How are skeletal-related events (SREs) prevented in multiple myeloma?

Updated: Aug 14, 2019
  • Author: Sara J Grethlein, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Skeletal events

Bisphosphonate treatment (eg, zoledronate) has been demonstrated in placebo-controlled studies to decrease the occurrence of skeletal-related events (defined as spinal cord compression, need for surgery, need for radiation, hypercalcemia, and pathologic fracture) in patients with myeloma bone disease. The exact duration of therapy and the role of these agents in patients without known bony disease remain ill defined.

Spinal cord compression is a common complication of multiple myeloma, occurring in as many as 20% of patients at some point during the course of their illness; a high index of suspicion is the key to diagnosis (although magnetic resonance imaging [MRI] is typically required to confirm). Physicians should be aware of the high frequency of multiple concurrent levels of compression and should screen accordingly.

In January 2018, denosumab was approved by the US Food and Drug Administration for prevention of skeletal-related events (SREs) in patients with multiple myeloma. It was originally indicated for SREs in patients with solid tumors. Denosumab is a human monoclonal antibody targeting and binding to RANKL; osteoclast-activating factors such as RANKL are implicated in an increased risk for SREs with multiple myeloma.

A phase 3 trial in 1718 patients with bone metastases found that denosumab was noninferior to zoledronic acid and showed an advantage in significantly reducing the risk for renal adverse events. A post hoc analysis at 15 months was also conducted, since many of the skeletal-related events (60%) occurred early, within 3 months, which led the authors to speculate that the data reflected events occurring before the treatment had enough time to take effect. Results did show superiority of denosumab (n = 450) over zoledronic acid (n = 459) in terms of the endpoint of time to the first SRE (hazard ratio [HR], 0.66; P = 0.039). Median PFS with denosumab versus zoledronic acid was 46.09 versus 35.38 months, respectively (HR, 0.82; P = 0.036). No difference in overall survival was noted between the treatment groups. [55]

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