Chapter 13

Whilst the 1% average annual risk of MGUS developing into MM or a related condition is well documented [249] progression among individual MGUS patients is highly variable [260]. Therefore, recognition of risk factors for progression is of clear benefit. Not only does this allow the identification of patients at highest risk, who will benefit most from close monitoring, it also provides reassurance to patients at low risk who do not need to be subjected to further tests. A summary of known risk factors is presented in Table 13.1.

Study n Monoclonal
protein size
BMPC % Monoclonal
protein type
FLCs Immunoparesis Additional
risk factors
Blade 1992 [268]128 No No (n=105) IgA>IgG, IgM Unknown No
Baldini 1996 [269]335 Yes Yes No Yes (uBJP) Yes (classical immunoparesis)
Cesana 2002 [252]1104 No Yes No Yes (uBJP) Yes (classical immunoparesis) Increased ESR
Mayo Clinic 2002 [249],
2005 [31]
and 2013 [40]
1384 Yes No (n=160) IgA, IgM>IgG No (uBJP)

Yes (sFLC ratio)
No (classical immunoparesis)

Yes (HLC pair suppression)
Rosinol 2007 [270]359 Yes No (n=228) IgA>IgG, IgM Unknown Unknown Evolving MGUS
Perez-Persona 2007 [271]407 No No No No (uBJP) No % aPC/BMPC
DNA aneuploidy
Perez-Persona 2010 [272]311 Unknown Yes Unknown Unknown Unknown % aPC/BMPC
Evolving MGUS
Turesson 2014 [32]728 Yes Unknown No Yes (sFLC ratio) Yes (classical immunoparesis)
Hajek 2017 [1029]1887 Yes Yes No Yes (sFLC ratio) Yes (classical immunoparesis) Age, serum haemoglobin
Landgren 2019 [1219]685 Yes n/a IgA>IgG, IgM Yes (sFLC ratio) Yes

Table 13.1. Summary of risk factors for MGUS progression identified by multivariate analysis. Yes: significant risk factor; No: non-significant risk factor; uBJP: urinary Bence Jones protein; aPC: aberrant plasma cells; BMPC: bone marrow plasma cells; HLC: immunoglobulin heavy/light chain (Hevylite); ESR: erythrocyte sedimentation rate.

In one of the largest studies to date, the long-term outcome of 1384 individuals in southeastern Minnesota with IgM and non-IgM MGUS was assessed by Kyle et al. [249][1016]. Patients enrolled between 1960 and 1994 were initially followed up for a median of 15.4 years, and subsequently for a median of 34.1 years (range: 0 – 43.6 years). During this time 147 (11%) progressed to MM or a related condition, a rate of approximately 1% per year [1016]. This represented a 6.5-fold increased risk compared to a matched control population. When the individual types of MGUS were considered separately, the risk of progression for IgM MGUS was higher than that of non-IgM MGUS (relative risk: 10.8 vs. 5.7). Interestingly, the risk of progression for IgM MGUS was not constant; the risk was highest in the first decade following diagnosis (2.0% per year), and then reduced to 1.3% per year thereafter. In contrast, the risk of progression for non-IgM MGUS remained unchanged throughout. Once the serum M-protein type had been taken into account, the most important prognostic factors for progression were the initial size of the serum monoclonal protein (>15 g/L) and an abnormal sFLC ratio [1016]. The prognostic value of sFLCs in the Minnesota MGUS cohort was first described in a separate article by Rajkumar et al. [31], discussed below.

13.2.1. Prognostic value of serum FLCs in MGUS

Rajkumar et al. [31] measured sFLCs in serum samples from 1148 MGUS patients at diagnosis by using archived (frozen) sera that had been collected from the original Minnesota cohort of 1384 patients [249]. An abnormal κ/λ sFLC ratio (<0.26 or >1.65) was detected in 379 (33%) cases at diagnosis. At a median follow-up of 15 years, malignant progression to MM or a related condition had occurred in 87 (7.6%) patients. The risk of progression in patients with abnormal sFLC κ/λ ratios was significantly higher (hazard ratio [HR] 2.6) than in patients with normal ratios, and was independent of the size and type of the monoclonal protein (Figure 13.2.). Furthermore, the risk of progression increased as κ/λ ratios became more extreme (Figure 13.3).

