together, these reports underline that unexpected biopsy or imaging findings can sometimes reflect an additional diagnosis or an uncommon pattern that needs careful interpretation. [12] [13]

For patients and caregivers, the value of these case reports is mainly in recognizing what is possible rather than what is likely. They show that WM symptoms may sometimes come from hyperviscosity or immune effects, and that uncommon overlaps (such as a second cancer or a second plasma cell disorder) can change what tests are needed to explain new problems. Because each report describes only 1 person (or an isolated observation), it remains uncertain how often any one situation occurs, and these findings are best seen as reminders to fully explain new or surprising symptoms or test results. [10] [11] [12] [13]

This month included a study that is less about immediate WM symptoms and more about building better future evidence. Denmark described a national resource (DALY-CARE Genetic Cohort) that connects inherited genetic data with detailed health records and lab results for people with lymphoid cancers, including WM/LPL. The main advance here is the ability to ask large, real-world questions about who gets which complications or outcomes over time, using linked data rather than small single-center snapshots. [14]

In the genotyped subset (8,675 individuals), the cohort includes common diagnoses such as DLBCL, MGUS, CLL, multiple myeloma, and WM/LPL, and it captures comorbidity burdens like polypharmacy and cardiovascular disease from registers and hospital records. The paper reported that overall survival patterns for genotyped versus non-genotyped individuals were broadly similar for most diagnoses, while also noting potential selection bias for some groups. For WM research, this type of dataset can support future studies on inherited risk, treatment tolerability, and long-term complications, but this report did not yet provide WM-specific genetic findings. [14]

For patients, this is mainly a future-facing development rather than a change in how WM is managed today. A large linked cohort makes it more realistic to study questions that are hard to answer in small trials, such as how other health conditions affect WM outcomes, or whether inherited genetics relates to complications. What remains uncertain is what specific WM results will come from this resource, since this paper focused on describing the dataset rather than reporting new WM outcome findings. [14]