Hematological System ORGAN SYSTEMS

Monoclonal gammopathy of undetermined significance (MGUS)

Premalignant, clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein, <10% clonal plasma cells in the bone marrow, and absence of multiple myeloma or related lymphoplasmacytic malignancies (LPMs).

Premalignant, clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein, <10% clonal plasma cells in the bone marrow, and absence of multiple myeloma or related lymphoplasmacytic malignancies (LPMs).

Plasma cell dyscrasias (PCDs):

Spectrum of progressively more severe monoclonal gammopathies characterized by the expansion of a population of monoclonal bone-marrow plasma cells that produce monoclonal immunoglobulins.


There are three distinct types of MGUS:
  1. Non-IgM MGUS (IgG, IgA, IgD): Accounts for the majority of MGUS cases and is characterized by a monoclonal plasma cell.
  2. IgM MGUS
  3. Light chain MGUS (LC-MGUS): Characterized by a monoclonal protein that lacks the immunoglobulin heavy chain component.

Disease course:

MGUS is generally considered a preneoplastic disorder that does not always progress to overt malignancy. However the subtypes lead to distinct pathologies if and when they progress further.
  • Non-IgM MGUS: Malignant plasma cell neoplasm
  • IgM MGUS: Waldenstrom macroglobulinemia, immunoglobulin light chain (AL) amyloidosis, or lymphoma
  • LC-MGUS: Idiopathic Bence Jones proteinuria, light chain PCM, AL amyloidosis, or light chain deposition disease
Definition of multiple myeloma and precursor plasma cell disorders, including monoclonal gammopathy of undetermined significance (adapted from International Myeloma Working Group definition).2 CRAB = hypercalcaemia, renal impairment, anaemia, bone disease; MGUS = monoclonal gammopathy of undetermined significance; MRI = magnetic resonance imaging; SFLC = serum free light chain | Atkin, C., Richter, A., & Sapey, E. (2018). What is the significance of monoclonal gammopathy of undetermined significance?. Clinical medicine (London, England), 18(5), 391–396.

According to a population-based cohort study, the risk of progression to multiple myeloma in patients with light-chain MGUS is 0.3%.


MGUS is both biologically and clinically heterogeneous with a spectrum of patients who eventually progress and others who have a durably indolent course.


MGUS is associated with infections, fractures, peripheral neuropathy (PN), thromboembolism, and monoclonal gammopathy of renal significance (MGRS).
  • Deficient humoral immune responses: High rates of infection and reduced antibody response to vaccination
  • Increased hip and spinal fractures:
    • Altered bone strength and microarchitecture
    • Elevated RANK-L/OPG ratios
    • Decreased bone mineral density and increased rates of osteoporosis
  • Peripheral neuropathy (PN):
    • IgM MGUS is associated with distal acquired demyelinating symmetric neuropathy that presents with sensory ataxia and mild distal motor deficits
    • IgG/IgA MGUS associated with chronic inflammatory demyelinating neuropathy (CIDP)
  • Monoclonal gammopathy of renal significance (MGRS): Group of kidney disorders (renal impairment and/or proteinuria) caused by the physiochemical and immunologic properties of deposited monoclonal immunoglobulins in premalignant PC dyscrasias and are diagnosed by renal biopsy
    • MGRS includes glomerulopathies with immunoglobulin depositions such as those with fibrillar amyloidosis (immunoglobulin light chain [AL], heavy chain [AH], and light and heavy chain [ALH]), microtubular (type I and type II cryoglobulinemias, immunotactoid glomerulopathy), or nonorganized deposits (monoclonal immunoglobulin deposition disease [MIDD]). Proliferative glomerulonephritis with monoclonal


2014 International Myeloma Working Group criteria (2014):

The diagnosis of non-IgM MGUS is based on three criteria:
  1. Serum monoclonal protein < 30 g/L (3 g/dL)
  2. < 10% of clonal plasma cells in the bone marrow
  3. Absence of CRAB symptoms (hypercalcemia, renal insufficiency, anemia and, bone lesions suspicious for PCM)

Differential diagnosis:

It is crucial to distinguish non-IgM MGUS from other advanced plasma cell neoplasms since these diseases will require a different management approach. The differential diagnosis of non-IgM MGUS include:
  • Plasma cell myeloma (PCM): Non-IgM serum monoclonal protein ≥ 30 g/L or ≥ 10% clonal plasma cells in the bone marrow should not be diagnosed as non-IgM MGUS
    • Smoldering PCM is distinguished from MGUS based on the size of the M protein and the percentage of clonal plasma cells in the bone marrow.
    • Smoldering PCM is distinguished from symptomatic PCM by the presence of CRAB symptoms
  • Waldenström macroglobulinemia: Lymphoplasmacytic lymphoma (LPL) in the bone marrow and an IgM monoclonal gammopathy.
    • Symptoms include blood hyperviscosity, lymphadenopathy, or splenomegaly
    • WHO (2017) diagnostic criteria:
      1. IgM monoclonal gammopathy
      2. Clonal plasma cells less than 10%
      3. Absence of end-organ damage (CRAB symptoms)
      4. Absence of symptoms or signs of amyloidosis
  • Monoclonal gammopathy of renal significance: Diagnostic criteria for MGUS + renal insufficiency and monoclonal immunoglobulin deposits in the kidney by immunofluorescence
  • Light chain smoldering multiple myeloma (LC-SMM) (idiopathic Bence Jones proteinuria):
    • Diagnostic criteria of LC-SMM include:
      1. Monoclonal light chains in the urine (Bence Jones proteinuria)
      2. No immunoglobulin heavy chain expression in the serum or urine
      3. No symptoms of PCM, WM, or amyloid light chain amyloidosis
  • Primary (amyloid light chain) amyloidosis and light chain deposition disease: Pathologic deposition of monoclonal light chains in tissue.
    • Diagnostic criteria include the presence of amyloid in tissue and evidence of plasma cell neoplasm.
  • B cell lymphoproliferative disorder


Treatment is usually not recommended for patients with MGUS. As there is a risk of progression to lymphoproliferative malignancy long-term follow-up is advised.

Suggested algorithm for follow-up of monoclonal gammopathy of undetermined significance.#Mayo Clinic Risk Stratification Model. CBC, complete blood count. | Ronald S. Go, S. Vincent Rajkumar; How I manage monoclonal gammopathy of undetermined significance. Blood 2018; 131 (2): 163–173. doi:

MGUS-associated neuropathies:

Usually not treated, except in the case of a disabling IgM monoclonal gammopathy or IgG/IgA MGUS associated with chronic inflammatory demyelinating neuropathy (CIDP). About 80% of patients with IgG/IgA MGUS CIDP respond to one of the typical CIDP treatments and some patients stabilize without therapy.
  • IgM neuropathy: IV immunoglobulin G (IVIG) and rituximab
  • IgG/A neuropathy: Plasmapheresis, IVIG, and steroids

MGUS patients with associated osteopenia or osteoporosis:

  • IV bisphosphonates

The intensity of follow-up in patients with MGUS is guided by risk stratification. Initial follow-up at six months is recommended, with subsequent visits scheduled according to the level of risk. If clinical trials of preventive strategies are available, patients at high risk for progression should be encouraged to participate.

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