The prognostic value of baseline sFLC measurements has been validated in a number of other studies [32][1029][881]. For example, in a retrospective study Turesson et al. [32] monitored 728 Swedish MGUS patients for up to 30 years (median 10 years). During this time, 84 patients developed a lymphoid disorder, with MM accounting for the majority (53/84) of cases. The κ/λ sFLC ratio was abnormal in 47% of the study population at baseline. Three risk factors were significantly associated with progression: an abnormal κ/λ sFLC ratio, monoclonal protein concentration (>15 g/L) and a reduction of one or two uninvolved immunoglobulin isotypes (immunoparesis). No association was found between the monoclonal protein isotype and risk of progression, which is in contrast to some previous reports [249][268][31], but in keeping with those of the Spanish PETHEMA group [271] and a large Czech study [1029]. The Spanish group also identified immunoparesis as a significant risk factor for MGUS progression in univariate but not multivariate analysis [271]. In the study of Hajek et al. [1029], 1887 Czech MGUS patients were monitored for up to 35 years (median 4 years). A total of 43.4% of patients had an abnormal κ/λ sFLC ratio at diagnosis, and, consistent with other studies, these patients were at increased risk of progression compared to those with a normal ratio (HR = 3.26).

Rajkumar et al. [31] constructed an MGUS risk-stratification model based on the size and type of monoclonal protein, and the presence of an abnormal κ/λ sFLC ratio at diagnosis (Table 13.2 and Figure 13.4). Using this model, low-risk patients were characterised as those with a small (<15 g/L) IgG monoclonal protein and a normal sFLC ratio. Such patients had a 2% absolute risk of disease progression at 20 years when competing causes of death were taken into account. Importantly, this low-risk group accounted for approximately 40% of the cohort. A smaller group of high-risk patients were identified as those with a large (>15 g/L) IgA or IgM monoclonal protein and an abnormal sFLC ratio. These patients had a 27% absolute risk of progression at 20 years. An alternate risk-stratification model was suggested by Hajek et al. [1029] based on the sFLC ratio, M-protein size, haemoglobin concentration and the presence of immunoparesis at baseline.

Risk of progression No. of abnormal risk factors No. of patients Absolute risk of progression at 20 years*
Low 0 449 2%
Low-intermediate 1 420 10%
High-intermediate 2 226 18%
High 3 53 27%
* Accounting for death as a competing risk.

The three risk factors are defined as an abnormal κ/λ sFLC ratio (<0.26 or >1.65), a high serum monoclonal protein concentration (>15 g/L), and a non–IgG subtype (IgA or IgM).

Table 13.2. Risk stratification model to predict progression of MGUS [31].

Other risk factors to identify MGUS patients at highest risk of malignant progression have been suggested by a number of other groups. Cesana et al. [252] reported that at MGUS diagnosis, a bone marrow plasma cell (BMPC) percentage of 6 – 9% carried twice the risk of MGUS progression compared with ≤5% BMPCs. Perez-Persona et al. [271] characterised the phenotype of BMPCs in 407 MGUS patients using multiparameteric flow cytometry. Aberrant plasma cells (aPC) were defined by the absence of CD19 and/or CD45, decreased expression of CD38, and overexpression of CD56. Using multivariate analysis, ≥95% aPC/total BMPCs, together with DNA aneuploidy, identified MGUS patients with the highest risk of progression [271].

