Understanding Waldenström’s Macroglobulinemia: How Doctors Diagnose It

Evergreen Chapter
May 30
4 min read

By: Janya Kumar

Waldenström’s macroglobulinemia (WM) is a rare type of blood cancer where abnormal cells build up in the bone marrow and produce too much of a protein called IgM. Diagnosing WM involves several steps, including blood tests, bone marrow checks, and genetic testing. Here’s a simple breakdown of how doctors determine if someone has WM and what happens next.

Step 1: Blood Tests

● Looking for IgM: Doctors start by testing

your blood for high levels of IgM, a protein

made by the cancer cells. High IgM can

cause symptoms like fatigue, bleeding, or

nerve problems.

● Checking Blood Cells: A complete blood

count (CBC) checks for low red blood cells (anemia), low platelets (which help blood clot), or other irregularities.

● Organ Health: Blood tests also check how well your kidneys and liver are working, since WM can affect these organs.

Step 2: Bone Marrow Biopsy

If blood tests suggest WM, doctors take a small sample of bone marrow (usually from the hip bone) using a needle. This helps confirm the diagnosis.

What’s in the Sample: Lab experts look for abnormal cells called lymphoplasmacytic cells, which are a key sign of WM.
Genetic Testing:
- MYD88 Mutation: Almost all WM patients have a specific genetic change called MYD88 L265P. Testing for this mutation helps confirm WM and rule out similar diseases.
- CXCR4 Mutation: About 30% of patients have another mutation called CXCR4, which can affect how well treatments work.

Step 3: Imaging Tests

CT Scans or X-rays: These pictures help doctors see if lymph nodes, the spleen, or liver are swollen.
Eye Exam: High IgM levels can thicken the blood, leading to vision problems, so an eye check may be needed.

Other Diseases to Rule Out

WM can look like other conditions, such as:

IgM-MGUS: A harmless version of high IgM that doesn’t need treatment.
Multiple Myeloma: Another blood cancer affecting different cells.
Other Lymphomas: Cancers that involve different types of abnormal cells. Genetic tests and bone marrow results help doctors tell these apart.

Why Genetic Testing Matters

MYD88: Patients with this mutation often respond well to drugs like ibrutinib, which target cancer cells.
CXCR4: If this mutation is present, treatment might need to be adjusted, as it can make the disease harder to control.

What Happens After Diagnosis?

Doctors use the test results to decide on treatment. Factors like symptom severity, age, and overall health help guide whether a patient needs immediate therapy or just monitoring.

Management Challenges

1. Determining When to Initiate Treatment

A central challenge in WM management is deciding when to start therapy. Approximately 25–40% of patients are asymptomatic at diagnosis and may not require immediate treatment3 12. Current guidelines recommend delaying therapy until symptoms such as anemia, hyperviscosity, neuropathy, or organomegaly develop3 12. However, distinguishing between active disease requiring intervention and indolent cases remains subjective. For example, some patients with mild anemia or fatigue may prefer early treatment to improve quality of life, while others opt for watchful waiting to avoid therapy-related side effects3 6. This balancing act requires careful patient-clinician communication and regular monitoring.

2. Lack of Standardized Therapies

WM has no universally accepted first-line treatment, and no therapy has been specifically approved by regulatory agencies for this condition4 6. Treatment choices depend on factors such as age, comorbidities, and genetic markers, leading to variability in clinical practice. For instance:

Chemotherapy (e.g., bendamustine) and anti-CD20 monoclonal antibodies (e.g., rituximab) are commonly used but yield complete responses in only 8–10% of cases.
Bruton tyrosine kinase (BTK) inhibitors like ibrutinib show promise, particularly in patients with MYD88 mutations, but CXCR4 mutations can cause resistance.
Stem cell transplants, though potentially curative, are underutilized due to toxicity risks and limited accessibility.

The absence of head-to-head trials comparing these options complicates decision-making, leaving clinicians to rely on retrospective data and expert consensus.

3. Genetic Variability and Personalized Treatment

WM’s molecular heterogeneity poses significant challenges. While MYD88 L265P mutations occur in 90% of cases, approximately 30–40% of patients also harbor CXCR4 mutations, which are linked to advanced disease and poorer responses to BTK inhibitors. Additionally, 5–10% of patients lack MYD88 mutations entirely, often presenting with aggressive disease resembling diffuse large B-cell lymphoma. Testing for these mutations is critical but not universally available, particularly in resource-limited settings. Even when genetic data are obtainable, translating them into tailored therapies remains an evolving science.

4. Long-Term Treatment Toxicity

Many WM therapies carry risks that accumulate over time:

BTK inhibitors may cause atrial fibrillation, bleeding, or secondary cancers.
Rituximab can exacerbate IgM levels temporarily (“IgM flare”), worsening hyperviscosity or neuropathy.
Alkylating agents (e.g., cyclophosphamide) and nucleoside analogs (e.g., fludarabine) increase the risk of myelodysplasia or transformation to aggressive lymphoma.

These toxicities are particularly concerning for older patients, who represent the majority of WM cases. Balancing efficacy with safety requires ongoing dose adjustments and supportive care.

5. Financial and Access Barriers

The shift toward targeted therapies has raised treatment costs. For example, Medicare payments for chemotherapy in WM nearly tripled between 1994 and 2013, driven by the adoption of rituximab and BTK inhibitors. In low-income regions, access to genetic testing, novel drugs, or stem cell transplants is limited, forcing reliance on older, less effective therapies. Even in high-resource settings, insurance denials or high copays can delay care, impacting outcomes