Evaluation of Frequency of Administration of Intravenous Bisphosphonate and Recurrent Skeletal-Related Events in Patients With Multiple Myeloma

This cohort study examines the risk of skeletal-related events associated with the frequency of bisphosphonate treatment in patients with multiple myeloma.


Introduction
Intravenous bisphosphonates have demonstrated efficacy in preventing the occurrence of skeletalrelated events (SREs), 1 defined clinically by hypercalcemia, spinal cord compression, pathological fracture, and other conditions requiring surgery or radiotherapy to the affected bone.
Bisphosphonates were the only treatment indicated for symptomatic bone disease in patients with multiple myeloma (MM) prior to the approval of denosumab in 2018. 2 Dosing interval studies have resulted in changes in clinical practice that de-escalate or extend the frequency of treatment from the recommended schedule of every 4 weeks to every 8 or 12 weeks 3 ; however, these studies mostly included patients with solid tumors with bone metastases vs patients with MM with osteolytic bone disease, and they typically evaluated risks of a first-time SRE, excluding information on recurrences.
To address these knowledge gaps, we investigated the association between bisphosphonate administration frequency with risks of recurrent SREs.

Methods
This retrospective cohort analysis using the IBM MarketScan Databases from January 1, 2009, through September 30, 2015, was approved by the University of Illinois at Chicago institutional review board. The requirement for informed consent was waived because these analyses of deidentified data did not meet the definition of human participant research, as defined by 45 CFR 46.102(e), 21 CFR 50.3(g), and 21 CFR 56.102(e). Data analyses were conducted between September 2019 and February 2020. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies was used in reporting this study. Following a 6-month delayed entry period, eligible patients ages 18 years and older with newly diagnosed MM and who initiated an intravenous (IV) bisphosphonate therapy (pamidronate, zoledronic acid, or both) regimen were included in the analytical cohort. Time-varying bisphosphonate administration frequency was defined using recommended intervals of every 4 weeks or delayed intervals of 5 to 8 weeks, 9 to 12 weeks, or longer than 12 weeks, assessed in consecutive 60-day windows after bisphosphonate initiation. The primary outcome of interest was recurrent SRE, defined as spinal cord compression, pathological fracture, or other condition requiring radiotherapy or surgery to the bone, assessed using diagnosis and procedure administrative claims codes.
Adjusted hazard ratios (HRs) and 95% CIs were calculated using robust estimators and SEs. We estimated the association of bisphosphonate use patterns with risk of first SRE with Andersen-Gill models 4 and with risk of subsequent recurrent SRE with Prentice-Williams-Peterson models, 5 with adjustment for measured confounders and time-dependent treatment. We used 21-day windows in cluster-related SRE claims from the same episode to identify recurrent SREs occurring independently of previous events; robust sandwich covariance matrix estimates were calculated to account for intracluster dependence of at-risk periods from the same individual. All tests were 2-tailed and considered to be statistically significant at P < .001 to maintain a family-wise type I error rate of .05

Discussion
The findings of this cohort study agree with findings from randomized clinical trials showing that less frequent IV bisphosphonate administration frequency was associated with comparable recurrent SRE risk reductions as more frequent administration. 6 In clinical practice, there are many reasons why oncologists administer IV bisphosphonates at longer dosing intervals, and additional attention should consider the potential benefits and risks of more or less frequent bone-directed therapy. One notable strength of our study was that we used a robust approach to assess first and recurrent SREs from the date of IV bisphosphonate initiation through 180 days after treatment discontinuation.
However, our findings should be interpreted considering its limitations: in this observational study, misclassification and unmeasured confounding cannot be ruled out.
Multiple reasons exist for delays or disparities in supportive care with IV bisphosphonates, including adverse events, such as osteonecrosis of the jaw, and other circumstances compromising the safety of supportive cancer care, such as the COVID-19 pandemic. In line with other clinical studies that primarily include patients with bone metastases, our findings support the relative safety, in terms of SRE risk, among patients with MM when the frequency of bisphosphonate therapy is reduced.