The presence of urinary Bence Jones protein (uBJP, monoclonal FLCs) was highlighted as risk factor in several, but not all studies (Table 13.1). In part, this may be related to the problems obtaining a urine sample (Chapter 24). For example, in the study of 1384 MGUS patients by Kyle et al. [249] urine data was unavailable for 70% of patients, and the presence of uBJP failed to reach statistical significance. Since the introduction of sFLC assays into routine practice, the κ/λ sFLC ratio has been identified as a more reliable prognostic marker than uBJP.

IMWG guidelines [260] recommend that patients with MGUS should be risk stratified at diagnosis to optimise counselling and follow-up, using the risk-stratification model outlined in Table 13.2 (see Section 25.3.2, Table 25.3). For patients with low-risk MGUS, follow-up is recommended at 6 months initially and, if stable, every 2 - 3 years or when symptoms suggest evidence of a plasma cell malignancy. For these patients, a baseline bone marrow examination or skeletal radiography is not routinely indicated. For patients with intermediate- and high-risk MGUS, follow-up is recommended at 6 months initially, then annually and/or upon any change in the patient's clinical condition. A bone marrow aspirate and biopsy should also be carried out at baseline to rule out any underlying plasma cell malignancy [260].

In future, additional markers may be added to risk stratification models to better define high-risk patients. Rawstron et al. [273] have recently showed that plasma cell phenotype (CD138/38/45 expression) and sFLCs provide independent and complementary prognostic information on the risk of progression. The use of additional genetic risk factors (including light chain gene rearrangements [274] and gene expression profiles [275]) are currently being investigated.

13.2.2. Prognostic value of Hevylite in MGUS

Suppression of uninvolved, polyclonal immunoglobulins (classical immunoparesis) has been identified as a risk factor of MGUS progression in some [269][252][32][1016], but not in all studies [249]. Using HLC immmunoassays, it is possible to measure the isotype-specific suppression of the uninvolved HLC pair (e.g. suppression of IgAλ in an IgAκ patient) (Section 11.2). Emerging evidence suggests that this ‘HLC pair suppression’ may have prognostic importance in MGUS patients.

In a preliminary study, Katzmann et al. [276] analysed HLC results from 105 IgG and 28 IgA MGUS patients. For the purposes of analysis the samples were separated into 3 different groups: initial samples from patients with stable MGUS, initial samples from patients with MGUS which progressed, and samples collected shortly before progression was diagnosed (Table 13.3). For the IgG MGUS patients, HLC ratio abnormalities and HLC pair suppression were increased in patients at greater risk of progression and the pair suppression was greater than the general immunoparesis. For the IgA MGUS patients the results were clearly different; ratio abnormalities were close to 100% in all groups and while HLC pair suppression was higher in subjects at greater risk of progression, the frequency of general immunoparesis was almost identical (Table 13.3).

IgG MGUS n Abnormal IgGκ/IgGλ HLC ratio (%) IgA or IgM suppression (%) HLC pair suppression (%)
MGUS stable
Initial sample*
36 64 6 22
Initial sample*
30 83 7 53
Pre-progression sample**
39 87 46 90
IgA MGUS n Abnormal IgAκ/IgAλ HLC ratio (%) IgG or IgM suppression (%) HLC pair suppression (%)
MGUS stable
Initial sample*
4 100 25 25
Initial sample*
10 100 50 40
Pre-progression sample**
14 93 71 71

Table 13.3. HLC pair suppression compared to classical immunoparesis in IgG and IgA MGUS [276]. Suppression is defined as below the lower limit of the normal reference range. * Initial diagnostic sera from Olmsted County study of MGUS; ** pre-MM sample from NIH PLCO cohort.

