Bortezomib significantly delays development of paraplegia in the 5TGM1 murine model of myeloma bone disease

3267 Despite recent therapeutic advances, there has been no significant improvement in overall survival of patients with multiple myeloma. Bortezomib (VELCADE®), a proteasome inhibitor whose anti-myeloma efficacy and safety has been validated in recent clinical trials, induces significant cytotoxicity in myeloma cells and reduces skeletal tumor burden in the well characterized murine 5TGM1 myeloma model compared with vehicle-treated controls. However, it remains unknown if bortezomib is also efficacious with respect to survival. Here, we evaluated the effect of bortezomib, using time to paraplegia as a surrogate end point for survival, in myeloma-bearing mice. Skeletal tumor growth and progression were followed temporally in mice by whole body optical fluorescence imaging, since there is concordance between development of paraplegia and extent of tumor in skeleton determined by GFP imaging. Syngeneic C57BL/KaLwRij mice inoculated with 5TGM1-GFP cells were treated, from time of tumor inoculation for 28 days, either with vehicle or bortezomib (0.5 or 1mg/kg). Bortezomib, which was well tolerated with no overt toxicity as evaluated by weight gain and at necropsy, dose-dependently prolonged time to development of paraplegia in tumor-bearing animals. Compared to vehicle-treated mice, time to paraplegia was significantly longer in bortezomib (1mg/kg)-treated mice (median, 31 vs 54 days). In contrast to vehicle-treated tumor-bearing mice which had all succumbed by day 33 post-tumor cell inoculation, all bortezomib-treated mice remained alive and well 49 days after tumor cell inoculation although small fluorescent tumor foci were detectable in parts of the skeleton in 5/10 mice from day 42. An additional group of mice, inoculated with tumor cells and treated with 1mg/kg bortezomib continuously from time of tumor cell inoculation, remained alive and well past day 60. To further delineate mechanisms by which bortezomib exerts its effect to delay development of paraplegia, mice inoculated with 5TGM1 cells were treated with vehicle for the first 21 days and thereafter all mice with confirmed skeletal tumors were randomized to receive either vehicle or bortezomib (1mg/kg) continuously. Bortezomib, begun after myeloma disease establishment, extended time to paraplegia relative to tumor-bearing mice that received vehicle (median, 43 vs 27 days). Despite its reported in vitro anti-osteoclastogenic activity, there was surprisingly no significant difference in number or activity of TRAP+ osteoclasts in bone in vivo between bortezomib- and vehicle-treated groups, at doses tested. Together, these results demonstrate efficacy of clinically-achievable doses of bortezomib in prolonging time to paraplegia in myeloma-bearing mice and highlight the potential utility of the 5TGM1 model in evaluating combinations of bortezomib and chemotherapeutic drugs for enhanced efficacy in prolonging survival.