Complications
The annual rate of progression from MGUS to multiple myeloma or other lymphoproliferative malignancies is about 1%.[10][11] Patients who have MGUS with monoclonal proteins <1.5 g/dL and with a normal serum free light chain ratio account for about 40% of all cases and have only a 2% lifetime probability of developing multiple myeloma or related malignancies. [29] Those with IgG or IgA MGUS may progress to multiple myeloma, but the exact mechanisms are not clear.
Diagnosis is based on the presence of well-defined criteria that help distinguish multiple myeloma from other plasma cell dyscrasias and B-cell malignancies associated with paraprotein production. Initial diagnostic workup includes a full history and physical exam with key diagnostic tests providing a definitive diagnosis.[31]
Between 5% and 10% of multiple myeloma patients have an indolent course, with no symptoms or end-organ damage, and do not require immediate therapy. Initiating treatment in these patients can be deferred until active disease appears. However, if a patient presents with active multiple myeloma, treatment is indicated at the time of diagnosis.
Patients with MGUS are at increased risk for progression to Waldenström macroglobulinemia.[25] About 15% of cases feature lymphadenopathy and splenomegaly.
Any symptoms and signs of hyperviscosity (such as skin and mucosal bleeding, retinopathy with visual disturbance, and neurologic symptoms such as headache, dizziness, and vertigo) are important clinical manifestations and should be treated urgently with plasmapheresis and chemotherapy.
Patients with IgG or IgA MGUS may progress to light chain amyloidosis.[23] It usually presents with unexplained weight loss, fatigue, and edema resistant to diuretic therapy. Immunofixation of the serum and urine confirms the presence of monoclonal immunoglobulin, along with an abnormal free light chain ratio in systemic light chain amyloidosis. Biopsy verification of amyloid deposits is essential.
Definitive treatment of systemic light chain amyloidosis includes myeloablative high-dose chemotherapy with stem cell reconstitution in selected patients, or chemotherapy.
Patients with IgM MGUS are at increased risk of progression to chronic lymphocytic leukemia, a hematologic malignancy with variable course that occurs with increasing age.[23] It usually presents with asymptomatic lymphadenopathy or with absolute lymphocytosis as an incidental finding on routine complete blood count (CBC). Diagnosis is made by CBC with differential, blood smear showing smudge cells, and flow cytometry.
Clinical and laboratory criteria determine the treatment approach and prognosis. Treatment options include a conservative (watch and wait) approach or chemotherapy.
Patients with IgM MGUS are at increased risk of progression to non-Hodgkin lymphoma.[23] Diffuse large B-cell lymphoma is the most common type of lymphoma. The malignant phenotype in non-Hodgkin lymphoma is due to abnormal gene mutations, which occur during lymphocyte production, maturation, or action. Mutations lead to growth advantage and expansion of a monoclonal population of malignant lymphocytes. The type of lymphoma depends on the stage of lymphocyte production, maturation, or action at which mutation occurs.
Diagnosis is confirmed by tissue (e.g., lymph node, bone marrow, skin) sampling, and treatment is based on the histologic subtype and severity of symptoms at presentation. R-CHOP-21 (rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone) is the most commonly used chemotherapy regimen.
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