Zoledronic Acid May Improve Survival Compared to Pamidronate in Patients with MM and High BALP Levels: Univariate and Multivariate Models of Hazard Ratios.
Authors: Berenson James R. , Dimopoulos Meletios A. , Chen Yin-Miao 
Published: October 2019

Abstract
In untreated patients with multiple myeloma, elevated bone-specific alkaline phosphatase (BALP) levels have shown a significant association with bone pain, bone lesions, and pathologic fractures, and have been correlated with reduced survival (Fonseca R, et al. Br J Haemotol.2000;109:24–29). Zoledronic acid reduces the risk of skeletal morbidity and levels of biochemical markers of bone metabolism in patients with bone lesions from multiple myeloma. Zoledronic acid has also demonstrated antimyeloma effects in preclinical studies in vitro and in vivo using mice bearing human or mouse myeloma. Therefore, it is possible that zoledronic acid may not only prevent skeletal complications but also increase survival in patients with multiple myeloma. We conducted a retrospective exploratory analysis of patients with multiple myeloma and bone lesions as part of a large, randomized, controlled trial comparing infusions of zoledronic acid 4 mg and pamidronate 90 mg to assess the effect of zoledronic acid on survival based on baseline bone marker levels. In the overall population of patients with multiple myeloma (N=353), survival was comparable between groups. The subset of multiple myeloma patients who had information on baseline BALP levels were examined in these analyses (n=212; 4 mg zoledronic acid [n=109] or 90 mg pamidronate [n=103]). Patients received treatment for up to 24 months with a final assessment at 25 months. Risk of death was assessed in univariate and multivariate models using Cox regression methodology. Factors included in the multivariate analyses were prior skeletal-related events and baseline ECOG performance status. Among patients who had a baseline BALP assessment, zoledronic acid significantly increased the 25-month overall survival compared with pamidronate (76% versus 63%; P=.026). In the univariate and multivariate analyses, zoledronic acid significantly reduced the risk of death by approximately 42% compared with pamidronate (P=.03 for both). The subset of patients was then retrospectively stratified by baseline BALP levels according to the following criteria: low BALP (<146 U/L) and high BALP (≥146 U/L). Among patients who had low baseline BALP (n=123), 25-month survival was similar for both treatment groups. Although zoledronic acid reduced the risk of death in this subset by approximately 30% compared with pamidronate in the univariate and multivariate analyses, the between-group differences were not statistically significant (P>.2 for both). In contrast, among patients with high baseline BALP (n=89), zoledronic acid significantly improved survival compared with pamidronate (82% versus 53%; P=.041). Zoledronic acid significantly reduced the risk of death in this subset by approximately 56% compared with pamidronate in both the univariate and multivariate analyses (P<.05 for both). These exploratory analyses suggest that, in addition to its established benefits in preventing skeletal complications, zoledronic acid may improve survival compared with pamidronate in patients with multiple myeloma who have high BALP levels. Prospective trials are needed to investigate the improved survival in this subset; the high-BALP subset may have higher statistical power to distinguish between the 2 bisphosphonates (higher event rate), or these patients may still have coupled bone metabolism and better recovery after response to antiresorptive therapy.