Clinical Challenges: Signs, Symptoms, and Diagnosis of Waldenström Macroglobulinemia

Waldenström macroglobulinemia is a rare lymphoplasmacytic lymphoma, with about 1,000 to 1,500 new U.S. cases diagnosed annually.

The disease is characterized by the presence of an abnormally large number of B lymphocytes, which is accompanied by the production of excessive amounts of immunoglobulin M (IgM).

The signs and symptoms of Waldenström usually begin gradually, and the disease is often suspected as a result of incidental lab findings or abnormal imaging results that prompt further testing, according to Jorge Castillo, MD, of the Bing Center for Waldenström Macroglobulinemia at the Dana Farber Cancer Institute in Boston.

If a clinician has a high enough suspicion that the patient has Waldenström, it is a relatively easy disease to diagnose, Castillo said. “The more complicated part is thinking about Waldenström as a diagnosis in the first place.”

Castillo’s department is one of the biggest practices for Waldenström in the country — with two full-time physicians. “In my practice, at least one-third of my patients are asymptomatic at the time of initial diagnosis,” said Castillo.

Patients who are symptomatic at presentation can have a variety of symptoms, with anemia the most common, he said. That can be manifested in fatigue, low exercise capacity, fever, night sweats, and weight loss.

Since Waldenström cells produce IgM in excess quantity, a classic symptom of the disease is hyperviscosity syndrome, which is marked by a number of neurological symptoms, mucosal bleeding, and visual problems. If untreated, it could lead to life-threatening complications such as gastrointestinal bleeding, thromboembolic events, myocardial infarction, as well as permanent vision loss.

Initial treatment of Waldenström involves addressing the symptoms due to hyperviscosity syndrome, with the first step likely to be plasmapheresis to reduce serum IgM levels.

“The way I conceptualize plasmapheresis is that Waldenström is like a house that is on fire,” said Joshua Richter, MD, of Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City. “The Waldenström itself is the fire, the paraprotein causing the hyperviscosity is the smoke, and sometimes you need to wave the smoke away to find out how to best put the fire out. With plasmapheresis, you are essentially getting rid of the smoke so you can deal with the fire.”

“The problem is if you just wave away the smoke, and don’t treat the fire, the smoke is going to come right back,” said Richter. “So if you are going to exchange the patient, you are going to exchange them for 2 to 3 days, and then hit them with some type of treatment.”

Another classic symptom is peripheral neuropathy causing numbness, tingling, pain, or stabbing and shooting sensations. Castillo explained that most likely it will be first experienced in the toes or feet, then typically move up to the knee. Then if the neuropathy is severe enough, it can begin to involve the hands and fingers.

“Other symptoms can include enlargement of the lymph nodes, liver, or spleen; pleural effusions; and even some meningitis has been associated with Waldenström,” Castillo said. “These clinical presentations are very diverse.”

Diagnosis begins with blood counts and checking protein levels, Castillo noted. A serum protein electrophoresis (SPEP) test measures the total amount of abnormal immunoglobulins in the blood, while another test — immunofixation electrophoresis — is then used to determine the type of antibody that is abnormal, which in the case of Waldenström is IgM.

While elevated IgM points to a diagnosis of Waldenström, a bone marrow biopsy can further identify the disease. The diagnosis can be further refined with genetic testing to identify whether the patient has a MYD88 mutation — present in about 90% of Waldenström patients — or the less frequent CXCR4 mutation.

“So if a patient comes to my clinic with a diagnosis of Waldenström, a bone marrow biopsy showing lymphoplasmacytic cells, and has these gene mutations, I think the likelihood of a patient having Waldenström is over 99%,” Castillo said.

So if a patient is diagnosed, when does treatment start?

Much will depend on whether a patient is symptomatic enough to need treatment, Castillo said, explaining that if a patient is asymptomatic, or symptoms are mild enough that quality of life is unaffected, surveillance is the best option.

“There is no data showing we are better off treating those patients sooner. We don’t prolong life, we don’t cure them, and although treatments are effective, they do have side effects,” he said. “If patients have a symptom or symptoms that are affecting daily life, and we are convinced that is caused by the disease, then we recommend treatment.”

Richter said the majority of Waldenström patients he follows are not on therapy, and that since the disease tends to be indolent, patients can be monitored for a very long time, even with fairly high IgM levels. He noted that he has some patients who sit at IgM levels in the 4,000-6,000 mg/L range, yet have no anemia, hyperviscosity, or neuropathy.

These are patients who don’t need treatment, and may not need treatment for years, he said. “And the best part of that is that while our therapies are great, you would rather get the therapies of 2021 than those of 2010, and if you delay treatment a few more years you may be able to get the latest and greatest therapies from 2030.”

When monitoring these patients, Richter said he gets “granular,” which means monthly monitoring to ensure their levels aren’t shooting up. If they are physiologically stable, that interval can extend to every 2 to 3 months.

“It is also really important, especially in patients with very high IgMs, that they get yearly ophthalmologic exams,” he said. “These patients can get subtle changes in the microvasculature of the eye.”

Additionally, a thorough evaluation for amyloidosis should be conducted in these patients, Richter said. While infrequent in Waldenstrom’s macroglobulinemia patients, it is a serious complication to be aware of.

This means 24-hour urine tests to make sure there is no sign of renal amyloid, blood tests to check for cardiac amyloid, as well as liver examinations to make sure there is no hepatosplenomegaly and no elevation in liver function tests, Richter said, “really making sure there is no evidence of any systemic amyloidosis.”