Comparison of Denosumab versus Bisphosphonates on Progression-free and Overall Survival in Newly Diagnosed Multiple Myeloma: A New User, Active Comparator Analysis of Real-World Data

Background: Denosumab and bisphosphonates are similarly efficacious in preventing skeletal-related events in multiple myeloma (MM). Secondary analyses of randomized clinical trials suggested that denosumab may have an anti-MM effect that improves progression-free survival (PFS) and overall survival (OS). Evidence demonstrating the real-world effectiveness of denosumab compared to standard bisphosphonate bone-modifying treatment is lacking.

Objectives: To compare the impact of denosumab versus bisphosphonates on PFS and OS in MM patients initiating first-line (1L) therapy.

Methods: This was a new user, active comparator retrospective cohort study of patients receiving bone-modifying treatment with either bisphosphonates alone (zoledronic acid or pamidronate) or denosumab (with or without bisphosphonates) within 90 days of 1L initiation in the nationwide Flatiron Health electronic health record-derived de-identified database. This analysis included adults (≥18 years) newly diagnosed with MM between January 2018 and September 2021. Patient demographics and clinical characteristics were determined using structured and unstructured data, curated via technology-enabled abstraction. Patients were followed from 1L initiation, with a delayed entry of 90 days, until progression (PFS analysis), death (OS analysis), last confirmed activity, or end of the study period (December 2021). Propensity score-weighted Cox proportional hazards models (accounting for baseline age, sex, race/ethnicity, practice type, MM treatment regimen, M-protein type, & transplantation) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI).

Results: Among 1089 denosumab users and 964 bisphosphonate users in this analysis, 54% of patients were male and 66% initiated triplet regimens. Compared to bisphosphonate users before weighting, denosumab users were older (mean, 69.2 vs. 67.0 years, p<.01), more likely to be treated in community oncology practices (91% vs. 87%, p<.01) and had a higher proportion of White (57% vs. 52%) and Black (17% vs. 14%) patients and a lower proportion of Latinx (6% vs. 9%) patients (p <.01). In propensity score-weighted models, denosumab use was not associated with PFS (HR 0.89, 95% CI 0.74-1.08, p=.20) nor OS (HR 0.93, 95% CI 0.75-1.14, p=.50) when compared to bisphosphonate use.

Conclusions: In this largest-ever real-world comparison of newly diagnosed MM patients receiving denosumab or bisphosphonates, we did not observe a signal for denosumab benefit consistent with the results of exploratory clinical trial analyses. These findings should be considered alongside other important factors, including renal function and potential financial toxicity, in treatment decision-making for osteolytic bone disease in MM.