1108TiP - Denosumab Compared with Zoledronic Acid for Preventing Skeletal Complications in Patients with Multiple Myeloma: A Randomized, Phase 3, Double-Blind, Double-Dummy Trial

Abstract

ABSTRACT Patients with multiple myeloma (MM) experience osteolytic bone destruction resulting in skeletal-related events (SREs: pathologic fracture, spinal cord compression, surgery or radiation to bone). Severity of bone destruction correlates with significant morbidity and is associated with decreased survival. Osteoclast activity is enhanced in MM and is primarily regulated by RANK Ligand (RANKL) and osteoprotegerin. Denosumab is a fully human monoclonal antibody which binds RANKL, preventing activation of RANK and inhibiting osteoclast differentiation, activation and survival. Bone resorption and cancer-induced bone destruction are thereby reduced. Denosumab was superior to zoledronic acid (ZA) in 3 large randomized trials in patients with breast, prostate, or solid tumors-only analysis. Denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors in many regions worldwide. The current trial will evaluate the efficacy and safety of denosumab compared with ZA in preventing skeletal complications in patients with MM. The primary endpoint will determine if denosumab is non-inferior to ZA in prevention of the first on-study SRE. If denosumab is found to be non-inferior to ZA, superiority in time to first on-study SRE and time to first-and-subsequent SRE will be assessed as secondary endpoints. Patients will be randomly assigned 1:1 to receive subcutaneous (SC) denosumab 120 mg and intravenous (IV) placebo or IV ZA 4 mg and SC placebo every 4 weeks (Q4W). Randomization will be stratified by planned autologous transplantation (yes/no), anti-myeloma therapy (novel therapy-based vs non-novel therapy-based), disease stage (International Staging System 1, 2, or 3), previous SRE (yes/no), and region (Japan vs other). Daily supplements of calcium ≥500 mg and vitamin D ≥400 IU will be strongly recommended. Patient screening and enrollment is underway. In this event-driven study, data cutoff for the primary efficacy analysis is planned for when approximately 800 patients are anticipated to experience an on-study SRE. The trial is sponsored by Amgen Inc. and registered with ClinicalTrials.gov (NCT01345019). Disclosure A. Palumbo: Advisory Board Member: Celgene and Janssen-Cilag Honoraria: Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millenium, Merck, Onyx and Amgen Consultancy: Celgene and Janssen-Cilag B.G. Durie: Advisory Board Member: Celgene Corporation, Millenium Pharmaceuticals, and Onyx Pharmaceuticals N. Raje: Advisory Board Member: Celgene, Millenium, Amgen Corporate-sponsored Research: Eli-Lilly, Acetylon R. Garcia Sanz: Honoraria: Amgen, Jansen Cilag, Celgene, Novartis O. Sezer: Advisory Board Member: Amgen, Janssen E. Terpos: Advisory Board Member: Amgen, Novartis W. Willenbacher: Advisory Board Member: Amgen Y. Qian: Employee and Stock Ownership: Amgen A. Balakumaran: Employee and Stock Ownership: Amgen All other authors have declared no conflicts of interest.