Early vs delayed bone-modifying agent initiation and zoledronic acid vs denosumab in newly diagnosed multiple myeloma.

Abstract

e19573 Background: Bone-modifying agents (BMAs) reduce skeletal-related events (SREs) in multiple myeloma, but real-world practice varies in both initiation timing and agent selection. Methods: Using the TriNetX Research network (2012–2024), adults with multiple myeloma initiating systemic therapy who received a BMA. Patients were categorized as early (≤60 days) vs delayed (61–180 days) BMA initiation relative to systemic therapy start. A 60-day landmark from systemic therapy initiation was applied to minimize immortal time bias. In a separate analysis, zoledronic acid (ZA)-only and denosumab-only users were compared. Cohorts were 1:1 propensity-score matched on demographics, comorbidities, renal function/CKD stage, baseline bone disease and prior SREs, myeloma treatment (including ASCT), and key laboratory values (including creatinine, calcium, and albumin). Outcomes included 1-year SRE risk and time-to-first SRE (Kaplan–Meier/Cox). Because median time-to-SRE was not reached, restricted mean time to first SRE (RMST) at 1 year was reported. Secondary safety outcomes included overall survival (OS) and safety outcomes (renal toxicity and hypocalcemia, lab-based when available, within 90 days; osteonecrosis of the jaw [ONJ] through 10 years). Results: After matching, 1,799 patients per cohort were included in the early versus delayed initiation analysis. Early initiation was associated with a lower 1-year SRE risk (16.0% vs 19.5%; p=0.0068) and a longer RMST to first SRE (315 vs 309 days). There was no significant difference in 10-year OS (49.7% vs 52.3%; p=0.2077), although 5-year OS was modestly higher with early initiation (71.3% vs 67.2%; p=0.0454). In the agent comparison, 1,233 matched patients per cohort received ZA or denosumab. There were no significant differences in 1-year SRE risk (21.7% vs 19.6%; p=0.196) or overall survival at 5 or 10 years. Renal toxicity within 90 days was lower with ZA (19.5% vs 25.8%; p=0.0002), while hypocalcemia rates were similar (60.6% vs 62.4%; p=0.341). ONJ events were infrequent but occurred less often with ZA (event-free probability at 10 years: 96.6% vs 95.3%; p=0.0068). Conclusions: In this large real-world cohort, initiating BMAs within 60 days of systemic therapy was associated with fewer early SREs compared with initiation at 61–180 days, without a difference in long-term survival. Zoledronic acid and denosumab demonstrated similar SRE and OS outcomes, supporting individualized agent selection, with distinct renal and ONJ safety profiles.