Predicting Bortezomib-Related Severe Neurologic Adverse Events by Measuring Proteasome Activity in PBMCs.

8094 Background: Although a proteasome inhibitor bortezomib (BOR) is one of the backbone drugs for the treatment of multiple myeloma, severe neurologic adverse event (sNE) is a major obstacle for continuing the treatment. As there is no clinically available biomarker for predicting the occurrence of sNAE, we measured the proteasome activity (PrsAtv) in peripheral blood mononuclear cells (PBMCs). Methods: Patients (Pts) were treated by either standard Q3wks or weekly (BOR 1.3mg/m2: day 1, 8, 15, 22; Q5wks) schedule depending on physician’s decision. PBMCs were collected from 21 Pts and 99 healthy volunteers. Pts’ samples were collected before treatment, 1 hour after the 1st injection of BOR, and at the end of the 1st course. PrsAtv in PBMCs was measured by using a specific substrate SUC-LLVY-AMC, which becomes fluorescent upon cleavage by proteasome. Results: Levels of PrsAtv among volunteers were highly variable with no certain correlation with age and sex. Pretreatment levels of PrsAtv among Pts were also variable, and didn't correlate with the occurrence of sNAE. After 1 hour of BOR injection, PrsAtv decreased to 33.2±20.5% (mean ± SD) of the pretreatment level, and it generally recovered (112.5±77.6%) at the end of the 1st course. However, in 12 out of 21 Pts, it didn’t recover to ≥ 100%. Among these Pts, 5 manifested with sNAE (≥G3) during the 2nd or 3rd course of the chemotherapy. In a sharp contrast, no patients whose PrsAtv recovered to ≥100% manifested with sNAE. Pts who manifested with sNAE (5 Pts) showed the lower levels of PrsAtv at the end of the 1st course than those without sNAE (16 Pts) (67.4±11.8 vs 126.6±83.8%, p=0.075). It should be also strengthened that all the Pts who manifested with sNAE were treated by the standard Q3wks schedule, although levels of PrsAtv at the end of the 1st course were not significantly different between Q3 and Q5wks groups (109.0±68.3 vs 121.1±96.4 %, p=0.38). Contrary, there was no significant difference of the bortezomib response between these two treatment groups. Conclusions: Pts whose PrsAtv does not recover to ≥100% at the end of the 1st course are at high risk of manifesting with sNAE, and these Pts should not be treated by the standard Q3wks schedule in the subsequent courses.