Association of Elevated Circulating Proteasome Levels at Diagnosis with Poor Outcome in Multiple Myeloma

Background: The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cell cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. Recent studies have shown that inhibition of the ubiquitin-proteasome system can be successfully used as a targeted therapy in multiple myeloma (MM). Recent data suggest a significant correlation between circulating proteasome levels (CPL) and outcome in patients with MM. Therefore, we investigated CPL in 110 patients in order to assess the role of CPL in MM.

Experimental design: CPL were measured in serum samples from healthy controls (N=10) as well as from patients with monoclonal gammopathies of undetermined significance (N=27), indolent MM (N=15) and symptomatic MM (N=68) using enzyme-linked immunoabsorbent assay (ELISA) techniques detecting circulating 20S proteasome components. All serum samples were collected at the University Hospital in Ulm at time of diagnosis.

Results: The median CPL were 123.5 ng/mL (range, 95–185 ng/mL) in healthy controls, 180 ng/mL (range, 100–485 ng/mL) in patients with MGUS (N=27) or indolent MM (N=15), and 227.5 ng/mL (range, 100–985 ng/mL) in patients with symptomatic MM (N=70). The CPL of patients with symptomatic MM were significantly elevated compared with healthy donors (p=0.0017) and to persons with asymptomatic gammopathies (p=0.046). While CPL were also significantly higher in the MGUS/indolent MM cohort as compared to controls (p=0.03), CPL in MGUS and indolent MM were comparable. Using ROC analysis in the symptomatic MM cohort patients with CPL >150ng/mL (N=50) had a significantly shorter progression-free survival (PFS) time than patients (N=18) with CPL<150 ng/mL levels (median PFS: 40 versus 57 months, log rank test p=0.026). Of note, all six patients who died in the observation interval had CPL >150ng/mL.

Conclusions: Here we demonstrate that increased CPL at diagnosis correlates with poor outcome in symptomatic MM patients. Evaluation of the prognostic significance of CPL in a larger cohort of uniformly treated patients with symptomatic MM is currently under way. This data will be presented at the meeting.