Bortezomib Alters Peripheral Blood Lymphocyte Subsets in Patients with Multiple Myeloma.

Bortezomib (VELCADE^®) is a potent inhibitor of the proteasome which exerts its antimyeloma effect in part by blocking the activation of NF-κB. As NF-κB is critical for lymphocyte development and survival, there is great interest in harnessing the potential immunomodulatory effects of bortezomib. In murine hematopoietic transplantation models, bortezomib inhibits in vitro mixed lymphocyte responses and promotes the apoptosis of alloreactive T cells protecting against acute graft-versus-host disease. However, no data exists on the in vivo effects of bortezomib on human T cells. To characterize the effects of bortezomib on immune function, we profiled peripheral blood lymphocytes subsets and T cell associated cytokines in 39 patients with multiple myeloma. Two cycles of bortezomib 1.3 mg/m² were administered by intravenous infusion on days 1, 4, 8, and 11 of a 21-day treatment cycle. The patients had received prior induction chemotherapy and would proceed to autologous transplant following treatment with bortezomib. Study population consists of 23 male and 16 female patients with the median age of 56 years (range 38–69). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (28), IgA (10), light chain only (1), with stage I (1), II (12), or stage III (26) disease. Peripheral blood was collected at baseline (cycle 1, day 1) and at one week after the last dose of bortezomib (cycle 2, day 18) and analyzed for lymphocyte subsets by standard multicolor flow cytometry. Th1 and Th2 serum cytokines were measured at the same timepoints using a multiplexed cytometric bead array (BD Biosciences). Following treatment with bortezomib, no significant changes were detected in either Th1 or Th2 serum cytokine levels: IL-2 (p=0.116), TNF-alpha (p=0.854), IFN-gamma (p=0.070), IL-4 (p=0.240), IL-6 (0.236), IL-10 (0.151) as analyzed by Wilcoxon signed ranks test. Analysis of lymphocyte subsets using a paired student’s T-test demonstrated a 38% decrease in CD56⁺ NK cells (p=0.02) and a 26% increase in CD4/CD8 ratio (p=0.0006) which appears to be secondary to a decrease in CD8⁺ cytotoxic T-cells (p=0.054). (Table 1.) In conclusion, we observe an alteration of lymphocyte subsets following only two cycles of bortezomib. Further analysis of the effects of long term treatment with bortezomib is warranted. These studies may provide insights into the role of bortezomib as an immunomodulatory agent.