Waldenstrom Macroglobulinemia (WM) is a very rare blood cancer. The disease’s name is from Swedish physician Jan Waldenstrom, who first reported three cases of WM in 1944 and characterized the disease by an overproduction of the immunoglobulin IgM (Immunoglobulin M), a large or macro immunoglobulin.

Like other rare blood cancers, the treatment environment for WM has been poor until recently. That changed on May 1. The second-generation Bruton tyrosine kinase (BTK) inhibitor, Brukinsa (zanubrutinib), a targeted therapy for blood cancers, won reimbursement as a treatment for WM.

Korea Healthlog, a sister paper of Korea Biomedical Review, talked to Dr. Byun Ja-min, a professor of hematology-oncology at Seoul National University Hospital, to listen to the changing treatment of WM.

Question: WM is a rare blood cancer between lymphoma and multiple myeloma. What is it exactly?

Answer: Blood cancers are divided into lymphoid and myeloid. The difference between the two depends on the level at which lymphocytes develop and mature. Leukemia is the most immature form of the disease. Lymphoma occurs when the lymphocytes are more mature, and multiple myeloma occurs when the plasma cells are abnormal. However, WM, which belongs to lymphoplasmacytic lymphoma (LPL), has both characteristics.

In WM, immunoglobulin M (IgM), the largest and heaviest immunoglobulin, is exceptionally high. When IgM travels in the blood, it can easily clog blood vessels. This is called hyperviscosity syndrome (HVS). The blood becomes sticky, leading to strokes and numbness in the hands and feet. It can also cause problems with the retinal blood vessels made up of microvessels, leading to retinal disease.

And if these bad cells get into the bone marrow and cause problems, the bone marrow may not be able to do its job and make white blood cells or hemoglobin properly. This can lead to anemia, thrombocytopenia, and infectious diseases. Other symptoms can be lymphomas, such as unexplained weight loss of more than 10 kilograms in six months, night sweats or fever, or enlarged lymph nodes.

Q: Are there any known causes of WM?

A: No one knows for sure. We know that WM is caused by abnormalities in lymphoid plasma cells, which make a lot of unnecessarily heavy proteins, and those proteins cause problems. It's also known that specific genetic mutations are associated with a slightly worse prognosis, but that's unclear.

Q: What are the trends in the incidence of WM in Korea, and what age groups are affected?

A: The incidence (number of people newly diagnosed with the disease within a given period) was 0.03 per 100,000 people in 2003, but it jumped to 0.1 in 2016, a threefold increase in 13 years. The prevalence (number of people who can have the disease) of WM has increased tenfold, from 0.04 per 100,000 in 2003 to 0.4 in 2016. As is the case with many chronic diseases, it gradually increases.

Compared to other countries, this is still very low in Korea. It's unclear if this is due to racial differences or other causes we don't know much about. This is something that needs to be tracked further. Also, WM seems more prevalent in people between 50 and 70 because it occurs in older people. So far, we don't know of any cases in children.

Q: Is WM well-diagnosed? What will be helpful for the public and healthcare providers to know about the disease to make diagnosis more effective?

A: In the past, when there was less awareness of WM, it was underdiagnosed, but since at least 2015, it hasn't been missed. A good thing for the public to know is that if you have a high protein level in your blood at a health checkup, it is a good idea to run further tests and not overlook it. This is because protein levels are often elevated in multiple myeloma, even if it's not WM.

Your healthcare provider can check for paraproteins (immunoglobulins made by abnormally proliferating clones of tumor plasma cells) and act according to your subtype to help detect it sooner. This is especially true when protein levels are high, and albumin is low. The albumin vs. globulin (A/G) ratio is often a sign of trouble when the ratio of albumin to globulin is reversed, so keep an eye out for this.

Q: We understand that 30-40 percent of patients diagnosed with WM are asymptomatic or have very mild symptoms, so they are monitored in the clinic every three to four months. How are these patients diagnosed, and how are other WM patients diagnosed?

A: Patients with asymptomatic or mild WM are almost always detected during regular checkups. If they have unexplained anemia or elevated serum protein levels, further testing is done, and they are diagnosed. Other symptomatic cases of WM are usually due to enlarged lymph nodes or various types of cytopenias.

Q: Typically, cancer is treated aggressively from the early stages, but patients with asymptomatic or mild WM are not treated. Why?

A: WM is not treated just because it is diagnosed. We treat it only when there is a reason to do so, such as when there is prominent bone marrow infiltration that is causing multiple problems or symptoms that are causing problems with quality of life.

Otherwise, if you don't have any symptoms, you can wait and see because treating it after you have symptoms is the same as treating it when you don't. This is the characteristic of WM and other chronic lymphocytic diseases. In addition to WM, chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma can be symptomatic or asymptomatic, but the standard of care is not to treat the latter case.

