Progression-Free Survival Subset Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study
Authors: Terpos Evangelos , Willenbacher Wolfgang , Shimizu Kazuyuki , García-Sanz Ramon , Glennane Anthony , Guan Xuesong , Niepel Daniela , Raje Noopur 
Published: October 2019

Abstract
Introduction: The full primary analysis of the international, double-blind, double-dummy, randomized controlled phase 3 study (20090482) that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing skeletal-related events (SREs) in newly diagnosed patients with multiple myeloma (NDMM) met the primary noninferiority endpoint of time to first on-study SRE (Raje N, et al. Lancet Oncol. 2018). Overall survival, a secondary endpoint, was similar in both arms; however, this result was based on a limited number of events having occurred (denosumab 14.1% vs zoledronic acid 15.0%), which might have affected the ability to detect a difference and also may have been further diluted by multiple subsequent lines of therapy. In addition, results from an exploratory endpoint, progression-free survival (PFS), demonstrated a clinically meaningful 10.7 months median PFS benefit (hazard ratio [HR], 0.82; 95% CI, 0.68-0.99; descriptive P=0.036; Table 1) of denosumab versus zoledronic acid on top of standard of care first-line anti-myeloma treatment. This result provided suggestive clinical evidence of a potential anti-myeloma effect based on RANKL inhibition. Here we present further analysis of PFS according to prespecified subgroups of patients from the 20090482 study.
Methods: Adult NDMM patients with ≥1 documented lytic bone lesion were included in this study. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo every 4 weeks. Both groups also received investigators' choice of first-line anti-myeloma therapy. The exploratory endpoint PFS (time from randomization to date of first overall disease progression or death due to any cause, investigator identified) was estimated using the Kaplan-Meier method and analyzed using a Cox proportional hazards model stratified by randomization stratification factors and adjusted for baseline covariates. PFS subgroup analyses were conducted according to the novel first-line therapy use (proteasome inhibitor [PI] use, immunomodulatory drug [IMiD] use, PI and IMiD use) and the intent to receive an autologous stem cell transplant (ASCT; yes, no).
Results: Overall, 1718 patients (denosumab, n=859; zoledronic acid, n=859) were included in the primary analysis. By the time of the primary analysis cut-off, 219 patients (25.5%) in the denosumab group and 260 patients (30.3%) in the zoledronic acid group had a PFS event. The percentages of patients receiving novel first-line therapy were balanced between the two groups (see Table 1). For patients who had received first-line PI-based therapy, PFS favored denosumab vs zoledronic acid (median, 40.0 vs 35.4 months; HR, 0.74; 95% CI, 0.58-0.95; descriptive P=0.019; Table 1). For patients who had received first-line IMiD only-based therapy, median PFS was not reached with denosumab therapy and was 34.3 months with zoledronic acid therapy (HR, 0.85; 95% CI, 0.53-1.35; descriptive P=0.49). Median PFS was also not reached for either denosumab or zoledronic acid for patients who had received first-line PI plus IMiD therapy (HR, 0.95; 95% CI, 0.62-1.46; descriptive P=0.82). For patients with the intent at baseline to receive an ASCT (54% in each treatment group; Table 1), PFS favored denosumab vs zoledronic acid (median, 46.1 vs 35.7 months; HR, 0.65; 95% CI, 0.49-0.85; descriptive P=0.002).
Conclusion: Overall results from this subanalysis indicated PFS impact and benefit of denosumab on top of anti-myeloma therapy, independent from first-line novel therapy which was balanced among treatment arms, mainly in the subgroup of patients receiving PI only-based first-line therapy. In addition, benefit was observed in patients with the intent to receive ASCT, described with an impressive HR of 0.65.

Disclosures
Terpos: Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; BMS: Consultancy; Novartis: Consultancy. Willenbacher:Amgen: Honoraria, Other: Steering board, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria. Shimizu:Daiichi-Sankyo, Co., Ltd: Consultancy; Fujimoto Pharmacuetical Corp: Consultancy; Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member. García-Sanz:Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership. Niepel:Amgen Inc.: Employment, Equity Ownership. Raje:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; Amgen Inc.: Consultancy.