Monoclonal gammopathy of undetermined significance (MGUS)

MGUS patients have M proteins (IgG kappa or lambda; or IgA kappa or lambda) in the serum but without features of multiple myeloma, macroglobulinaemia, amyloidosis, or lymphoma (1).

• they have fewer than 10% of plasma cells in the bone marrow
• patients are asymptomatic and should avoid treating them (1)

In smouldering myeloma, patients have similar characteristics but may have more than 10% of marrow plasma cells (1)

MGUS can be seen in 2% of people older than 50 years (2) and around 1% of MGUS patients per year will progress to myeloma (most commonly), amyloidosis, lymphoma, or chronic lymphocytic leukaemia.

• they must be followed carefully because patients who develop these diseases require treatment
• almost all patients with multiple myeloma are preceded by a gradually rising level of MGUS
• the following risk factors suggest disease progression
  • an abnormal serum-free light chain ratio
  • non-IgG class MGUS.
  • a high serum M protein level (≥15 g/L) (1)

Note that although the risk of malignant progression among patients with MGUS is considered to be 1% per year, the actual lifetime probability of progression is lower when adjusted for competing causes of death and is approximately 11% at 25 years (3):

• MGUS is asymptomatic but can progress to cancer — specifically, multiple myeloma, Waldenström’s macroglobulinemia, or solitary plasmacytoma - at a rate of 1% per year
• risk is persistent and does not diminish over time, even after 25 years of follow-up
• risk increases proportionally with the serum M protein concentration and the degree of skewing in the serum free light-chain (FLC) ratio
• risk is higher with the IgM or IgA subtype of MGUS
• for persons with all three risk factors (a serum M protein level of ≥1.5 g per deciliter, IgA or IgM MGUS, and an abnormal serum FLC ratio), the risk of progression at 20 years is 58%, as compared with 5% for persons who have none of these risk factors

The following criteria are used for the diagnosis of MGUS (all three are required):

• serum monoclonal protein low *
• monoclonal bone marrow plasma cells of 10%
• no evidence of end-organ damage attributable to the clonal plasma cell disorder:
  • normal serum calcium, haemoglobin level and serum creatinine
  • no bone lesions on full skeletal X-ray survey and/or other imaging if performed
  • no clinical or laboratory features of amyloidosis or light chain deposition disease (1)

* low is defined as serum M protein of 3.0 g per 100 ml (4).

Reference:

1. National Cancer Institute 2011. Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment
2. Nau KC, Lewis WD. Multiple myeloma: diagnosis and treatment. Am Fam Physician. 2008;78(7):853-9.
3. Rajkuma SV et al. Monoclonal Gammopathy of Undetermined Significance. NEJM 2025;393:1315-1326
4. Palumbo A et al. International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia. 2009;23(10):1716-30.