Background: Monoclonal Gammopathy of Undetermined Significance (MGUS) is a premalignant stage that eventually all multiple myeloma (MM) patients have suffered. According to the Mayo Clinic, risk factors to progression include M-protein size and isotype as well as free light chain (FLC) ratio. Classic immunoparesis is defined as the suppression of uninvolved immunoglobulins (Igs) and its role as MGUS to MM progression factor remains controversial. Nowadays, we can measure the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC). However, little data have been reported regarding its role as a progression factor from MGUS to MM.
Objective: The aim of this prospective, single center study was to assess the prognostic value of uHLC suppression (Isotype Matched Immunoparesis or IMI) in MGUS to MM progression.
Methods: The study group was composed by 232 stored serum samples from 116 MGUS patients attending our hospital. Light chain only MGUS patients were not included in the analysis. We analyzed classic immunoglobulins and uHLC in the laboratory of our institution at diagnosis and in each routine visit. MGUS risk progression factors were assessed following Mayo Clinic guidelines. We considered classic immunoparesis (IP) at diagnosis when one or more uninvolved classic Ig were under lower limit of normality (LLN) and IMI when uHLC was under LLN. We defined the decrease of uHLC (duHLC) as the rate of change of uHLC concentration in the last follow-up or at progression compared to uHLC concentration at diagnosis. Recovery of uHLC was considered when suppressed uHLC at diagnosis reached at least LLN+10% in the last follow-up or at progression.
Results: At diagnosis we found classic IP in 32% (37/116) of patients, whereas IMI was found on 43% (50/116) of them. Both classic IP and IMI were more common in IgA patients (40% and 83%, respectively) in comparison to IgG (30% and 41%) or IgM (33% and 21% respectively) patients. Interestingly, the presence of IMI was more frequent in patients with a higher risk of progression to MM, thus, IMI was only found in 31% of patients with no risk factors whereas the percentage increased as the number of risk factors did (1 risk factor 43% of patients and 2 risk factors 56%). Furthermore, MGUS patients who presented duHLC>50% had a higher risk of progression to MM (p=0.0067) with a median of progression of 8.35 years whereas in patients with a duHLC≤50% the median was not reached. Additionally, patients with duHLC>90% presented a median to progression of 5.5 years (p=0.047). Finally, MGUS patients that did not recover uHLC had a higher risk of progression to MM (p=0.029) with a hazard ratio of 3.821.
Conclusions: Both uHLC decrease and recovery of uHLC have shown to be a risk factor in the progression from MGUS to MM in our patient cohort. Therefore, the measurement of uHLC in MGUS patients could be an additional tool to predict progression to MM.
