Proinflammatory Cytokines Profile, a Link Between Multiple Myeloma and Gaucher Disease
Authors: Gervas Javier , Andrade Marcio M , Giraldo Pilar 
Published: October 2019

Abstract
Gaucher disease (GD) is characterized by a latent chronic inflammatory macrophage activation expressed by an imbalance of pro-inflammatory cytokines, hyperferritinemia, hypergammaglobulinemia, altered calcium homeostasis and metabolic syndrome. The incidence of Monoclonal Gammopathy of Uncertain Significance (MGUS) and multiple myeloma (MM) is increased in GD1 patients (3.5-12.5). The hypothesis is that deregulation of immune system resulting from glucocerebroside accumulation may influence the development of hematological malignancies. However, the pathological mechanisms that influence in MM development in GD1 patients are unknown. Cytokines produced secondary to glucocerebroside accumulation, may be a critical factor to explain the pathogenesis of MM in GD. This cytokine environment could trigger lymphocyte expansion and ultimately transformation. Objective: To analyze and compare the proinflammatory cytokines profile among MGUS, MM and GD1patients.
Methods: Between February-May 2014 we have analyzed a panel of eight cytokines (IL4, IL6, IL7, IL10, IL13, MIP1α, MIP1β and TNF) by Luminex®100 platform and Millipore cytokine kits. The analysis was performed in plasma samples stored at diagnosis in Aragon Biobank. We have studied four cohorts: 71 healthy controls, 38 GD1 patients (36.8% women, mean age 39.2 years, range: 17-79), 36 MGUS (58.3% women, mean age: 75 years, range 53-89), 11 IgGk; 6 IgGL; 5 IgAk; 8 IgAL; 3 IgMk; 3 doble IgG+IgA and 49 MM (42% women, mean age 68 years, range 39-89), 20 IgGk; 5 IgGL; 8 IgAk; 5 IgAL, 8 ligth chain disease and 3 doble IgG+IgA. Concerning ISS classification 44.0% MM patients had a score 1, 24.3% score 2 and 31.7% score 3. All patients with MGUS or MM had been diagnosed consecutively during 2009 and followed until now. Clinical and analytical data of MGUS and MM were obtained from the records of the Hematology Department; and the data of GD1 patients from the Spanish Registry (FEETEG). Data were analyzed using non-parametric tests (Mann-Whitney-U and Kruskall-Wallis).
Results: After 5 years in follow-up 21 MM patients had died (42.8%) and 8 in the MGUS group (22.2%), 4 MGUS developed a MM (11.1%); and 8 another neoplasia (22.2%); in MM patients 7 developed a second tumor (14.2%). Between GD1 patients one developed a MM and two a solid tumor (7.9%). Concerning the cytokine analysis, a significant difference (p<0.05) was observed in IL4; MIP-1α; MIP-1β and TNFα values between controls; MGUS; MM and GD1 patients; and also IL13 in MM and GD1. MM and GD1 not showed differences in the median values of IL4 and IL13. These groups showed significant differences in MIP-1α, MIP-1β and TNFα values. In MM there are significant differences in IL4 (p=0.012) and MIP-1α (p=0.022) between ISS 1 and ISS 3. In addition there are significant differences in MIP-1α between IgGk vs IgAL and MGUS patients that will be transformed to MM (p=0.018).(See table 1)There are not significant differences in cytokines profile between patients who developed a second neoplasia.
Conclusions: These results support that GD1 and MM patients share similar proinflammatory profiles. The chronic cytokines increase in GD patients would contribute to the development of malignancies in these patients.
GD1 and MM share skeletal complications, MIP-1α as osteoclast-activating factor could be a good biomarker during follow-up of GD1 or MGUS to detect patients in risk to develop bone complications. MIP-1α is described as significantly elevated in osteopenic MGUS patients(1).
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.