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

Intravenous bisphosphonates have demonstrated efficacy in preventing the occurrence of skeletal-related 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 weeks³; 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.

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 models⁴ 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 accounting for multiple comparisons (≤50). Data were analyzed using SAS statistical software version 9.4 (SAS Institute).

We identified 4281 eligible patients with MM, with a mean (SD) age at diagnosis of 64.8 (11.5) years, and 2452 (57.3%) were men. The median (interquartile range [IQR]) follow-up was 13.3 (8.8-17.3) months from MM diagnosis. Of 4281 patients who began IV bisphosphonate treatment, 2567 (60%) experienced at least 1 SRE (Table 1). During follow-up, we identified a total of 3345 SREs during IV bisphosphonate therapy, and in the 180 days after treatment discontinuation, the overall SRE rate was 96.2 (95% CI, 93.0-99.5) events per 100 person-years (Table 2). Adjusted Andersen-Gill risk estimates for the longer than 12 weeks (HR, 0.90; 95% CI, 0.75-1.09), 5 to 8 weeks (HR, 1.00; 95% CI, 0.89-1.13) , and 9 to 12 weeks (HR, 0.95; 95% CI, 0.84-1.08) dosing schedules were not statistically significant compared with the every 4 weeks dosing schedule. No significant or clinically meaningful differences were found in risks of first and subsequent SREs in Prentice-Williams-Peterson models.

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.

Accepted for Publication: May 22, 2021.

Published: July 27, 2021. doi:10.1001/jamanetworkopen.2021.18410

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Zhou J et al. JAMA Network Open.

Corresponding Author: Gregory S. Calip, PharmD, MPH, PhD, Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, 833 S Wood St, MC 871, Chicago, IL 60612 (gcalip@uic.edu).

Author Contributions: Dr Calip had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zhou, Sweiss, Han, Calip.

Acquisition, analysis, or interpretation of data: Zhou, Sweiss, Ko, Patel, Chiu, Calip.

Drafting of the manuscript: Zhou, Sweiss, Han, Patel, Calip.

Critical revision of the manuscript for important intellectual content: Zhou, Sweiss, Ko, Chiu, Calip.

Statistical analysis: Zhou, Calip.

Obtained funding: Chiu, Calip.

Administrative, technical, or material support: Zhou, Sweiss, Calip.

Supervision: Calip.

Conflict of Interest Disclosures: Dr Ko reported receiving grants from Pfizer outside the submitted work. Dr Patel reported personal fees from Amgen, Celgene , and Janssen outside the submitted work. Dr Calip reported being an employee of Flatiron Health, owning stock in Roche, and receiving grants from Pfizer outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the National Institutes of Health, National Center for Advancing Translational Sciences (grant No. KL2TR002002), National Heart, Lung and Blood Institute (grant No. R21HL140531), and National Cancer Institute (grant Nos. R01CA223662, U54CA202995, U54CA202997, and U54CA203000).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: Edith Nutescu, PharmD, and Todd Lee, PhD, (University of Illinois at Chicago) provided comments and feedback on this work. They were not compensated for this work.