Circulating Proteasome Level Is an Independent Prognostic Factor for Survival in Patients with Multiple Myeloma.
Authors: Jakob Christian , Egerer Karl , Feist Eugen , Zavrski Ivana , Eucker Jan , Heider Ulrike , Burmester Gerd , Possinger Kurt , Kloetzel Peter M. , Sezer Orhan 
Published: October 2019

Abstract
The proteasome is a nonlysosomal proteolytic complex which is essentially involved in intracellular degradation of ubiquitinated proteins. This process includes the turnover of proteins which are involved in cell cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in multiple myeloma. Treatment with the proteasome inhibitor bortezomib resulted in induction of remission in a substantial portion of patients with relapsed or refractory multiple myeloma. The objective of the present study was to investigate the clinical significance of circulating levels of the 20S proteasome in patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM). To detect proteasome concentrations in peripheral blood samples, we developed a sandwich enzyme-linked immunosorbent assay (ELISA) using anti-20S proteasome antibodies. Serum proteasome levels were measured in 200 individuals, 85 normal donors and 115 patients with MGUS or multiple myeloma. Patients with multiple myeloma had significantly (P<0.001) higher serum proteasome values (median 624 ng/mL, range 108–5181) than healthy controls (209.9 ng/mL, range 68–392). The proteasome levels increased significantly (P<0.001) from Durie and Salmon stage I to stage III. Furthermore the proteasome concentrations were significantly elevated in MM versus MGUS (P=0.026) and in MM stages II/III versus stage I (P<0.001). In 55 patients with multiple myeloma in stages II and III, who received chemotherapy, there was a significant (P<0.001) decrease from pre- to post-treatment proteasome concentrations in those patients, who achieved a remission after chemotherapy, while no difference could be found in refractory patients (P=0.981). In a univariate Kaplan-Meier analysis myeloma patients in stages II and III with elevated circulating proteasome levels had a significantly (log-rank: P<0.001) shorter overall survival than patients with proteasome levels lower or equal to the median value. Furthermore, circulating proteasome concentration, b2-microglobulin (b 2-MG) and C-reactive protein (CRP) were included in a Cox’s proportional-hazards regression analysis. In the multivariate analysis, circulating proteasome concentration and b 2-MG were found to be powerful independent prognostic factors (hazard ratio 6.79 and 2.95, respectively). Our study shows that advanced disease stages in multiple myeloma are associated with increased circulating proteasome concentrations and that remission after chemotherapy is accompanied by a significant decrease. Furthermore we demonstrate for the first time, that the circulating proteasome concentration is an independent prognostic factor for overall survival. We conclude that assessment of the circulating proteasome could be a novel tool to monitor disease activity and to predict therapy response and survival in multiple myeloma.