P-151: Incidence of adverse events in patients with Multiple Myeloma who continued with Denosumab after receiving Denosumab or Zoledronic acid: an open-label extension study

Abstract

<h3>Background</h3> In a randomized phase 3 study of denosumab (XG) vs zoledronic acid (ZA) in patients with newly diagnosed multiple myeloma (MM) (Raje et al. Lancet Oncol 2018), XG was shown to be non-inferior to ZA and had a safety profile comparable to that of ZA with less renal toxicity. The mean treatment duration was 17.5 months for XG, and interest remains on the long-term safety profile of XG. Here, we report safety in the open-label extension (OLE) phase of this study of further XG treatment in patients with newly diagnosed MM. <h3>Methods</h3> This was an international, phase 3, randomized, double-blind, active-controlled study comparing XG with ZA in patients with newly diagnosed MM (NCT01345019). Due to the positive benefit-risk profile of XG, patients were offered open-label XG for up to 2 years. In the OLE phase, eligible patients receiving XG or ZA from the double-blind phase continued with or switched to XG that was administered subcutaneously at 120 mg every 4 weeks. Patients who received XG in the double-blind phase are designated as XG/XG (n = 426), while those receiving ZA are designated as ZA/XG (n = 418). All patients were strongly recommended to receive vitamin D and calcium supplementation, necessary to treat or prevent hypocalcemia. <h3>Results</h3> The cumulative mean exposure to XG for the entire study period consisting of double-blind and OLE phases was 29.2 months. The cumulative mean exposure to XG in the OLE phase was 17.5 months for XG/XG and 17.6 months for ZA/XG patients. Among 844 patients who received open-label XG, 443 (52.5%) were male, 401 (47.5%) were female, and the median age was 62 years. At diagnosis, 303 (35.9%) patients were at ISS stage I, 315 (37.3%) at stage II, and 208 (24.6%) at stage III. At study entry, 557 (66.0%) patients had a history of skeletal-related events. During the OLE phase, 361 (84.7%) XG/XG and 366 (87.6%) ZA/XG patients had treatment-emergent adverse events (AEs). Treatment-emergent AEs led to discontinuation of the investigational product in 99 (23.2%) XG/XG and 81 (19.4%) ZA/XG patients. The treatment-emergent AEs of interest for XG/XG and ZA/XG patients, respectively, in the OLE phase included hypocalcemia (7.0%, 7.2%), AEs potentially associated with hypersensitivity (12.0%, 11.5%), musculoskeletal pain (32.4%, 33.7%), and infections and infestations (55.9%, 58.1%). The incidence of positively adjudicated osteonecrosis of the jaw (ONJ) that occurred during the OLE phase was 7.7% for XG/XG (grade 3: 2.3%) and 6.2% for ZA/XG (grade 3: 2.4%). No adjudicated positive atypical femur fracture events were reported. As of October 25, 2019, a notably higher number of ONJ events resolved in XG/XG patients (14 [42%]) than in ZA/XG patients (6 [23%]). <h3>Conclusions</h3> The safety results were comparable to those of previous skeletal-related event studies. XG has an acceptable safety profile when administered for >2 years in patients with MM.