September 2026 Research Update

Across these studies, the overall message was that different first treatments can control Waldenstrom macroglobulinemia for meaningful periods; in the one study that compared treatments, the clearest differences showed up in response rates and how long people went before needing the next treatment, not in overall survival. Because both studies were retrospective (looking back at care), the results point to trends rather than definitive head-to-head answers. [1] [2]

In a 348-patient cohort comparing three common first-line approaches, Bruton's tyrosine kinase inhibitors had the highest major response rate and a longer time to the next treatment than the other regimens studied. Median progression-free survival and overall survival were reported as similar across the groups, and differences in Waldenstrom-related death at 5 years were not statistically certain. [1]

A separate 206-patient study focused only on people who started with dexamethasone-rituximab-cyclophosphamide and asked whether early progression (within 24 months) identified a higher-risk group. About one in five had early progression, and this group had lower 5-year overall survival and higher Waldenstrom-related mortality even after adjusting for a risk score and other factors. [2]

For patients and caregivers, these results mainly provide context for discussions about what outcomes different upfront treatments tend to affect: some regimens may produce deeper responses or delay the next treatment, while overall survival may look similar in available retrospective data. They also highlight that needing a treatment change within 2 years after starting dexamethasone-rituximab-cyclophosphamide can mark a group with higher Waldenstrom-related risk in that study. What remains uncertain is whether the observed differences are due to the treatments themselves, differences in which patients received which regimen, or follow-up time, which is why longer follow-up and prospective comparisons are still needed.

Across two case reports in Waldenstrom macroglobulinemia, side effects included infection risk that appeared months after therapy ended and inflammatory eye problems during targeted therapy. Because both papers describe single patients, they show what can happen but cannot tell how common these problems are or who is most at risk. [3] [4]

One 71-year-old man developed probable Pneumocystis jirovecii pneumonia (a specific kind of pneumonia) 10 months after finishing bendamustine-rituximab, after stopping TMP-SMX preventive medication. He had very low CD4-positive helper T cells (37 cells/uL), and his count was still not back to normal 18 months after treatment (183 cells/uL), suggesting immune recovery can be slow in some people. He improved with TMP-SMX treatment. [3]

A man in his early 50s developed uveitis and keratitis (eye inflammation) while taking Bruton tyrosine kinase (BTK) inhibitors. The inflammation improved after stopping ibrutinib, came back when the drug was restarted at a lower dose, and then worsened quickly with zanubrutinib before improving again after stopping, which the authors interpreted as a possible BTK inhibitor class effect. [4]

For patients and caregivers, these reports add context that some treatment-related risks may show up late (such as a specific pneumonia after chemotherapy-based treatment) or may involve organs outside the blood and bone marrow (such as inflammatory eye symptoms during BTK inhibitor therapy). These papers mainly serve as safety signals and background information, not proof of frequency or typical timing, and it remains uncertain which patient factors best predict prolonged immune suppression or eye inflammation. [3] [4]

Across these reports, rituximab-based treatments were commonly used when Waldenstrom macroglobulinemia (WM) or related IgM conditions caused nerve problems (peripheral neuropathy) or blood problems from cold agglutinins (a type of antibody that can cause anemia). Both studies suggest symptom-related measures can improve, but the evidence is limited because the data come from small, single-center, retrospective groups without randomized comparisons. [5] [6]

In a 28-person cohort with IgM-related peripheral neuropathy linked to WM or IgM MGUS, nerve disability scores improved after mainly rituximab-based regimens, with improvements still seen out to 2 years for many patients. Reductions in IgM levels tracked with better neuropathy scores at 6 and 12 months, suggesting that lowering the abnormal IgM may relate to nerve symptom improvement in this setting. [5]

In a separate 39-person study comparing primary cold agglutinin disease (pCAD), WM-associated cold agglutinin syndrome (WM-CAS), and WM without cold agglutinin syndrome, rituximab-based chemoimmunotherapy led to high response rates in the cold agglutinin groups. No overt blood clotting events were reported in the cold agglutinin groups, while low white blood cell counts (neutropenia) occurred and some infections were reported, emphasizing that side effects still need monitoring in real-world care. [6]