In a second and much larger study, Katzmann et al. [40] investigated the prognostic significance of HLC analysis utilising 999 MGUS patient samples taken at diagnosis. These were cryopreserved sera collected from the 1384 MGUS patients who had participated in the earlier, Kyle et al. MGUS study [249]. An abnormal HLC ratio was identified in two-thirds of patients. The frequency depended on the monoclonal protein isotype (Table 13.4): an abnormal HLC ratio was present in at least 90% of IgA and IgM MGUS patients, but in only 56% of IgG MGUS patients. The insensitivity of IgG HLC for IgG MGUS is thought to be due to the higher concentration of background polyclonal IgG compared with IgA and IgM (Section 11.5.3). HLC pair suppression (defined as an uninvolved HLC concentration below the lower normal limit) was present in 27% of patients overall, this represented a higher frequency than classical immunoparesis, which was present in only 11% of cases.

MGUS isotypeMonoclonal protein
concentration (g/L)
nAbnormal HLC
ratio (%)
HLC pair
suppression (%)
immunoparesis (%)
All casesAny999662711

Table 13.4. Frequency of abnormal HLC ratios and HLC pair suppression in IgG, IgA and IgM MGUS [40].

In univariate analysis, Katzmann et al. [40] showed that HLC pair suppression and abnormal HLC ratios were both significantly associated with an increased risk of progression to MM (both p <0.001). On multivariate analysis, HLC pair suppression remained significantly associated with progression to MM or a related condition, along with monoclonal protein size, type and an abnormal κ/λ sFLC ratio (Table 13.5). A risk-stratification model was developed to include these variables in which patients are categorised into five groups, according to the number of risk factors (0, 1, 2, 3 or 4) they possess. The probability of progression to MM increased with the number of risk factors (Figure 13.5).

Prognostic factorHazard ratio
(95% Cl)
HLC pair suppression
1.8 (1.1-3.0)
Serum monoclonal protein
size ≥15 g/L
2.3 (1.5-3.8)
Abnormal κ/λ sFLC ratio
2.0 (1.2-3.4)
IgA or IgM heavy chain isotype
2.7 (1.6-4.6)

Table 13.5. Prognostic factors for progression of MGUS to

MM identified by multivariate analysis [40].

Supportive data were reported by Jiménez et al. [277][1023] and Pika et al. [857]. In the initial study by Jiménez et al. [277], 248 MGUS patients were initially grouped as low- to high-risk based on the Rajkumar et al. MGUS risk stratification model [31]. The incidence of HLC pair suppression increased with MGUS risk group (Figure 13.6). Moreover, in IgG MGUS patients, both the HLC ratio and the degree of HLC pair suppression became more extreme in higher risk groups (Figure 13.7). In a follow-on study of 154 MGUS patients by the same group [1023], patients with severe HLC pair suppression (defined as values 50% below the lower limit of normal) were found to have a higher risk of malignant progression during follow-up than those without severe HLC pair suppression (p=0.024). In contrast, the presence of classical immunoparesis was not prognostic. The authors developed a risk-stratification model based on two HLC parameters: the involved HLC concentration (>15 g/L) and presence of severe HLC pair suppression. Risk of progression of MGUS to MM using a risk stratification model that incorporates HLC-pair suppression (Figure 13.8). A total of 8 patients had both risk factors, and this was associated with a significantly shorter time to progression compared to that of the remaining group (median: 17 months vs. 100 months, p<0.0001).

Espiño et al. [278] found that in IgG MGUS patients, the frequency of involved/uninvolved HLC ratios above 9.5 correlated with the classification of evolving/non-evolving MGUS proposed by Rosinol et al. [270] (p<0.001) (Figure 13.9). Moreover, all patients that actually progressed to MM during the study had an involved/uninvolved HLC ratio above 9.5 at MGUS diagnosis. The authors speculated that suppression of normal plasma cells, indicated by HLC pair-suppression, may be a prerequisite for malignant transformation of MGUS. This may be particularly important for IgG MGUS, due to the high levels of normal IgG-secreting plasma cells that would otherwise prevent invasion of bone marrow niches by tumour cells [278]. In the future, HLC assays may be used routinely alongside sFLC analysis and other prognostic markers, to guide the optimal follow-up of MGUS patients.