Prognosis

Patients with IgG or IgA types of MGUS may progress to multiple myeloma, light chain amyloidosis, or related plasma cell proliferative disorders (such as plasma cell leukaemia and light chain deposition disease). Patients with IgM MGUS are at increased risk of progressing to Waldenström's macroglobulinaemia, chronic lymphocytic leukaemia, or non-Hodgkin's lymphomas. Very rarely, IgM MGUS progresses to multiple myeloma. Some smaller studies have reported MGUS to be associated with solid tumours and various non-malignant conditions. However, the literature on this topic is sparse.

Almost all cases of MGUS are diagnosed incidentally. However, once MGUS is diagnosed, patients must be appropriately counselled that it is a pre-malignant entity with a relatively low risk of progression. Patients who have MGUS with monoclonal (M) proteins <15 g/L (1.5 g/dL) and with a normal serum free light chain ratio account for about 40% of all cases and have only a 2% lifetime probability of developing multiple myeloma or related malignancies.[29]

Although for the individual patient it is not possible to predict whether the underlying MGUS will remain benign or transform to multiple myeloma, from a population standpoint the significance of MGUS has been well characterised. Several studies have determined the risk of transformation of MGUS over time and identified risk factors for such transformation.[23][29][25][34] Important tasks for the future are to develop individualised follow up and intervention approaches for MGUS patients.

Risk stratification

There are no markers or clinical findings at diagnosis of MGUS that can reliably be used to distinguish patients who will remain stable from those who will progress to a malignant disease at an annual rate of about 1%.[11][25] On average, the risk of progression from MGUS to multiple myeloma or related lymphoproliferative malignancies is low when the M protein is <15g/L (1.5 g/dL), bone marrow plasma cells are <5%, levels of polyclonal immunoglobulin are not decreased, and no light chain proteinuria is detectable.[30][34] An abnormal kappa-to-lambda free light chain ratio detectable in serum has been associated with a significantly higher risk of progression to multiple myeloma.[29]

The Mayo Clinic has developed a risk stratification model based on 3 adverse risk factors:[30]

  • Serum M protein level >15g/L (1.5 g/dL)

  • Non-IgG MGUS

  • Abnormal serum free light chain ratio.

Based on this model, the average risk of progression from MGUS to multiple myeloma or related malignancies during 20 years' follow up has been estimated as follows:[29]

  • 3 risk factors (high-risk MGUS): 58%

  • 2 risk factors (high- to intermediate-risk MGUS): 37%

  • 1 risk factor (low- to intermediate-risk MGUS): 21%

  • 0 risk factors (low-risk MGUS): 5%.

Life expectancy

One study from Scandinavia 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 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.

Serum and urine monoclonal protein markers

One prospective cancer screening trial of 77,469 healthy adults found that MGUS consistently preceded multiple myeloma (MM) diagnosis among the 71 people who developed MM during the course of the study (as determined by serial assays of prediagnostic serum samples obtained up to 10 years prior to MM diagnosis).[28] The proportion of patients with an abnormal kappa-lambda FLC-ratio at 2 years prior to MM diagnosis was 85%. In about one-half of the study population, the M protein concentration and FLC-ratio levels increased year on year before the multiple myeloma diagnosis, while the other one-half maintained largely stable abnormal serum-protein levels up to the diagnosis of multiple myeloma. Thus, stable M protein or free light chain levels did not exclude the development of multiple myeloma.[28]

Until better molecular markers for progression to multiple myeloma are available, clinicians must use clinical measures in combination with routine blood tests (including renal function, haemoglobin, and serum calcium) and serum and urine M protein markers in monitoring MGUS cases.[31]​ Novel biomarkers, molecular profiles, and microenvironmental interactions of interest in myelomagenesis are being investigated to better understand the underlying mechanisms of the transformation from MGUS to multiple myeloma, and to help find more effective treatments at every stage of the disease.[35][36]

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