Update on Severe Isotype-Matched Immunosuppression By Hevylite® Confirms Its Predictive Value in MGUS Patients: A Real-Life Study
Authors: Jimenez Juana , Barbosa Nuno , Pais Tiago Moreira , Campos Maria Luisa , Peñálver Mª Antonia , Hernando de Larramendi Carmen 
Published: October 2019

Abstract
Several studies have now shown that monoclonal gammopathy of undetermined significance (MGUS) constantly precedes all multiple myelomas (MM). Risk adapted follow-up may increase chances of early diagnosis of progression and, therefore, increase the chances of a better outcome for the patient, as also shown by two long-term follow-up studies. However, in real-life patients it is still difficult to identify MGUS cases at very high risk of progression. On a previous study we showed that Severe Isotype-Matched Immunosuppression (IMI) by Hevylite® was a potential risk factor of progression for MGUS patients. We have now expanded the median follow-up time by an additional year.
Methods:
The clinical records of 154 MGUS patients for which a Hevylite determination was available together with monoclonal protein quantification by gel electrophoresis (EP) and free light chains by Freelite were reviewed. Samples were analyzed with Hevylite® (The Binding Site, UK) in a BNII analyzer (Siemens) according to the monoclonal protein isotype. Normal ranges were those provided by the manufacturer. Values 50% below the lower normal ranges of the immunoglobulins determined by Hevylite were defined as severe IMI. Statistical analysis done using Graph pad V5. Progression free survival (PFS) curves calculated by Kaplan-Meyer method and curve differences by Log-rank (Mantel Cox) test.
Results:
The median follow-up of the 154 MGUS patients (150 IgG, 20 IgA, and 27 IgM) was 944 days (range:27-3471), during which 16 progressions to MM, 3 progressions to smoldering (by plasma cell infiltration >10%) and 1 progression to Non-Hodgkin lymphoma were registered. These numbers represent an increase in 366 days of follow-up and 3 extra progressions, with respect to the previous study. The median time to progression of the cohort is now 9,5 years.
Severe IMI determined by Hevylite was observed in 14% of the patients while severe immunoparesis (i.e. more than 50% suppression of the immunoglobulins not associated to the isotype of the tumor cells; e.g. suppression of IgA or IgM in an IgG MGUS) was observed in 7% of the patients.
The frequency of IMI was very similar among patients of different isotypes: IgG=60%, IgA=69%, IgM=57%, (p=0.37).
When patients were analyzed according to the presence/absence of severe IMI or severe immunoparesis (IP), only the presence of severe IMI was observed to be predictive of shorter time to progression (p=0.009; HR=6.3, 95% IC=1.6-24.9) as shown in Fig.1A. Patients with severe IP were as likely to progress as patients without (p=0.604; Fig.1B). Additionally, patients showing simultaneously severe IMI and involved HLC >1.5g/dL showed a median time to progression 4 times shorter than the remaining group (Fig.2).
Conclusions
The results obtained strengthen the conclusions obtained previously showing that severe IMI is a risk factor for MGUS progression, mainly if combined with an involved HLC greater than 1.5g/dL. This means that, potentially, with one assay, two risk factors could be easily and quickly assessed for, virtually, every MGUS patient.
The limitations of this study are its retrospective nature and a moderate over-representation of higher risk MGUS groups, which is expected since, being a real-life study, these are the patients that are most likely to maintain the follow-up with the specialist.

Disclosures
Barbosa: The Binding Site: Employment. Pais:The Binding Site: Employment. Campos:The Binding Site: Employment.