MGUS is a pre-malignant, asymptomatic plasma cell proliferative disorder that is estimated to affect 3% of the general population aged 50 years or older [10]. Patients with MGUS progress to myeloma or a related malignancy at a rate of around 1% per year [249]. Three distinct types of MGUS can be defined based on the monoclonal protein type: IgM MGUS, non-IgM (IgG or IgA) MGUS, and FLC MGUS (Table 12.1) [42]. In general, IgM MGUS is associated with evolution to lymphoplasmacytic tumours such as Waldenström’s macroglobulinaemia (WM), wherease non-IgM MGUS is associated with evolution to MM [250].

Monoclonal protein Pre-malignancy with a
low risk of progression
(0.3 - 2% per year)
Pre-malignancy with a
high risk of progression
(5 - 10% per year)
IgG or IgA
Non-IgM MGUS SMM MM, Plasmacytoma,
NHL, CLL, AL amyloidosis
IgM IgM MGUS Smouldering WM WM, IgM MM,
NHL, CLL, AL amyloidosis
Light chain Light chain MGUS Smouldering LCMM
(idiopathic Bence Jones proteinuria)
LCMM, AL amyloidosis,

Table 12.1. Clinical types of MGUS and their evolution into malignant lymphoproliferative disorders [251][252][253][254]. The most common associated malignancies are highlighted in bold. MGUS: monoclonal gammopathy of undetermined significance; MM: multiple myeloma; SMM: smouldering MM; LCMM: light chain MM; NSMM: nonsecretory MM; WM: Waldenström’s macroglobulinaemia; NHL: non-Hodgkin lymphoma; CLL: chronic lymphocytic leukaemia.

SMM is an intermediate clinical stage between MGUS and MM which carries a higher risk of progression to malignant disease (around 10% per year for the first 5 years) [255]. Recent studies indicate that in the spectrum of disease development from MGUS, through SMM to symptomatic MM, monoclonal FLC production becomes progressively more probable. Approximately one-third of MGUS patients have an abnormal κ/λ sFLC ratio at diagnosis; this increases to around 80% in patients with SMM and 95% in MM.
In both MGUS (Chapter 13) and SMM (Chapter 14) an abnormal κ/λ sFLC ratio indicates a higher risk of progression to malignancy than a normal ratio [256][31][32][259]. In these patients, sFLC analysis plays an important role in risk stratification and disease management, such that international guidelines recommend that patients with either MGUS or SMM should be risk-stratified at diagnosis to optimise counselling and follow-up (Chapter 25) [260]. Whilst the benefits of sFLC analysis in MGUS and SMM risk-stratification are well established, HLC analysis is emerging as a new prognostic tool in these pre-malignant conditions.