Q: We know that some asymptomatic WM patients may experience worsening symptoms. Is there a follow-up strategy to ensure they are treated in time?

A: Education of patients. We tell them if they experience specific symptoms and tell them to come immediately. As for follow-up, it varies from person to person, but I usually see them every three to four months and ask them how they've been doing. I ask about subjective symptoms, like weight loss, night sweats, or feeling too tired, things we wouldn't know if they didn't tell us.

I also do many tests at each appointment to see how their objective numbers have changed. Typical blood tests include white blood cells, red blood cells, platelet counts, and kidney and liver levels. Since IgM causes WM, we also check how much IgM has changed, and if there are any abnormalities, we may do additional imaging tests or consult an ophthalmologist to perform an eye exam.

Q: We heard that the treatment landscape for WM has improved significantly with the reimbursement of a WM-targeted therapy, a BTK inhibitor, in May. What is the new treatment environment for WM?

A: WM treatment is divided into primary and secondary treatment, and there are not many treatments that can be covered by health insurance in primary treatment. Since WM has the characteristics of both lymphoma and multiple myeloma, we use a combination of drugs for those diseases. The mainstay is rituximab, which is not covered by insurance.

But rituximab is not very expensive, and it only needs to be given four to six times, so chances are half-and-half patients can or cannot get rituximab. If you don't get rituximab, you're either losing your hair or using a cytotoxic chemotherapy drug with severe side effects. However, because of the difference in progression-free survival (PFS), rituximab-based treatment is much better than other options, and the side effects are less severe than cytotoxic chemotherapy, so bendamustine + rituximab is recommended for uninsured patients.

The situation for relapse after this first-line treatment was not good in the past, but the recent coverage of BTK inhibitors has changed the game. Patients who relapse can now use Brukinsa as a covered option. Before the reimbursement of Brukinsa, we prioritized conducting clinical trials for new drugs. Without clinical trials, we treated it with other cytotoxic drugs.

Q: We are curious about WM’s outcomes when treated with Brukinsa.

A: Zanubrutinib was directly compared to ibrutinib in a phase 3 study and demonstrated significantly better treatment outcomes. The primary efficacy endpoint was different (the proportion of patients achieving a complete response and excellent partial response was 29 percent with zanubrutinib vs. 20 percent with ibrutinib), and progression-free survival was significantly different (the event-free rate at 18 months among patients achieving a complete response and outstanding partial response was 90 percent with zanubrutinib vs. 64 percent with ibrutinib).

The adverse event profile was also favorable for zanubrutinib in cardiac toxicity. This is why zanubrutinib has been elevated to Category 1 (highest priority) in the U.S. National Comprehensive Cancer Network (NCCN) guidelines.

Q: We understand that the known cardiac toxicities of BTK inhibitors include atrial fibrillation and hypertension, but how much difference is there between the second-generation BTK inhibitor zanubrutinib and the first-generation BTK inhibitors?

A: In addition to atrial fibrillation and hypertension, there are also ventricular problems, and with BTK inhibitors, there is a risk of bleeding, and zanubrutinib is a little lower in that regard. For atrial fibrillation, ibrutinib is about 1 percent, and zanubrunitib is 0.1 percent, a big difference. Hypertension was 1.2 percent for ibrutinib, 0.7 percent for zanubrutinib, and major bleeding was 7 percent for ibrutinib and 4 percent for zanubrutinib.

Q; In the U.S., Brukinsa is recommended as a first-line treatment for WM. Do you see a similar change in the Korean WM treatment?

A: BTK inhibitors are good drugs but expensive because you must keep taking them once you start. It would be great to see it become a first-line treatment, but we still need to consider it.

Chronic Lymphocytic Leukemia (CLL) is treated similarly to WM, and BTK inhibitors work very well in CLL. However, if you use it continuously, resistance and compliance issues exist. So, it's an area that we're investigating to see if we can find people who can take other agents in combination and eventually stop.

Similarly, WM remains to be seen if a CD20 antibody (rituximab) can be used in combination with BTK inhibitors for a period and then discontinued. If so, it would completely change the treatment paradigm for WM, including first-line treatment.

For now, in the absence of second-line treatment options, we should be grateful for the option of Brukinsa. It seems premature to discuss it as a first-line treatment in Korea, but we are moving in that direction in the overall treatment and must move to that destination.

Q: What is your message to people with WM and their caregivers?

A: WM is not a disease that needs to be treated as soon as it is diagnosed. Even if you are very anxious, I hope you don't worry too much when your doctor tells you you can be monitored. I hope that patients being treated will talk to their doctors and manage it well because promising new drugs are coming out. It is a disease that can be treated well if you take the medication on time.