Retrospective analysis of ALP variation in 2 large Bortezomib trials in the refractory setting confirmed the finding. In the SUMMIT trial (Zangari, et al., 2005), 77 patients were evaluated. The media increment ALP in levels of responding patients (patients with >50% decrease in paraprotein) upon completion of 3 cycles of therapy was statistically higher of those individuals with less than partial response (week 8, P=0.0015; responder range, 62-837 mL/L). In the APEX trial (Zangari et al. 2005), 422 patients were analyzed; 217 patients were randomized to bortezomib, 205 to dexamethasone. Within the bortezomib arm, the increment in serum ALP levels in responder patients (>CR) was statistically higher at week 3 (P=0.014), week 6 (P=0.002; responder rage, 31-272 mL/L) and week 9 (P=0.036). Comparing only responders patients in both arms of the study, we observed a significantly higher median ALP increase in the bortezomib compared to the dexamethasone arm (P<0.01; responder ran, 31-272 mL/L) (Zangari et al., 2007). A 25% increase in ALP (N=105) at week 6 was also the strongest indicator associated with quality of response (P<0.0001) and also with the time to progression (206 vs. 169 days) relative to patients with less than a 25% increase in ALP (N=228; P=0.01) (Zangari et al., 2007). We will now test the bone anabolic effect of bortezomib in a cohort of smoldering multiple myeloma patients.