Abstract
Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient’s monoclonal Ig for only 37 patients (15.9%); for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease.
Highlights
Multiple myeloma (MM) is preceded by an asymptomatic stage termed monoclonal gammopathy of undetermined significance (MGUS), eventually followed by an intermediate stage called smoldering multiple myeloma (SMM)
These findings are of major importance since, for the first time, treatments that aim to suppress the target of the monoclonal Ig can be envisioned for MGUS patients, offering the possibility to prevent evolution toward SMM and MM
We report that auto-antibodies specific for GlcSph were detected in the serum of 49.3% MGUS/SMM and 38.9% MM
Summary
Multiple myeloma (MM) is preceded by an asymptomatic stage termed monoclonal gammopathy of undetermined significance (MGUS), eventually followed by an intermediate stage called smoldering multiple myeloma (SMM). Nair et al recently showed that GlcSph is a frequent target of monoclonal Igs of GD-associated MGUS and MM [8,9]. These findings are of major importance since, for the first time, treatments that aim to suppress the target of the monoclonal Ig can be envisioned for MGUS patients, offering the possibility to prevent evolution toward SMM and MM. For GD patients with a MGUS, eliglustat therapy aimed at reducing their level of GlcSph, the immunogenic lipid target of GD monoclonal Igs, successfully reduced the amount of monoclonal
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