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13.2.2. Prognostic value of Hevylite in MGUS

Chapter 13

Suppression of uninvolved, polyclonal immunoglobulins (classical immunoparesis) has been identified as a risk factor of MGUS progression in some [269][252][32], 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
MGUS-progressed
Initial sample*
30 83 7 53
MGUS-progressed
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
MGUS-progressed
Initial sample*
10 100 50 40
MGUS-progressed
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 (%)
Classical
immunoparesis (%)
IgG
Any
726
56
29
5
≤5
161
24
19
4
6-10
150
57
35
7
11-20
365
65
29
5
21-30
50
90
50
10
IgA
Any
117
97
36
33
≤5
39
95
23
41
6-10
19
100
47
37
11-20
55
96
44
27
21-30
4
100
0
25
IgM
Any
156
90
10
21
≤5
49
84
2
18
6-10
28
93
14
21
11-20
70
93
13
20
21-30
9
100
22
33
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 13.4).

Prognostic factorHazard ratio
(95% Cl)
P-value
HLC pair suppression
1.8 (1.1-3.0)
0.018
Serum monoclonal protein
size ≥15 g/L
2.3 (1.5-3.8)
<0.001
Abnormal κ/λ sFLC ratio
2.0 (1.2-3.4)
0.007
IgA or IgM heavy chain isotype
2.7 (1.6-4.6)
<0.001

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][931] 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 13.5) Moreover, in IgG MGUS patients, both the HLC ratio and the degree of HLC pair suppression became more extreme in higher risk groups (Figure 13.6). In a follow-on study by the same group [931], 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=0.023). In contrast, the presence of classical immunoparesis was not prognostic.

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 Rosinal et al. [270] (p<0.001) (Figure 13.7). 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.

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References