How to Diagnose Monoclonal Gammopathy of Undetermined Significance

By Jack Khouri, MD, Christy Samaras, DO, Jason Valent, MD, Alex Mejia Garcia, MD, Beth Faiman, PhD, CNP, Saveta Mathur, CNP, Kim Hamilton, CNP, Megan Nakashima, MD, Matt Kalaycio, MD

The monoclonal gammopathies encompass a number of disorders characterized by the production of a monoclonal protein (M protein) by an abnormal clone of plasma cells or other lymphoid cells. Monoclonal gammopathy of undetermined significance (MGUS) is the most common of these disorders. Its clinical relevance lies in the inherent risk of progression to hematologic malignancies such as multiple myeloma or other lymphoproliferative disorders, or of organ dysfunction due to the toxic effects of the M protein.

What is the differential diagnosis of monoclonal gammopathies?

MGUS should be differentiated from other plasma-cell and lymphoproliferative disorders that feature an M protein and would otherwise require treatment.

Based on the International Myeloma Working Group consensus, a formal diagnosis of MGUS is established when a serum M protein is detected and measured at a concentration less than 3 g/dL on serum protein electrophoresis along with less than 10 percent clonal plasma cells in the bone marrow. Nevertheless, bone marrow biopsy can be omitted in certain patients as discussed below. The absence of myeloma-related organ damage — particularly osteolytic bone lesions, anemia, otherwise unexplained renal failure and hypercalcemia — is fundamental and necessary for a diagnosis of MGUS.

Smoldering multiple myeloma

Compared with patients with MGUS, patients with smoldering multiple myeloma have higher M protein concentrations (≥ 3 g/dL) or 10 percent or more clonal plasma cells in the marrow or both, and are at higher risk of progression to symptomatic multiple myeloma. Nevertheless, like patients with MGUS, they have no myeloma symptoms or evidence of end-organ damage.

Symptomatic multiple myeloma

By definition, patients with multiple myeloma develop organ damage related to their malignancy and need therapy to halt disease progression. Multiple myeloma causes clinical manifestations through cellular infiltration of the bone and bone marrow (anemia, osteolysis and hypercalcemia) and light chain-induced toxicity (renal tubular damage and cast nephropathy).

In 2014, the definition of multiple myeloma was updated to include three new myeloma-defining events that herald a significantly higher risk of progression from smoldering to symptomatic multiple myeloma, and now constitute an integral part of the diagnosis of symptomatic multiple myeloma. These are:

• Focal lesions (> 1 lesion larger than 5 mm) visible on magnetic resonance imaging
• ≥ 60 percent clonal plasma cells on bone marrow biopsy
• Ratio of involved to uninvolved serum free light chains ≥ 100 (the involved light chain is the one detected on serum protein electrophoresis and immunofixation).

Bone pain, symptoms of anemia and decreased urine output may suggest myeloma, but are not diagnostic. Although the “CRAB” criteria (elevated calcium, renal failure, anemia and bone lesions) define multiple myeloma, the presence of anemia, hypercalcemia or renal dysfunction do not by themselves mark transformation from MGUS to multiple myeloma. Thus, other causes need to be considered, since the risk of transformation is so low. Importantly, hyperparathyroidism must be ruled out if hypercalcemia is present in a patient with MGUS.

Waldenström macroglobulinemia

Waldenström macroglobulinemia, also called lymphoplasmacytic lymphoma, is an indolent non-Hodgkin B-cell lymphoma that can invade the marrow, liver, spleen and lymph nodes, leading to anemia and organomegaly. It features a monoclonal IgM protein that can be associated with increased blood viscosity, cold agglutinin disease, peripheral neuropathy and cryoglobulinemia.

Waldenström macroglobulinemia should be suspected in any patient with IgM type M protein and symptoms related to hyperviscosity (headache, blurry vision, lightheadedness, shortness of breath, unexplained epistaxis, gum bleeding); systemic symptoms (fever, weight loss and night sweats); and abdominal pain (due to organomegaly).

Light-chain amyloidosis

Misfolded light-chain deposition leading to organ dysfunction is the hallmark of light-chain amyloidosis, which constitutes a subset of MGRS. An abnormal light-chain ratio, especially if skewed toward lambda, should trigger an investigation for light-chain amyloidosis.

Abnormal light chains may infiltrate any organ or tissue, but of greatest concern is infiltration of the myocardium with ensuing heart failure manifestations. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive marker for cardiac amyloidosis in the presence of suggestive features on transthoracic echocardiography (e.g., left ventricular hypertrophy) but is not specific as it can be elevated in heart failure regardless of the underlying cause.

Glomerular injury with nephrotic syndrome may also point toward renal involvement by light-chain amyloidosis and establishes a key distinctive factor from myeloma in which tubular injury is the main mechanism of kidney dysfunction.

Clinical clues for light-chain amyloidosis include heart failure symptoms, neuropathy and macroglossia. If any of these symptoms and signs is present, we recommend electrocardiography (look for low voltage in limb leads), transthoracic echocardiography, measuring the NT-proBNP level and urinalysis to look for albuminuria. Notably, carpal tunnel syndrome may be a very early clinical manifestation of amyloidosis, but by itself it is nonspecific. Light-chain amyloidosis is a common cause of macroglossia in adults.

Neuropathy associated with M proteins is a clinical entity related to a multitude of disorders that may necessitate treating the underlying cellular clone responsible for the secretion of the toxic M protein. These disorders include light-chain amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes or sclerotic bone lesions) syndrome and IgM-related neuropathies with antimyelin-associated glycoprotein antibodies.

Notably, weight loss and fatigue in a patient with MGUS may be the first signs of light-chain amyloidosis or Waldenström macroglobulinemia and should prompt further evaluation.

Dr. Khouri is a fellow in the Department of Hematology and Medical Oncology. Drs. Samaras, Valent and Mejia Garcia are staff in the Department of Hematology and Medical Oncology. Dr. Faiman, Ms. Mathur and Ms. Hamilton are clinical nurse practitioners in the Department of Hematologic Oncology and Blood Disorders. Dr. Nakashima is staff in the Department of Clinical Pathology. Dr. Kalaycio is Chairman of the Department of Hematology and Medical Oncology.

This abridged article was originally published in Cleveland Clinic Journal of Medicine.