Results of a Multicenter Open-Label Randomized Trial Evaluating Infusion Duration of Zoledronic Acid in Multiple Myeloma Patients (the ZMAX Trial)
Discussion
During the past decade, bisphosphonate therapy has become an important adjunctive treatment to prevent the emergence, or worsening, of SREs in patients with MM involving the bone.15 Kidney failure is a common and severe complication of MM that may be exacerbated by chronic administration of zoledronic acid.7 A study evaluating zoledronic acid in patients with cancer and bone metastases suggests that increasing the infusion time decreases the Cmax, which may result in fewer renal AEs.[9] and [12] This study was designed to assess whether prolonging the infusion time of zoledronic acid from the recommended 15 to 30 minutes would improve kidney safety in MM patients, as evidenced by fewer rises in SCr levels. To our knowledge, this is the only trial that has been designed to evaluate the impact of infusion duration on renal effects in this population.
The 12-month results of this pilot study showed a trend toward improved renal safety with the longer infusion time, this difference not being statistically significant. By 24 months, however, there were no differences in SCr level elevations between the two groups. The clinically relevant SCr increases observed in our study, however, differ from those reported by Rosen and colleagues,[5] and [6] who first evaluated zoledronic acid for patients with MM. In that study, 4%–11% of patients experienced kidney function deterioration, manifested by SCr increases, which is much lower than the rate observed in our study. However, several differences exist between our trial and the Rosen study. The Rosen study included both breast cancer patients with at least one bone metastasis and Durie-Salmon stage 3 MM patients with at least one osteolytic lesion, whereas our study only included MM patients with at least one bone lesion. Additionally, the criteria for defining a clinically relevant SCr increase differ between the two studies; therefore, one cannot directly compare the incidence of kidney dysfunction between these two studies. Although in our study the sample size was small, confidence intervals were wide, and protocol deviations did not permit a robust comparison, the results of this pilot study suggest that the longer infusion time of 30 minutes every 3–4 weeks for 2 years for MM patients with bone disease is also safe and well-tolerated.
As expected, PK data showed that the median zoledronic acid concentrations were greater in the samples obtained from the 15-minute group compared to those from the 30-minute group. This effect was observed in samples obtained both 5 minutes before the end of infusion and at the end of infusion.
Increasing the infusion time did not significantly alter the AE profile and was not associated with any new or unexpected AEs. The incidence rates of deaths, SAEs, treatment-related AEs, and overall AEs were generally comparable between treatment groups. Overall, the incidence rates of reported SREs and ONJ were as expected for this patient population, which are important factors when considering zoledronic acid for patients with MM, where the goal of ongoing monthly IV bisphosphonate therapy is to prevent the development of new SREs without increasing the risk of AEs, such as ONJ.
Finally, the FDA-approved current labeling for zoledronic acid recommends decreasing the dose of this bisphosphonate based on baseline kidney function.7 Because these recommendations were not in place at the time that this study was designed, whether the implementation of these dosing guidelines for patients with MM along with varying infusion durations would have impacted the results observed in our study cannot be ascertained.
In summary, the results of this study suggest that the safety profile of IV zoledronic acid is similar regardless of a 15-minute or a 30-minute infusion duration. However, because the study was not powered to detect statistical significance and the current renal dosing guidelines for zoledronic acid were not used in this study, large randomized studies, using current dosing recommendations, will be required to further assess the effects on kidney safety of prolonging the infusion time of ongoing monthly IV zoledronic acid therapy for patients with MM.
Acknowledgments
The authors thank Syntaxx Communications, Inc., specifically, Kristin Hennenfent, PharmD, MBA, BCPS, and Lisa Holle, PharmD, BCOP, who provided manuscript development and medical writing services, and Holly Matthews, BS, who provided editorial services, with support from Novartis Pharmaceuticals Corporation. We also thank all participating patients and study personnel. Research support was provided by Novartis Pharmaceuticals Corporation (East Hanover, NJ).
