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Attendees at ASCO 2017
Annual Meeting
Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.


The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).


“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

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