Changing Pattern of Presentation in Monoclonal Gammopathy of Undetermined Significance: A Study on 1400 Cases
Authors: Varettoni Marzia , Pica Gian Matteo , Cocito Federica , Mangiacavalli Silvia , Pascutto Cristiana , Lazzarino Mario , Corso Alessandro 
Published: April 2020

Abstract
Background. Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of a serum M-protein &lt;3 g/dL, bone marrow plasma cells (BMPC) &lt;10% and absence of end-organ damage. The risk of malignant transformation is 1% per year. Size and type of M-protein and an abnormal serum free-light chains (FLC) ratio at diagnosis are reported as the main risk factors for transformation.
Aims of the study. To evaluate whether the pattern of presentation of MGUS has changed over the last three decades.
Patients and methods. The charts of MGUS patients (pts) diagnosed from 1975 to 2007 were reviewed. The following data were gathered: age, sex, haemoglobin (Hgb), type and size of serum M-protein, uninvolved Ig levels, serum FLC, urine M-protein, BMPC, serum albumin and β2-microglobulin. The study included 1400 pts divided into three groups according to the date of diagnosis: 1975–1987 (group I, 102); 1988–1997 (group II, 380); 1998–2007 (group III, 918). Differences among groups were evaluated using chi-square test for categorical variables and Kruskal-Wallis non-parametric Anova for numerical variables. A P-value ≤0.05 was considered statistically significant.
Results., The median age of patients was 63 years (range 20–92), 740 were males and 660 females. The median time from the first detection of M-protein to diagnosis of MGUS was 3.2 months (range 1–264). Serum M-protein was 73% IgG, 13% IgM, 11% IgA, 3% biclonal; light chain was k in 63% of pts, λ in 37%. The serum M-protein was &lt;1 g/dL in 284 patients (21%), 1–1.5 g/dL in 502 (36%), 1.5–2 g/dL in 373 (27%) and ≥2 g/dL in 216 (16%). M-protein size was not reported in 25 cases. The median levels of uninvolved IgG, IgM and IgA were 1350 mg/dL (range 110–7460), 94 mg/dL (range 40–4680) and 162 mg/dL (range 22–2370) respectively. In 236 evaluable pts, median levels of serum FLC k and λ were 17.1 mg/L (range: 1.4–423) and 17.3 mg/L (range: 2–299). Urine M-protein was detected in 19% of pts with a median level of 23.8 mg/L (range 4–450). The median BMPC percentage was 5 (range: 1–10). The median values of Hgb, serum albumin and β2-microglobulin were 14 g/dL (range: 8.6–19.7), 4.3 g/dL (range 2.5–6) and 1930 mcg/L (range 865–44300) respectively. The comparison among the three groups showed statistically significant reduction of serum M-protein levels (p&lt;0.0001), BMPC (p&lt;0.0001), β2-microglobulin (p=0.0001) and increase of Hgb (p&lt;0.0001) and albumin (p=0.0001) over time. In particular, the proportion of pts with a serum M-protein &lt;1 g/dL increased from 4% in group I to 12% in group II and to 26% in group III. A serum M-protein ≥2 g/dL was present in 35%, 22%, 11% of pts in the three groups respectively (p&lt;0.0001). With a median follow-up was 40 months (range: 3–396), corresponding to 7577 person-year, the cumulative probability of malignant transformation was 9%, 18%, 28% at 5, 10, 15 years respectively. Group III pts had a significantly lower 5-year probability of transformation (5%) as compared to groups I and II (20% and 11% respectively).
Conclusions. The pattern of presentation of MGUS has changed over time. Patients diagnosed in the last decade have more favourable presenting features as compared to those diagnosed before. This could be due to the availability of more sensitive diagnostic techniques able to detect minimal M-proteins. Another possible explanation is that pts are more frequently and promptly referred by their treating physicians to an hematologic centre, allowing an earlier diagnosis. Both circumstances could led to the identification of a subset of pts with different presentation and maybe a better outcome with respect to the MGUS diagnosed in the past decades. This could entail a different approach of physicians in the management of MGUS patients.