For patients and caregivers, these studies add real-world information about complications that can strongly affect daily life: nerve damage (numbness, weakness, balance problems) and cold agglutinin-related anemia (fatigue and other anemia symptoms). The results mainly matter as background evidence to inform discussions about how WM-directed therapy can sometimes also improve complication-related symptoms, but it is still uncertain how well these results apply to all patients because both studies were small, retrospective, and used different treatment regimens rather than a single standardized approach. [5] [6]

Across these reports, diagnosis was challenging because the first symptoms did not look like a typical blood cancer problem, and because a standard blood test for abnormal proteins could miss the disease. In all cases, confirmation depended on combining blood testing with bone marrow and/or tissue biopsy and additional lab methods. The evidence is limited because the papers describe individual patients rather than large studies. [7] [8] [9]

Two men were diagnosed after developing a right-sided chylothorax, a milky lymph-fluid pleural effusion that can cause shortness of breath and keep coming back. Their workup used pleural fluid testing plus imaging and tissue sampling (bone marrow and/or lymph node biopsy) to confirm lymphoplasmacytic lymphoma with an IgM blood protein. One patient had the MYD88 L265P mutation while the other did not, showing that test results can differ across people even when the overall diagnosis is similar. [7]

One 79-year-old man had anemia and symptoms linked to thickened blood, but the usual serum protein electrophoresis test was negative because his IgM formed aggregates that hid the abnormal signal. The diagnosis was clarified using other blood-protein methods (including immunofixation), bone marrow biopsy, and genetic testing that found MYD88 L265P and a CXCR4 mutation. This case highlights that a negative result on one commonly used blood test does not always rule out Waldenstrom macroglobulinemia. [8]

A separate single-patient study described a man whose bone marrow contained both acute myeloid leukemia (AML) cells and a Waldenstrom-related B/plasma-cell compartment at the same time. Using single-cell RNA sequencing plus flow cytometry and IgM testing, the authors showed these were distinct cell groups, and MYD88 L265P supported the Waldenstrom-related compartment. This illustrates how overlapping blood and bone marrow conditions can complicate interpretation of symptoms and test results. In this case, routine tests established that both conditions were present; the single-cell work was exploratory research into how they coexist. [9]

For patients and caregivers, these papers are mainly background information about why diagnosis can take time or require multiple steps, especially when symptoms start outside the bone marrow (like recurrent chest fluid) or when one blood test is misleading. They also show that genetic results may vary between people, and that rare situations can involve more than one blood or bone marrow disease at the same time. What remains uncertain is how often these specific diagnostic pitfalls happen, since the evidence here comes from a few individual cases rather than larger studies. [7] [8] [9]

Two retrospective studies looked at outcomes at different points: progression in people with asymptomatic precursor conditions, and survival in people with diagnosed Waldenstrom macroglobulinemia, where the person's overall health was linked with how long they lived. In the first study, no one under 50 with asymptomatic Waldenstrom macroglobulinemia had progressed during the observed follow-up, but the study did not show a difference in progression risk by age. In diagnosed Waldenstrom macroglobulinemia, having other medical conditions and being older were linked with shorter overall survival. [10] [11]

In a single-center cohort of 1,237 people with asymptomatic monoclonal gammopathies (including asymptomatic Waldenstrom macroglobulinemia), no one under 50 with asymptomatic Waldenstrom macroglobulinemia progressed to symptomatic disease during follow-up. In smoldering myeloma, younger patients had lower progression rates than older patients at 2, 3, and 5 years, although the age difference was not clearly separate after accounting for baseline risk. [10]

In a National Cancer Database study of 17,130 people with histologically confirmed Waldenstrom macroglobulinemia, a Charlson comorbidity score of 1 or more (meaning at least one significant additional health condition) was linked with higher risk of death. Median overall survival was shorter for those with comorbidities than for those without (66 vs 126 months). Other factors linked with worse survival included older age, lower income, non-academic treatment centers, and having multiple cancers, while female sex was linked with better survival. [11]

For patients and caregivers, these results reinforce that the expected course can differ depending on whether disease is asymptomatic or diagnosed, and that general health and age are linked with meaningful differences in outcomes alongside the cancer itself. The progression results in younger, asymptomatic patients come from relatively small subgroups and limited follow-up, so they may not predict longer-term risk. The survival results come from a very large database study, but databases cannot capture every detail that may influence survival (such as specific symptoms, lab results, or reasons for choosing certain treatments).

