Comparative Effectiveness of Bisphoshonates In Multiple Myeloma
Authors: Mhaskar Rahul , Redzepovic Jasmina , Wheatley Keith , Clark Otavio , Glasmacher Axel , Miladinovic Branko , Kumar Ambuj , Djulbegovic Benjamin 
Published: October 2019

Abstract
Abstract 3028

Background:
Bisphosphonates are used as supportive therapy for patients with multiple myeloma (MM) to prevent bone destruction. There are multiple types of bisphosphonates. Currently, which bisphosphonate is superior to others in the treatment of patients with MM is not known. There are only three randomized controlled trials (RCTs) which employed head to head comparison of bisphsophonates in patients with MM. We performed indirect meta analysis of various bisphohsphonates and did not find the superiority of any particular type of bisphosphonate over others (Mhaskar et al Cochrane Database Syst Rev. 2010 Mar 17;3). In June 2010, Morgan et al published largest RCT to date involving 1960 MM patients employing head to head comparison of zoledronate and clodronate (Morgan et al J Clin Oncol, 2010. 28(15_suppl): p. 8021). Hence, the aim of this analysis is to assess if any specific type of bisphosphonate is superior to others incorporating data from this RCT.

Methods:
We extracted data regarding overall survival (OS), progression free survival (PFS), skeletal related events (SREs), and grade III-IV treatment related harms. Superiority of bisphosphonates was assessed by the mixed treatment comparison (MTC) as described by Lu and Ades (Lu et al. Stat Med, 2004. 23(20): p.3105-24). The fixed and random effects MTC models were compared using the deviance information criterion. Network consistency was checked using the back-calculation method. Since there was no evidence suggesting the superiority of random effects model we have reported fixed effects model estimates.

Results:
Eighteen RCTs were included enrolling 4,970 patients. For the outcome of OS the pooled analysis demonstrated a beneficial effect of zoledronate in comparison with clodronate [HR = 0.83 (95% CI: 0.73 to 0.94)] and etidronate [HR = 0.48 (95% CI: 0.31 to 0.71)]. However, there was no evidence that zoledronate was superior to pamidronate [HR = 0.84 (95% CI: 0.61 to 1.13)], or ibandronate [HR = 0.70 (95% CI: 0.42 to 1.11)] for the outcome of OS. Zoledronate was superior to clodronate [HR = 0.88 (95% CI: 0.78 to 0.99)] for the outcome PFS. Zoledronate was also superior to clodronate [HR = 0.75 (95% CI: 0.64 to 0.88)], pamidronate [HR = 0.65 (95% CI: 0.42 to 0.95)], and ibandronate [HR = 0.44 (95% CI: 0.26 to 0.72)] for the outcome of SREs. There were no significant adverse effects associated with the administration of bisphosphonates. Only three RCTs reported the incidence of osteonecrosis of jaw (ONJ). The incidence of ONJ was higher in zoledronate [OR: 12.03 (95% CI: 3.68 to 39.26)] compared to clodronate. We also identified 7 observational studies evaluating 1068 patients for ONJ. These studies suggest that ONJ may be a common event (range: 0%− 51%).

Conclusion:
The results demonstrate a beneficial effect of zoledronate on OS compared to clodronate and etidronate. Similarly, zoledronate was superior to clodronate in improving PFS. zoledronate is superior to clodronate, pamidronate and ibandronate in prevention of SREs in patients with MM. In the context of MTC uncertainty analysis, zoledronate ranked as the best treatment followed by clodronate and pamidronate. These finding underscore the need for RCT with head to head comparison of zoledronate and pamidronate for their efficacy and safety in MM patients.

Disclosures:
No relevant conflicts of interest to declare.