Large MM trial finds denosumab non-inferior to ZA for SRE

“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).

Safety

“[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.