Macroglobulinemia

Most patients are asymptomatic, but some present with anemia or manifestations of hyperviscosity syndrome: fatigue, weakness, skin deposits, skin and mucosal bleeding, visual disturbances, headache, symptoms of peripheral neuropathy, and other changing neurologic manifestations. An increased plasma volume can precipitate heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more . Cold sensitivity, Raynaud syndrome Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more , or recurring bacterial infections may occur.

Examination may disclose lymphadenopathy, hepatosplenomegaly, and purpura (which rarely can be the first manifestation). Marked engorgement and localized narrowing of retinal veins, which resemble sausage links, suggests a hyperviscosity syndrome. Retinal hemorrhages, exudates, microaneurysms, and papilledema occur in late stages.

Macroglobulinemia is suspected in patients with symptoms of hyperviscosity or other typical symptoms, particularly if anemia is present. However, it is often diagnosed incidentally when protein electrophoresis reveals an M-protein that proves to be IgM by immunofixation.

Laboratory evaluation includes tests used to evaluate plasma cell disorders (see Multiple Myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones that cause... read more ) as well as measurement of cryoglobulins, rheumatoid factor, and cold agglutinins; coagulation studies; and a direct antiglobulin (Coombs) test.

Moderate normocytic, normochromic anemia, marked rouleau formation, and a very high erythrocyte sedimentation rate (ESR) may occur. Leukopenia, relative lymphocytosis, and thrombocytopenia are occasionally found. Cryoglobulins, rheumatoid factor, or cold agglutinins may be present. If cold agglutinins are present, the direct Coombs test usually is positive. Various coagulation and platelet function abnormalities may occur. Results of routine blood studies may be spurious if cold agglutinins, cryoglobulinemia, or marked hyperviscosity is present. Normal immunoglobulins are decreased in half of the patients.

Immunofixation electrophoresis of concentrated urine frequently shows a monoclonal light chain (more often kappa [κ]), but gross Bence Jones proteinuria is unusual.

Bone marrow studies show a variable increase in plasma cells, lymphocytes, plasmacytoid lymphocytes, and mast cells. Periodic acid-Schiff–positive material may be present in lymphoid cells. Lymph node biopsy, done if bone marrow examination is normal, is frequently interpreted as diffuse well-differentiated or plasmacytic lymphocytic lymphoma.

Plasma viscosity is measured to confirm suspected hyperviscosity. When hyperviscosity is present, plasma viscosity is usually > 4.0 milliPascal-second (normal, 1.4 to 1.8 milliPascal-second) (1 Diagnosis reference Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurrent infections... read more ). Retinal fluorescein angiography can also be used to demonstrate hyperviscosity.

The course is variable, with a median survival of 7 to 10 years. Age > 60 years, anemia, and cryoglobulinemia predict shorter survival (for review, see [1] Treatment references Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurrent infections... read more ).

Often, patients require no treatment for many years (1) Treatment references Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurrent infections... read more . If hyperviscosity is present, initial treatment is plasma exchange Plasma exchange Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more , which rapidly reverses bleeding as well as neurologic abnormalities. Plasma exchange often needs to be repeated.

Corticosteroids may be effective in reducing the tumor load. Treatment with oral alkylating drugs may be indicated for palliation, but bone marrow toxicity can occur. Nucleoside analogs (fludarabine and 2-chlorodeoxyadenosine) produce responses in large numbers of newly diagnosed patients but have been associated with a high risk of myelodysplasia and myeloid leukemia.

Rituximab can reduce tumor burden without suppressing normal hematopoiesis. However, during the first several months, IgM levels may increase, requiring plasma exchange. The combination of this monoclonal antibody with bendamustine is highly effective.

The proteasome inhibitors bortezomib and carfilzomib and the immunomodulating agents thalidomide, lenalidomide, and pomalidomide are also effective in this cancer.

BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, have shown high levels of activity. Acalabrutinib and zanubrutinib cause less toxicity than ibrutinib. MYD88 and CXCR4 mutational status can predict the likelihood of response to these drugs.

The BCL2 (BCL2 apoptosis regulator) inhibitor venetoclax has shown significant clinical activity (2 Treatment references Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurrent infections... read more ).

Two other classes of drugs, PI3 kinase inhibitors such as idelalisib, and mTOR inhibitors, including everolimus, have been used effectively for previously treated patients.