Waldenström Macroglobulinemia: A Plain-Language Guide

Waldenström macroglobulinemia is the same disease as lymphoplasmacytic lymphoma. NCI's PDQ summary on adult non-Hodgkin lymphoma treats them under one heading.

The link between the two names is a protein. PDQ says lymphoplasmacytic lymphoma usually comes with a monoclonal serum paraprotein of the IgM type. That combination is what earns the name Waldenström macroglobulinemia. A paraprotein is an abnormal antibody, made in bulk by one clone of cells.

PDQ describes where the disease sits. Most patients have it in the bone marrow, the lymph nodes, and the spleen. Some develop hyperviscosity syndrome. That means the blood grows too thick to flow well.

Most patients with Waldenström macroglobulinemia carry a variant in the MYD88 gene. PDQ notes that some pathologists consider it indicative of the disease.

PDQ also flags a caution that matters at diagnosis. Other lymphomas can be associated with serum paraproteins too, so an IgM protein alone does not settle the question.

And it names one test that is easy to overlook. PDQ says patients with lymphoplasmacytic lymphoma should be checked for hepatitis C virus infection.

PDQ states that patients without symptoms can be monitored for evidence of disease progression, without immediate need for chemotherapy. That is not a delay in care. It is the recommended approach for that group.

PDQ lists three factors associated with symptoms that require therapy.

• Age 70 years or older.
• Beta-2-microglobulin of 3 mg/dL or more.
• Increased serum LDH, meaning lactate dehydrogenase.

A separate prognostic model, which PDQ describes as externally validated, uses age, albumin, and LDH.

This is one of the few places in lymphoma care where a single lab value routes the treatment.

PDQ says serum viscosity is measured against water. Above four, a patient may have symptoms of hyperviscosity. Plasmapheresis is useful there for sudden, short-term symptoms. PDQ names three: retinopathy, congestive heart failure, and central nervous system trouble. Plasmapheresis filters the plasma to strip out the excess protein. PDQ says it can also be paired with chemo for longer control.

Because those symptoms come on as emergencies, it is worth knowing them before they happen. Call 911 if you have sudden blurred or lost vision, confusion, slurred speech, weakness on one side, a seizure, or severe shortness of breath. Nosebleeds or bleeding gums that will not stop are also a reason to call your team the same day. Hyperviscosity is treated urgently, and plasmapheresis works quickly once it is started.

What about symptomatic patients whose viscosity is four or lower? PDQ says the usual approach is chemoimmunotherapy, or biologically directed therapy.

PDQ reports response rates of 60% to 80% in untreated patients given rituximab. But it attaches a warning to that number.

Serum IgM has to be watched closely. The paraprotein can rise suddenly at the start of therapy. PDQ says that rise can be avoided in two ways. One is an alkylating agent at the same time, such as cyclophosphamide. The other is a proteasome inhibitor, such as bortezomib or ixazomib. PDQ notes that bortezomib, dexamethasone, and rituximab together have been used without that rebound.

That detail explains something confusing. A rising IgM number soon after starting rituximab is not automatically a sign that treatment is failing.

PDQ lists several first-line options. Zanubrutinib with rituximab. Ibrutinib with rituximab. Rituximab alone. Nucleoside analogues. And alkylating agents, alone or in a combination. Zanubrutinib and ibrutinib are BTK inhibitors. BTK is short for Bruton tyrosine kinase.

Two randomized trials give the numbers.

The first enrolled 150 symptomatic patients. Some were untreated, some were relapsing. One arm got ibrutinib with rituximab. The other got rituximab with a placebo. At a median follow-up of 50 months, the 4.5-year PFS rate was 68% in the ibrutinib arm. It was 25% in the placebo arm. The hazard ratio was 0.25, with a P value below .0001. Overall survival at 30 months was no different, at 92% to 94%. PDQ grades this Level of evidence B1.

The second compared zanubrutinib with ibrutinib. It enrolled 164 patients with relapsed disease and 38 who were untreated. At a median follow-up of 44.4 months, PFS was similar in both, at 70% to 78%. Overall survival was similar too, at 85% to 87%. The difference was in side effects. The zanubrutinib group had fewer cases of atrial fibrillation, 1 against 11. It also had 50% fewer cases of high blood pressure. PDQ grades this Level of evidence C3.

Read together, those trials say something practical. The choice between the two BTK inhibitors turns on heart and blood pressure effects. It does not turn on how well they control the lymphoma.

Two complications get their own treatment paths in PDQ.

Cold agglutinin disease is antibody-driven destruction of red blood cells, set off by cold. PDQ says rituximab, bendamustine, and steroids are often used. It notes that a heated room is sometimes needed. That is for patients whose cold agglutinins switch on with even minor chilling. Sometimes lymphoma-directed treatment does not work. PDQ says sutimlimab can reduce red cell destruction in that case. It is an IgG4 antibody that blocks part of the complement pathway.

PDQ also reports a small series on ibrutinib. All 13 patients reached clinical remission, whatever their MYD88 status. They had cold-antibody hemolytic anemia with acrocyanosis. Acrocyanosis is a bluish color of the hands and feet.

Bing-Neel syndrome is the rare case where the lymphoma involves the central nervous system. PDQ reports an 85% response rate with ibrutinib in an anecdotal series of 28 patients, graded Level of evidence C3.

PDQ makes one point about sequencing that is worth raising early.

Myeloablative therapy with stem cell support is still under study. That covers both autologous and donor cells. PDQ says candidates for it should avoid long-term alkylating agents. The same goes for purine nucleoside analogues. The reason is specific. Those drugs can deplete blood-forming stem cells. They can also raise the risk of myelodysplasia or acute leukemia.

PDQ also reports a trial in patients who relapsed after an alkylating agent. It assigned 92 patients at random. One arm got fludarabine. The other got cyclophosphamide, doxorubicin, and prednisone. Relapse-free survival favored fludarabine, with a median of 19 months against 3 months. Overall survival showed no difference.

The wider family here is described in lymphoma. Test details are covered in diagnosis questions. Drug choices are covered in treatment questions.

• NCI PDQ: adult non-Hodgkin lymphoma, HP version