Identification of Key Factors That Are Associated with the Clinical Anti-Tumor Effect of Zoledronic Acid in Multiple Myeloma

Despite compelling preclinical data, only anecdotal reports have shown that zoledronic acid (ZOMETA, Zol) exerts an anti-multiple myeloma (MM) effect in humans. We postulate that this could be related to the dose-intensity of Zol, since anti-MM effects were clearly observed in mice given a dose equivalent of 8.0 mg (8.0 EQmg) weekly; but not in humans who received only 4.0 mg monthly. We describe 3 patients, who were treated with 2- to 3-fold higher dose-intensity of Zol; who demonstrated brisk clinical improvements. When the equivalent dose of Zol was normalized to the patient’s body surface area, the maximum EQmg rate of Zol administered was between 11.4 EQmg^max and 12.0 EQmg^max per 28 days. Since the potency of Zol is measured by the degree of inhibition of differentiation of osteoclast precursors (pOC) (i.e. monocytes) to osteoclasts (OC) in vitro, we next investigated whether high-dose rate Zol had an in vivo inhibitory effect on this renewable pOC pool. We demonstrate that there was a linear relationship between the absolute monocyte count (AMCO) and the stage of MM at presentation. Specifically, patients with International Staging System (ISS) stage I disease had the lowest AMCO levels, whereas ISS stage III patients had the highest. We also show that treatment with Zol resulted in progressive decreases in AMCO levels, and these changes correlated with response to therapy. By contrast, AMCO levels increased in patients who either failed to respond to treatment or who had progressive disease. Finally, since Zol is known to induce the gamma delta T cells in vitro, we studied the recovery patterns of various T cell subsets following treatment using a high dose-intensity Zol-based regimen called “dtZ”. To our surprise, there was no difference in gamma delta T cell numbers, but instead bone marrow CD4+ CD25+ regulatory T cells were significantly decreased in patients who achieved CR, as compared to those that did not. These data suggest that high dose-intensity Zol has a very desirable anti-tumor profile in MM that could be related to inhibition of both myelomagenic processes as well as the immunosuppressive elements of host anti-tumor defense.