Like many health conditions, multiple myeloma can have symptoms that look like other illnesses. This includes conditions such as monoclonal gammopathy of undetermined significance (MGUS), POEMS syndrome, and Waldenström’s macroglobulinemia (WM).

Telling the difference between Waldenström’s macroglobulinemia and multiple myeloma is a little bit like differentiating between jam and jelly. They may seem the same at first, but a closer look reveals some key differences.

While small differences may not matter as much when it comes to what you spread on your bread, telling WM from multiple myeloma has life-changing consequences. The right diagnosis is a crucial first step in getting the best cancer care. Here’s what you should know.

What Are Multiple Myeloma and Waldenström’s Macroglobulinemia?

Multiple myeloma is a cancer of plasma cells, which are a key part of the immune system. Plasma cells develop from B lymphocytes (B cells) and produce antibodies to help fight infections. In multiple myeloma, plasma cells start growing out of control, crowding out healthy blood cells in the bone marrow (the spongy tissue inside bones) and making abnormal proteins that can damage organs.

Waldenstrom’s macroglobulinemia, also called lymphoplasmacytic lymphoma, is a type of non-Hodgkin lymphoma (NHL) that starts in the B cells. Unlike in multiple myeloma, WM cancer cells include a mix of lymphocytes, plasma cells, and plasmacytoid lymphocytes (cells that share features of both B cells and plasma cells). This overlap explains why WM shares some similarities with multiple myeloma.

In both diseases, cancerous cells build up in the bone marrow, making it harder for the body to produce healthy red and white blood cells.

Both conditions also lead to the production of abnormal antibodies, but there is a key difference: WM primarily produces IgM antibodies, which are larger and more likely to cause hyperviscosity syndrome (a condition where thickened blood slows circulation). Multiple myeloma typically produces IgG antibodies, though some cases involve IgA or IgD, which can occasionally contribute to hyperviscosity.

How Do the Symptoms Differ?

Because they’re both blood cancers, Waldenström’s macroglobulinemia and multiple myeloma can have similar symptoms, including:

• Fatigue (extreme tiredness that does not improve with rest)
• Weight loss
• Loss of appetite
• Neuropathy (nerve damage causing tingling, numbness, or a "pins-and-needles" sensation)
• Confusion
• Anemia (low red blood cell count, leading to weakness and shortness of breath)

Hyperviscosity syndrome is much more common in WM because IgM antibodies are large and tend to accumulate in the blood at high levels. Multiple myeloma can also cause hyperviscosity, but this is rare and typically linked to excess IgA or IgG antibodies. Regardless of the cause, symptoms include severe headaches, dizziness, blurred vision, skin discoloration, and bleeding problems.

If bone pain is one of the first symptoms you notice, multiple myeloma is the more likely cause. Bone pain is one of the most common early symptoms of multiple myeloma because the cancer causes lytic bone lesions — weak areas in the bone that increase the risk of fractures (breaks). However, bone pain is rare in Waldenström’s macroglobulinemia, since the disease does not typically attack the bones in the same way.

It’s possible to have WM or multiple myeloma without noticeable symptoms — this is known as asymptomatic WM or smoldering multiple myeloma, respectively. In these cases, doctors usually recommend regular monitoring, rather than starting immediate treatment.

Which Tests Can Confirm the Diagnosis?

Although WM and multiple myeloma share symptoms, healthcare providers can distinguish between them through specific tests. For both conditions, a thorough diagnostic process typically includes:

• Blood tests to check for abnormal protein levels and blood cell counts
• Bone marrow biopsy to examine cancerous cells and determine their type
• Genetic testing to identify mutations (changes) linked to WM or MM
• Imaging, such as X-rays, MRI, CT scans, or positron emission tomography (PET) scans, to detect bone damage or tumor growth

Among these, bone marrow biopsy and genetic testing are especially important for differentiating WM from multiple myeloma. They help identify the specific types of abnormal cells present and which antibodies are being overproduced.

Blood Tests

Certain blood tests, such as serum protein electrophoresis (SPEP) and immunofixation, help detect abnormally increased antibodies produced by the plasma cells in both WM and multiple myeloma. As described earlier, in WM, these antibodies are of the IgM class, while in MM, they are most commonly IgG.

