Review

Monoclonal gammopathy of undetermined significance: A primary care guide

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 and Matt Kalaycio, MD
Cleveland Clinic Journal of Medicine January 2019, 86 (1) 39-46; DOI: https://doi.org/10.3949/ccjm.86a.17133

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Monoclonal gammopathies begin with uncontrolled division of a single plasma cell, leading to abnormal production of monoclonal (M) proteins, consisting of an antibody (immunoglobulin) or free light chain.

  • Figure 2
    Figure 2

    Serum protein electrophoresis from a patient with monoclonal gammopathy of undetermined significance (right) shows an abnormal band of gamma globulin (labeled M) that is not present in a normal study (left).

Tables

  • TABLE 1

    Diagnostic criteria for MGUS, smoldering multiple myeloma, and active multiple myeloma

    Monoclonal gammopathy of undetermined significance (MGUS)
    Serum monoclonal (M) protein < 3 g/dL
    Clonal bone marrow plasma cells < 10%a
    Absence of myeloma-defining events or light-chain amyloidosis
    Smoldering multiple myeloma
    Serum M protein ≥ 3 g/dL or clonal bone marrow plasma cells 10%–60%, or both
    Absence of myeloma-defining events or light-chain amyloidosis
    Symptomatic multiple myeloma
    Clonal bone marrow plasma cells ≥ 10% or plasmacytoma and ≥ 1 myeloma-defining event:

    • Calcium: hypercalcemia, ie, serum calcium > 1 mg/dL higher than the upper limit of normal or > 11 mg/dL

    • Renal insufficiency: creatinine clearance < 40 mL/minute or serum creatinine > 2 mg/dL

    • Anemia: hemoglobin > 2 g/dL below the lower limit of normal, or < 10 g/dL

    • Bone involvement: ≥ 1 lytic lesions on skeletal radiography, computed tomography, or positron emission tomography– computed tomography

    Clonal bone marrow plasma cell percentage ≥ 60%
    Involved: uninvolved serum free light chain ratio ≥ 100 with involved free light chain ≥ 100 mg/L
    More than 1 focal lesion on magnetic resonance imaging b

    • ↵a Can be omitted in patients with low-risk MGUS.

    • ↵b As opposed to diffuse lesions (diffuse marrow infiltration). Magnetic resonance imaging of the whole body–or at least of the spine and pelvis if whole-body imaging is not feasible–is preferred. Lesions should be > 5 mm in size.

    • Based on information in reference 7.

  • TABLE 2

    Indications for testing for monoclonal gammopathy

    Symptoms and signs
    Peripheral neuropathy (demyelinating or axonal) with or without autonomic features
    Pathologic fractures
    Raynaud phenomenon, acrocyanosis (suggestive of cryoglobulinemia)
    Hyperviscosity symptoms (headaches, blurry vision, lightheadedness, shortness of breath) in the presence of an immunogloblin M monoclonal protein
    Heart failure symptoms of unclear etiology with findings on ultrasonography suggestive of cardiac amyloidosis
    Unexplained peripheral edema: a key caveat is nephrotic syndrome, in which testing for light-chain amyloidosis should be considered
    Laboratory and imaging findings
    Normocytic anemia of unclear etiology
    High erythrocyte sedimentation rate
    Elevated serum viscosity
    Elevated total serum protein
    Nephrotic-range proteinuria
    Unexplained renal failure
    Elevated calcium level
    Osteolytic lesions on imaging
    Recurrent infections (mostly sinopulmonary)
    Hypo- or hypergammaglobulinemia
  • TABLE 3

    Initial laboratory tests in MGUS

    Complete blood cell count
    Serum calcium level
    Serum creatinine level
    Serum free light chains
    Serum immunofixation
    24-hour urine protein electrophoresis
    Immunoglobulin quantification

    • MGUS = monoclonal gammopathy of undetermined significance

  • TABLE 4

    Monoclonal gammopathy: Differential diagnosis

    Monoclonal gammopathy of undetermined significance (MGUS)
    Smoldering multiple myeloma
    Multiple myeloma
    Light-chain amyloidosis
    Waldenström macroglobulinemia
    POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes/sclerotic bone lesions, usually lambda)
    Plasmacytoma (solitary or multiple, medullary or extramedullary)
    Miscellaneous MGUS-related disorders:

    • Monoclonal gammopathy of renal significance (including light-chain deposition disease, usually kappa type), Fanconi syndrome, and light-chain amyloidosis

    • Immunoglobulin M-related neuropathy, and anti-myelin-associated glycoprotein antibody neuropathy

    • Cryoglobulinemia

  • TABLE 5

    Risk factors for progression in MGUS

    Risk factors
    Non-immunoglobulin G-type M protein
    M protein concentration ≥ 1.5 g/dL
    Abnormal serum free light chain ratio
    Risk category
    Low risk: All 3 risk factors absent
    Low intermediate: 1 risk factor present
    High intermediate: 2 risk factors present
    High risk: All 3 risk factors present
  • TABLE 6

    MGUS: When to refer patients to a hematologist

    Intermediate- and high-risk MGUS
    Suspicion of multiple myeloma or other concomitant malignancy
    Suspicion of light chain amyloidosis (including abnormal serum free light chain ratio), for help with diagnostic workup
    Possible MGUS-related disorders (peripheral neuropathy, monoclonal gammopathy of renal significance)

    • MGUS = monoclonal gammopathy of undetermined significance

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