Comparison of Skeletal Complications and Treatment Patterns Associated with Early Versus Delayed Zoledronic Acid Therapy In Multiple Myeloma
Authors: Yu Andrew Peng , Bensimon Arielle G , Marynchenko Maryna , Wu Eric Qiong , Namjoshi Madhav , Guo Amy , Ericson Solveig G , Raje Noopur 
Published: October 2019

Abstract
Abstract 1956

Introduction:
Zoledronic acid (ZOL) is currently the standard of care to reduce/delay progressive skeletal-related events (SREs) in multiple myeloma (MM). However, limited evidence is available on the relationship between the timing of ZOL initiation and patient outcomes in this indication. This study retrospectively compared the risks of SREs and ZOL treatment discontinuation associated with early versus delayed ZOL therapy for patients with symptomatic MM.

Methods:
Data were collected from a physician-administered medical chart review among patients with a confirmed diagnosis of symptomatic MM treated after 01/01/2002. Participating hematologists and oncologists were asked to provide detailed information for patients meeting the inclusion criteria, including demographics, comorbidity profiles, disease severity and bone health at diagnosis, bisphosphonate treatment patterns, and timing of SREs. Analyses were conducted among patients who received early or delayed ZOL therapy, defined respectively as initiating ZOL ≤60 days versus >60 days after the first symptomatic MM diagnosis. Kaplan-Meier analysis with a log-rank test was performed to compare the risk of SREs between the study cohorts. Patients were followed from their diagnosis date until the first subsequent SRE, or until loss of follow-up. SREs included pathologic fractures (vertebral or non-vertebral), spinal cord compression, radiation to relieve bone pain, hypercalcemia, and prophylactic surgery to treat impending fractures. Cox proportional hazard modeling was used to compare the risk of SREs associated with early versus delayed ZOL treatment, controlling for demographic factors, stage of MM, bone health status, and presence of major comorbidities at diagnosis. To evaluate the implications of early treatment on persistence, risk of ZOL discontinuation was compared between the cohorts in a survival analysis framework. Time to discontinuation for any reason was evaluated using the Kaplan-Meier method, which followed patients from the date of ZOL initiation; as a sensitivity analysis, time to discontinuation for reasons other than stable or remitted MM was also assessed.

Results:
A total of 312 patients met the study inclusion criteria. Median time to ZOL initiation from symptomatic MM diagnosis was 25 days in the early treatment cohort (N=126) and 242 days in the delayed treatment cohort (N=186). Baseline characteristics assessed at the time of diagnosis were generally well-balanced between the study groups; however, patients with early ZOL therapy were older on average (62.3±10.0 vs. 60.1±10.6 years; p=.022), were more likely to have Durie-Salmon stage III MM (57.9% vs. 44.1%; p=.034), and had a higher average number of lytic lesions (7.1±7.8 vs. 4.8±7.0; p<.001) than those with delayed therapy. Following the diagnosis date, time to the first SRE was significantly longer for patients who received early treatment with ZOL (p=.005). At 2 years post-diagnosis, the SRE-free rate was 74.6% in the early treatment group compared to 56.5% in the delayed treatment group. Adjusting for baseline characteristics, Cox regression analysis confirmed that early ZOL therapy was associated with a significantly lower risk of any SRE (hazard ratio=.625 vs. delayed ZOL therapy; p=.029). The risk of ZOL treatment discontinuation over time was also significantly lower in the early treatment group. At 2 years from ZOL initiation, rates of discontinuation for any reason were 9.6% versus 16.4% among patients with early versus delayed therapy, respectively (p=.032). Rates of discontinuation for reasons other than stable or remitted MM showed a similar pattern in the early versus delayed treatment groups (6.5% vs. 12.0% at 2 years; p=.044).

Conclusion:
This retrospective chart review among patients with symptomatic MM found that early treatment with ZOL was significantly associated with reduced risks of SREs and with better persistence compared to delayed treatment. Results indicate that early initiation of ZOL therapy may have important clinical implications in MM.

Disclosures:
Yu: Novartis Pharmaceuticals Corporation: Consultancy. Bensimon:Novartis Pharmaceuticals Corporation: Consultancy. Marynchenko:Novartis Pharmaceuticals Corporation: Consultancy. Wu:Novartis Pharmaceuticals Corporation: Consultancy. Namjoshi:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Guo:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Raje:Novartis Pharmaceuticals Corporation: Consultancy.