Bone Marrow Biopsy

Blood tests can show signs of both WM and multiple myeloma, but only a bone marrow biopsy can confirm the correct type of cancer. During a bone marrow biopsy, a healthcare professional removes a sample of tissue from your bone marrow and looks at it closely under a microscope.

In order to be diagnosed with WM, at least 10 percent of the cells from your bone marrow sample must be lymphoplasmacytoid lymphoma cells. If you have multiple myeloma, the biopsy will show that at least 10 percent of the cells in the bone marrow are plasma cells. These key diagnostic differences can help healthcare providers distinguish between the two conditions.

Genetic Testing

Healthcare providers can also do genetic testing to tell Waldenström’s macroglobulinemia and multiple myeloma apart. Genetic differences are especially important when trying to distinguish IgM multiple myeloma — an extremely rare type of multiple myeloma — from WM because both cause high IgM levels.

There’s a specific gene mutation called MYD88 L265P that’s found in around 90 percent of people with WM but in less than 5 percent of people with IgM multiple myeloma. Additionally, sometimes people with multiple myeloma who have a certain genetic change, called t(11;14), may have cells that look similar to those in WM. However, this genetic change is not found in WM.

The Role of a Genetic Counselor

Having all of this genetic information helps providers make a diagnosis. If you decide to have genetic testing, a genetic counselor can help make sense of the genetic information you find out. They can also help you decide if you should share this information with your close relatives who might have similar risk factors for various conditions.

If you’re worried that you or your loved one may have been misdiagnosed, you can talk to your healthcare provider or a blood cancer specialist. Feel free to ask the oncologist questions to learn more about the difference between these two similar conditions.

How Do the Treatments Compare?

Knowing the differences between Waldenström’s macroglobulinemia and multiple myeloma is essential because they require different treatment approaches.

There are several preferred drug therapies for Waldenström’s macroglobulinemia. The most commonly used drug to treat WM is rituximab (Rituxan), a monoclonal antibody that helps kill lymphoma cells. Rituximab is usually combined with other drugs.

The treatment for multiple myeloma, on the other hand, involves three or four types of drugs. Here are some common drug combinations that may be prescribed:

• Bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone
• Carfilzomib (Kyprolis), lenalidomide, and dexamethasone
• Daratumumab (Darzalex), bortezomib, lenalidomide, and dexamethasone
• Daratumumab, lenalidomide, and dexamethasone

Along with these drug therapy differences, the use of other treatment strategies also distinguishes WM and multiple myeloma. For example, stem cell transplant is a common option for multiple myeloma but is rarely used to treat WM.

Is There a Difference in Prognosis?

The prognosis (outlook) also differs between these conditions. The survival rate can give you an estimate of how many people are still alive after a certain length of time after diagnosis. The relative survival rate, which compares people with cancer to those who don’t have that cancer type, provides a way to estimate cancer survival.

The average relative five-year survival rates are 78 percent for Waldenström’s macroglobulinemia and 62 percent for multiple myeloma. A five-year relative survival rate of 78 percent means that people with WM are about 78 percent as likely as people who don’t have this disease to live at least five years after diagnosis. Additionally, the prognosis of multiple myeloma depends on many factors such as albumin levels, lactate dehydrogenase (LDH) levels, and genetic mutations.

It’s important to remember that every person’s situation is unique and different factors influence survival rate. Statistics can’t always predict the future. The current information on survival rates is based on data from at least five years ago, so this doesn’t take into account any new treatments in the last five years. To learn more about survival rates, talk to your healthcare provider.

Talk With Others Who Understand

MyMyelomaTeam is the social network for people with multiple myeloma and their loved ones. On MyMyelomaTeam, more than 27,000 members come together to ask questions, give advice, and share their stories with others who understand life with multiple myeloma.

Have you been diagnosed with multiple myeloma? Are you concerned that you may have Waldenström’s macroglobulinemia? Share your experiences in the comments below, start a conversation by posting on your Activities page, or connect with like-minded members in Groups.