Page 21 - Haematologica-5

PERSPECTIVES
Denosumab for bone lesions in multiple myeloma – what is its value?
Daniel A. Goldstein
Davidoff Cancer Center, Rabin Medical Center, Petach Tikvah, Israel
E-mail: danielagoldstein@gmail.com doi:10.3324/haematol.2017.185264
In June 2017 the Food and Drug Administration (FDA) accepted a supplemental biologics license application seeking to expand the currently approved indication of denosumab to patients with bone lesions from multiple myeloma. The FDA set a prescription drug user act (PDUFA) action date of February 3, 2018. Denosumab is an inhibitor of receptor activator of nuclear factor κ-B ligand (RANKL) and was previously approved for post- menopausal women at risk of osteoporosis in addition to patients at risk of skeletal-related events due to bone metastases from solid tumors and giant cell tumors of the bone. The application for use in patients with myeloma is based on the findings of the recently presented ‘482 trial.1 This commentary seeks to understand the value of this therapy for patients with multiple myeloma.
Denosumab is a monoclonal antibody and uses a novel mechanism to decrease bone resorption. RANKL is a pro- tein expressed on osteoblastic stromal cells. It binds to receptor activator of nuclear factor-κB (RANK) and thus mediates osteoclastic differentiation, activation, and sur- vival. RANKL therefore controls osteoclast-mediated bone resorption. Osteoprotegerin is a soluble RANKL decoy receptor which binds RANKL and is the key regu- lator of the RANKL–RANK pathway. Denosumab binds to RANKL thus blocking the interaction of RANKL with RANK, mimicking the endogenous effects of osteoprote- gerin. This agent has been shown to lead to a decrease in bone resorption, based on changes in serum and urinary N-telopeptide, which are markers of osteoclastic bone resorption.2
Until recently bisphosphonates had been the standard therapy for strengthening bone in a variety of conditions such as osteoporosis and cancer. Bisphosphonates essen- tially bind to bone mineral and inhibit the activity of mature osteoclasts. Non-nitrogen containing bisphospho- nates achieve this goal by being metabolized to ATP analogs that block osteoclast function and induce osteo- clast apoptosis. Nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate synthase, thus preventing the post-translational modification of guanosine triphos- phate binding proteins which are essential for osteoclast function and survival.3 The essential difference between bisphosphonates and denosumab is that bisphosphonates inhibit mature osteoclasts while denosumab inhibits osteoclastic precursors.
Denosumab has already gained FDA approval for mul- tiple indications based on advanced phase clinical trials. In postmenopausal women with low bone mineral densi- ty, it was found to lead to a 3.0% to 6.7% increase in bone mineral density of the lumbar spine.2 Multiple trials have compared zoledronic acid and denosumab in patients with solid tumors. In patients with bone metas- tases from breast cancer, denosumab was superior to
zoledronic acid in delaying or preventing first on-study
haematologica | 2018; 103(5)
skeletal-related event [hazard ratio (HR)=0.82; 95% con- 4
fidence interval (95% CI): 0.71- 0.95; P= 0.01). Likewise, denosumab was superior in terms of time to first skeletal- related event in patients with bone metastases from prostate cancer. The median time to first on-study skele- tal-related event was 20.7 months (95% CI: 18.8-24.9) with denosumab compared to 17.1 months (95% CI: 15.0-19.4) with zoledronic acid (HR=0.82, 95% CI: 0.71- 0.95; P=0.008 for superiority).5 Despite the reduction in skeletal-related events with denosumab, there was no associated improvement in overall survival in patients with either breast or prostate cancer.4,5 In patients with giant cell tumors of the bone, an open label study with denosumab demonstrated a high level of efficacy: 96% of patients with surgically unsalvageable giant cell tumors of the bone did not have disease progression after a median follow-up of 13 months.6
The ‘482 trial was an international phase 3, random- ized, double-blind trial comparing the safety and efficacy of monthly denosumab to monthly zoledronic acid in patients with multiple myeloma.1 The trial enrolled 1718 patients and the primary endpoint was the time to first on-study skeletal-related event, and was powered to demonstrate non-inferiority. Secondary endpoints were time to first skeletal-related event (powered to superiori- ty), time to first and subsequent skeletal-related events (powered to superiority), and overall survival. The study met the primary endpoint and demonstrated that deno- sumab was non-inferior to zoledronic acid in terms of skeletal-related events (HR=0.98; 95% CI: 0.85-1.14; P=0.01). The trial failed to meet the secondary endpoints of demonstrating superiority in terms of time to first skeletal-related event or overall survival. The authors per- formed an unplanned exploratory analysis to evaluate progression-free survival as an endpoint and found a pro- longed progression-free survival in the denosumab group (HR=0.82; 95% CI: 0.68-0.99; P=0.036). Although the trial was well conducted with double-blind randomiza- tion, this finding should be considered only as hypothe- sis-generating, as it was an unplanned endpoint analysis and such analyses are known to have a lack of statistical reliability.7
There were no significant differences between the two groups in terms of adverse events apart from hypocal- cemia and renal toxicity. In patients with baseline creati- nine clearance ≤60 mL/minute, 13% of patients in the denosumab group developed renal toxicity, compared to 26% of patients in the zoledronic acid group (P<0.01). The rate of creatinine doubling from baseline in the zole- dronic acid group was nearly twice as high as in the deno- sumab group (6.5 versus 3.3%). Conversely, there were higher rates of hypocalcemia in patients receiving deno-
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