Aetiology

No aetiological risk factors for MGUS have been established, but there is evidence for a familial component. Studies report that risk for MGUS is increased approximately 2- to 3-fold in first degree family members of patients with MGUS or multiple myeloma.[13][14][8][9] MGUS is 2 to 3 times more common in black people than in white people. [6][7][8] These findings support but do not prove a role for genetic factors in causation. 

Population-based studies suggest an association between a personal history of autoimmune disease or infection and a subsequent diagnosis of MGUS.[8][15] Clinical observations indicate that decreased immunoglobulin levels (which in turn may cause recurrent infections) could be a manifestation of undetected MGUS. Anecdotal evidence suggests that MGUS may be more common among HIV-infected or transplant patients.[16]

Radiation exposure has been found to be associated with an increased risk of MGUS.[6] In a large screening study of atomic bomb survivors, younger age at exposure and higher radiation doses were associated with higher risk for developing MGUS.[17]​ However, the association between radiation exposure and the malignant progression of MGUS is not clear.

Occupational exposure to pesticides has been associated with an increased risk for MGUS.[6] In one study, the prevalence of MGUS among men involved in the application of agricultural pesticides was twice that of a population-based sample of men.[18] Interphase fluorescence in situ hybridisation analyses show chromosomal aneuploidy in about 50% of MGUS patients.[19] Cytogenetic abnormalities, in conjunction with conventional risk factors, may have prognostic value.[20]

About 50% of MGUS patients have translocations of the immunoglobulin heavy-chain locus on chromosome 14q32. These include: t(11;14) affecting the cyclin D1 gene; t(4;14) affecting the FGFR-3 and MMSET genes; t(6;14) affecting the cyclin D3 gene; t(14;16) affecting the cmaf gene; and t(14;20) affecting the mafB gene[21] Gene expression profiling has been used to distinguish normal plasma cells from those seen in MGUS and other plasma cell disorders. Based on current knowledge, no defined genetic abnormalities are available to differentiate MGUS from multiple myeloma.[22][19] Similarly, no established molecular markers are available to differentiate patients with MGUS who will have a benign clinical course from those who will eventually develop multiple myeloma or a related plasma cell proliferative disorder.

Pathophysiology

Patients with IgG or IgA MGUS may progress to multiple myeloma, light chain amyloidosis, or related plasma cell proliferative disorders (such as plasma cell leukaemia or light chain deposition disease). The IgM variant occurs in about 15% to 20% of all MGUS patients.[23][24] Patients with IgM MGUS are at increased risk of progressing to Waldenström's macroglobulinaemia, chronic lymphocytic leukaemia, or other types of non-Hodgkin's lymphomas.[23][25]​​ Very rarely, IgM MGUS progresses to multiple myeloma.

One Scandinavian study showed that life expectancy is shortened among patients with MGUS diagnosed in a clinical setting.[26] The excess mortality among patients with MGUS increased with longer follow-up. IgM (versus IgG or IgA) MGUS was associated with longer survival. In accordance with findings from other studies, patients with MGUS had an increased risk of dying from multiple myeloma, Waldenström's macroglobulinaemia, and other related lymphoproliferative malignancies. Death from other haematological malignancies or conditions, bacterial infections, ischaemic heart disease and other heart disorders, liver disorders, and renal diseases were also more common in patients with MGUS than in the general population. Although the underlying mechanisms of these patterns may be causally related to MGUS, they are also likely due to the underlying disease process that led to the detection of MGUS.

Classification

International Myeloma Working Group (IMWG) classification of monoclonal gammopathies[1]

The IMWG has identified 3 clinical types of monoclonal gammopathy of undetermined significance (MGUS), each with distinct rates for progression and primary progression events.

  • Non-immunoglobulin (Ig) M MGUS:

    • Most common clinical type (approximately 80%)

    • Asymptomatic

    • Progression rate 1% per year

    • Potential progression to myeloma, solitary plasmacytoma, or immunoglobulin-related amyloidosis (e.g., immunoglobulin light chain amyloidosis).

  • IgM MGUS:

    • Progression rate 1.5% per year

    • Asymptomatic; some patients may present with symptoms of peripheral neuropathy

    • Potential progression to Waldenström's macroglobulinaemia, or immunoglobulin light chain amyloidosis; rarely progresses to IgM myeloma.

  • Light chain MGUS:

    • Progression rate 0.3% per year

    • Potential progression to light chain myeloma or immunoglobulin light chain amyloidosis.

The 5th edition of the World Health Organization (WHO) classification of lymphoid neoplasms[2]

The 5th edition WHO classification of lymphoid neoplasms classifies MGUS based on IgM type and IgG/IgA type. This remains unchanged from the 2016 revised WHO classification.[3] However, some diseases have been reorganised. IgM and non-IgM MGUS are now classified under monoclonal gammopathies, alongside cold agglutinin disease and monoclonal gammopathy of renal significance. 

The international consensus classification of mature lymphoid neoplasms: a report from the Clinical Advisory Committee[4]

A special report from the Clinical Advisory Committee classifies MGUS as two types: IgM and non-IgM. Of the IgM subtype, this is further categorised into the plasma cell or not otherwise specified type. Non-IgM MGUS is classified under plasma cell neoplasms, which also encompassess multiple myeloma.

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