Denosumab Shows Benefits in Multiple Myeloma Bone Disease

Nancy A. Melville

June 27, 2017

MADRID — Patients with multiple myeloma regularly receive bisphosphonates to protect their bones against lytic lesions, but a new study suggests that the novel agent denosumab (Xgeva, Amgen) could be used instead.

In a head-to-head comparison with zoledronic acid in a trial involving more than a thousand patients, denosumab was noninferior and showed an advantage in significantly reducing the risk for renal adverse events.

“We found the bone-specific benefits and observed prolongation of progression-free survival, in combination with a better renal toxicity profile, provide denosumab the potential to be the new standard of care for multiple myeloma–related bone disease,” said Evangelos Terpos, MD, from the University of Athens School of Medicine and Alexandra General Hospital, Greece. He presented the new findings here at the European Hematology Association (EHA) 2017 Congress.

Osteolytic bone disease is highly common in multiple myeloma, with as many as 80% of patients presenting with detectable lesions, while renal disease is also common, presenting in approximately 60%, Dr Terpos explained.

Denosumab, a human monoclonal antibody targeting and binding to RANKL, is seen as beneficial for treatment. Osteoclast-activating factors such as RANKL are implicated in an increased risk for skeletal-related events with multiple myeloma.

Unlike bisphosphonates, such as zoledronic acid — which is the most common treatment for bone disease in multiple myeloma — denosumab can be administered subcutaneously. Furthermore, zoledronic acid requires dose adjustments according to patients' creatinine clearance and cannot be used in patients with creatinine clearance below 30 mL/min, whereas denosumab does not require dose adjustment, potentially avoiding renal complications, Dr Terpos explained.

In comparing denosumab with zoledronic acid, Dr Terpos and his colleagues randomly assigned 1718 adult patients with newly diagnosed multiple myeloma to groups of 859 patients each for treatment with subcutaneous denosumab 120 mg every 4 weeks or intravenous zoledronic acid every 4 weeks, in addition to treatment with myeloma therapy.

Patients with renal insufficiency were excluded if they had baseline creatinine clearance below 30 mL/min, and most baseline characteristics were similar: 66.0% of denosumab recipients and 67.2% of zoledronic acid recipients reported a history of a skeletal-related event, and 26.7% of patients had creatinine clearance below 60 mL/min.

The study achieved its primary endpoint of noninferiority of denosumab compared with  zoledronic acid in terms of time to the first on-study skeletal-related event, with 43.8% of patients in the denosumab group and 44.6% in the zoledronic acid group having a first on-study skeletal-related event within the primary blinded period within a median follow-up of 17.4 months.

There was no significant difference between the two groups in terms of the median time to the first skeletal-related event; this event occurred at a median of 22.38 months with denosumab and 23.98 months with zoledronic acid.

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.

“Patient exposure to antiresorptive therapy may not have been long enough to result in treatment differences,” Dr Terpos said.

They therefore conducted a landmark post hoc analysis at 15 months that did show superiority of denosumab (n = 450) over zoledronic acid (n = 459) in terms of the endpoint of time to the first skeletal-related event (hazard ratio [HR], 0.66; P = .039).

Totals in terms of specific skeletal-related events included fractures in 31 denosumab recipients and 43 in zoledronic acid recipients; radiation to the bone in 5 and 12, respectively; surgery to the bone in 9 and 13; and spinal cord compression in 2 and 1.

The analysis showed no significant differences between the groups in terms of overall survival (P = .41), with fewer deaths in the denosumab group (n = 121 [14%]) than in  the zoledronic acid group (n = 129 [15%]).

And in the exploratory endpoint of median progression-free survival in the analysis, a difference of more than 10 months was observed between the denosumab (46.09 months) and zoledronic acid (35.38 months) groups (HR, 0.82; P = .036).

Treatment-emergent adverse events occurred in similar rates in both groups; those occurring in more than 25% of patients included diarrhea and nausea. The rates of serious adverse events were consistent with those associated with each drug, including hypocalcemia (16.9% in the denosumab group and 12.4% in the zoledronic acid group) and positively adjudicated osteonecrosis of the jaw (4.1% and 2.8%, respectively).

Importantly, significantly fewer patients receiving denosumab had adverse events that were potentially related to renal toxicity (10.0% vs 17.1%; P < .001). The events were particularly notable in patients with creatinine clearance of 60 mL/min or less (12.9% vs 26.4%, respectively).

Treatment-emergent adverse events resulted in discontinuation of the drug in 12.9% of denosumab recipients and 11.5% of zoledronic acid recipients.

"We found that overall, adverse events were similar between treatment arms, with renal toxicity higher with zoledronic acid and hypocalcemia occurring more frequently with denosumab," Dr Terpos said.

An Alternative but Not New Standard of Care

This study was discussed at the recent American Society of Clinical Oncology annual meeting by S. Vincent Rajkumar, MD, professor of medicine at the Mayo Clinic, Rochester, Minnesota. Speaking at an "ASCO Highlights of the Day " session, in which he reviewed new studies in myeloma, he said that "one of the critical things we do is give bisphosphonates regularly (every month or every three months) to prevent bone lytic lesions."

Noting that denosumab had shown noninferiority in terms of efficacy in skeletal-related events  and has an advantage in its side-effect profile (with the lower risk for renal adverse events), he concluded that it offers another alternative to zoledronic acid.

However, it is not yet time to declare denosumab as a new standard of care, he said.   

There is a big cost deferential, he pointed out  — zoledronic acid costs around  $70 per month, while denosumab costs more than $2000 per month. For "that much increase in cost, I would like to see a survival advantage," he commented. None has been seen in the current trial so far. The overall survival was similar in both groups, he added.  

The study was funded by Amgen. Dr Terpos has consulted for and received research grants from Amgen, Genesis, and Janssen. Dr Rajkumar has disclosed no relevant financial relationships.

European Hematology Association (EHA) 2017 Congress. Abstract S782. Presented June 25, 2017.

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