Extending Dosing Intervals of Denosumab As a Maintenance Strategy in Multiple Myeloma: A Real-World Experience at a Large Academic Cancer Center
Authors: Kim E. Bridget , Kahn Yael N. , Branagan Andrew R. , Yee Andrew J. , Burke Jill N. , Harrington Cynthia C. , Agyemang Emerentia , Raje Noopur S. , O'Donnell Elizabeth K. 
Published: November 2020

Introduction: Osteolytic bone destruction is a defining characteristic of multiple myeloma (MM) and patients with MM have an increased risk of skeletal related events (SREs) - including pathologic fractures, spinal cord compression, and the need for radiation therapy or surgery to bone - which is a significant source of impaired quality of life and mortality. Bone modifying agents (BMAs), such as bisphosphonates or denosumab, have shown to substantially decrease or delay onset of new SREs. Optimal duration or frequency of a BMA, however, is less clear. Data supporting zoledronic acid administered at an extended dosing interval of every 3 months compared to the traditional 3-4 weeks interval in patients with MM have been previously reported in the Z-MARK study (Raje N, et al. Clin Cancer Res. 2016). Denosumab, an anti-RANKL monoclonal antibody, received approval for the prevention of SREs in patients with MM in early 2018, but there is a paucity of data for extending denosumab dosing intervals as maintenance. Herein, we report real-world observations by characterizing our use, safety and efficacy, and other practical considerations of denosumab administered at extended dosing intervals.
Methods: In this retrospective study, patients with MM at Massachusetts General Hospital Cancer Center who received at least two doses of denosumab at extended intervals (&gt;3 months) as a maintenance strategy between January 1, 2018 and September 30, 2019 were identified. The corresponding electronic medical records (EMRs) were reviewed for incidences of new SREs, hypocalcemia, and disease progression including those with bone-related progression requiring change in therapy. Incidences of new SREs were captured by reviewing radiologic reports/EMRs for pathologic and compression fractures and radiation/surgery to treat bone lesions while on treatment. Evaluation of hypocalcemia included the need for intravenous calcium repletion.
Results: Over the 21-month period, a total of 194 patients received denosumab at various extended dosing intervals as maintenance. All patients had received monthly BMA preceding the maintenance therapy. Extended dosing intervals were: 3 months, between 3-6 months, and ≥6 months (58.8%, 26.8%, 14.4%, respectively). Majority of the patients (171, 88.1%) had received bisphosphonates prior to denosumab and evidence of bone disease at diagnosis was seen in 169 (87.1%) patients. Time from diagnosis of MM ranged from 0.3 - 17 years; 51.5% and 16.5% were ≥4 years and ≥8 years since diagnosis, respectively. New SREs while on denosumab maintenance occurred in 6 (3.1%) patients; these consisted of vertebral compression fractures and pathologic fractures of humerus and femur requiring surgical interventions or radiation. These SRE events were associated with disease progression and average time from MM diagnosis to these events was 7.9 years (range 6.2 - 9.5 years). Hypocalcemia (≥grade 1) was seen in 29 (14.9%) patients, and among these, only 6 required intravenous calcium repletion. Disease progression requiring change in therapy occurred in 46 (23.7%) patients and 34 (17.5%) patients had bone-related progression.
Conclusions: Our data support the use of denosumab extended dosing during maintenance. However, our study has several limitations including retrospective nature of analysis, heterogeneity in the patient pool, and exclusion of patients with more frequent dosing of denosumab. Our experience therefore underscores the need to study denosumab extended dosing prospectively.

Disclosures
Branagan: Sanofi: Other: Advisory Board; Pharmacyclics: Other: Advisory Board. Yee:GSK: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptide: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Raje:Celgene: Consultancy; Janssen: Consultancy; Bluebird Bio: Consultancy; BMS: Consultancy; Amgen: Consultancy. O'Donnell:Celgene: Consultancy.