Together, these papers point to Waldenstrom macroglobulinemia (WM) being driven by both (1) how B-cell cancer clones expand and take over over time and (2) specific genetic changes that can turn on cell-survival signaling. The patient-sample study suggests WM is often dominated by one main clone with features of both memory B cells and plasma cells, while the lab study shows how a subtle DNA change can still strongly activate a key growth pathway. [12] [13]

In a small single-cell study of 12 patients comparing IgM MGUS, smoldering WM, and symptomatic WM, early stages (IgM MGUS and lower-risk smoldering WM) had multiple B-cell clones, while symptomatic WM was usually dominated by one clone. That dominant clone showed a mix of memory B-cell-like and plasma cell-like features, and it was marked by genes including CD9 and JCHAIN, suggesting a particular cell state may be better at expanding in WM. [12]

The same single-cell work found that the MYD88 L265P mutation appeared across clones, and higher-risk cases showed genetic changes such as loss of part of chromosome 6 (6q deletion), which appeared to give cells a fitness advantage. The study also reported that smaller, "minor" clones often shared many mutations with the dominant clone, supporting the idea that WM can contain related subclones within the same patient. [12]

In exploratory lab experiments using engineered B-cell cancer cell lines, researchers found that two recurring "silent" (synonymous) DNA variants in MAP3K14 (also called NIK), seen across several B-cell cancers including WM, can change RNA splicing in a way that removes a regulatory region needed for TRAF3 binding. This led to activation of non-canonical NF-kB signaling, along with faster growth and survival of the engineered cells and higher release of an immune signaling protein (IP10/CXCL10). [13]

That lab study also reported distinctive changes in proteins on the cell surface, and highlighted CD132 as a possible single-cell marker of NF-kB activation measurable by flow cytometry in their models. This is an early, model-based result, but it illustrates how researchers are searching for practical markers that reflect which growth pathways are active inside the cancer cells. [13]

For patients and caregivers, these studies mainly add background understanding of why WM behaves differently from earlier IgM-related conditions and why the disease can vary within the same person. The single-cell patient work suggests WM often becomes dominated by one main cancer clone and that certain genetic changes (like 6q loss) may be linked to higher-risk biology, but it does not by itself change how care is decided. The MAP3K14 work is lab-based and helps explain one way the NF-kB pathway could be switched on, and it proposes CD132 as a possible marker in models; it remains uncertain how often these variants occur in people with WM and how well such markers would perform in real patient samples.

Across these papers, two linked messages stood out: treatment choices affect both personal priorities (what matters most to patients) and healthcare spending (where costs tend to come from). Costs in routine care were largely driven by disease-related medical services, while patients, when asked to choose between options, strongly prioritized longer time before the disease worsens and avoiding difficult side effects. [14] [15]

In a US insurance claims study that included 791 people with Waldenstrom macroglobulinemia, average total costs were $8,445 per patient per month, and more than half of total costs were from disease-related medical care. The most common treatments overall were bendamustine-based regimens and rituximab alone, with a shift in later lines toward more rituximab alone and more ibrutinib-based therapy. [14]

In an international survey study of 1,455 people with Waldenstrom macroglobulinemia, all six treatment features tested influenced choices, but the biggest drivers were longer response duration and avoiding severe temporary side effects. People were also less likely to choose options with ongoing treatment rather than fixed-duration treatment, hospital infusions rather than at-home oral treatment, persistent side effects, or higher risk of a second cancer. [15]

In a China-focused cost-effectiveness analysis based on ASPEN trial data and a 15-year model, zanubrutinib was estimated to provide slightly more quality-adjusted life years while saving costs compared with ibrutinib when used as first-line therapy. The authors reported a gain of 0.084 quality-adjusted life years and cost savings of $26,768 per patient in the model. [16]

For patients and caregivers, this set of studies helps separate two questions that often get mixed together: what tends to drive healthcare costs in everyday practice, and what treatment features patients say matter most when weighing options. The cost studies reflect specific healthcare systems (US insurance claims; a China-based model), so the numbers may not apply to an individual person, but they highlight that disease-related medical care and hospital use can be major cost drivers. The preference survey provides structured evidence that many patients place high value on longer control of disease and on avoiding severe or lasting side effects, but it cannot predict what any one person will prefer or what options are available in a given setting.