Proteasome inhibitor bortezomib is one of the most promising agents for MM and exerts numerous biologic effects in part by blocking the activation of nuclear factor-kB-mediated pro-inflammatory cytokines. However, fever is one of the adverse events that could interfere with the patient’s activities of daily living. There have been some reports of fever following bortezomib administration not associated with infection or neutropenia, however its mechanism has not been elucidated. We hypothesized that fever following bortezomib administration is associated with serum cytokine levels. To clarify this hypothesis, we analyzed serum cytokines (IL-6, TNF-alpha and IFN-gamma), C-reactive protein (CRP) and clinical symptoms. In the multicenter phase I/II study of bortezomib in patients with relapsed or refractory MM in Japan (treating 34 patients in total), a total of 10 patients were treated at our institution. Bortezomib, of 0.7mg/m2 (n=2), 1.0mg/m2 (n=2), 1.3mg/m2 (n=6), was administered by bolus intravenous administration on days 1, 4, 8 and 11 every 3 weeks. Peripheral blood for cytokine determination was collected at pre-administration (cycle 2, day 1, 4, 8, 11) and post-administration (each 12–24 hours after) in a total of 5 patients who consented to participate in this study. We defined the fever following bortezomib administration as a transient fever which occurred within 36 hours after drug administration, and we graded fever according to the National Cancer Institute Common Toxicity Criteria Version 2.0. Seven of the 10 patients developed fever after bortezomib administration: none at the 0.7mg/m2 cohort, 2 of the 2 patients at 1.0mg/m2 and 5 of the 6 at 1.3mg/m2. Four of the 7 patients had recurrent fever with each injection, two had occurred from day 12 and one from day 5. Because subjective symptoms such as fatigue of grade 2 related to fever were observed, one of the 7 patients required prednisolone (40mg) for prevention of fever, and her fever disappeared after prednisolone administration. According to the modified European Group for Blood and Marrow Transplantation criteria, 3 of the 7 patients who developed fever achieved response, including 2 immunofixation-positive complete responses and 1 partial response, 3 no change and 1 not evaluable. In contrast, none of the 3 patients without a fever had objective responses. In 5 patients, serum IL-6 levels (p=0.04), body temperature (p=0.04) and CRP (p=0.04) increased significantly post-administration, whereas no significant changes were detected in neither serum IFN-gamma nor TNF-alpha levels as analyzed by Wilcoxon signed rank test. Significant correlation was observed between serum IL-6 levels and body temperature in 2 of 5 patients (p=0.002 and 0.005, respectively). In 2 of the remaining 3 patients, significant correlation was observed between serum IFN-gamma levels and body temperature (p=0.05 and 0.03, respectively) as analyzed by Spearman rank correlation test. In conclusions, this is the first report suggesting a correlation of fever following bortezomib administration with serum IL-6 and IFN-gamma levels. It may suggest that the adverse events related to these cytokines elevation can be reduced by the concomitant use of steroids. However, the relation between the fever following bortezomib administration and other cytokines is still unclear. Because this investigation was a preliminary study with a small number of patients, accumulation of further data is needed.

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