NEW YORK CITY—The monoclonal antibody denosumab is not recommended for treatment of bone disease in patients with multiple myeloma, but the intravenous bisphosphonate zoledronic is. That was the conclusion of James R. Berenson, MD, Medical and Scientific Director of the Institute for Myeloma & Bone Cancer Research in Los Angeles, speaking here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies.
Denosumab is approved by the FDA for postmenopausal women at risk of osteoporosis and for the prevention of skeletal-related events in patients with bone metastases from solid tumors, but the drug is not approved for treatment of multiple myeloma.
He reviewed data here showing no advantage to the monoclonal antibody in reduction of risk of skeletal events including pathological fractures, spinal cord compression, and hypercalcemia. And overall survival for use of denosumab was inferior to that of zoledronic acid in one trial, he noted.
However, Berenson said, a randomized Phase III international trial (NCT01345019) is now enrolling an estimated 1,520 myeloma patients, to compare the two agents. While the preliminary endpoint of the new trial is time to first skeletal-related event and not survival, he said it will more thoroughly address the question of whether the lower survival rate with denosumab in the earlier trial was real, or whether the apparent survival advantage to zoledronic acid was the result of subset analysis and “noise” in one clinical trial.
Denosumab offers the convenience of subcutaneous administration, there is no requirement for renal monitoring or dose adjustment, and does not carry the burden of acute-phase reactions experienced by many patients receiving zoledronic acid.
The first trial he reviewed was a Phase III randomized study of 1,776 patients (an easy number to remember, he quipped) comparing denosumab and zoledronic acid in treatment of bone metastases in patients with advanced cancer (excluding breast and prostate) or multiple myeloma (Henry et al: JCO 2011;29:1125-1132). Overall, denosumab was shown to be noninferior but not statistically superior to zoledronic acid in delaying time to first on-study skeletal-related events.
“Importantly, there were more than twice as many deaths in the subset of myeloma patients in the denosumab arm, and overall survival was actually inferior in denosumab-treated patients, with a hazard ratio of 2.26,” he said, noting that there were three possible reasons for the increased mortality rate with denosumab: It may have been a question of subset analysis, considering that there were more patients with poor prognostic features in the denosumab group, and more patients underwent aggressive treatment in the zoledronic acid group, especially autologous stem cell transplantation. To date, causes of death in the myeloma patients have not been reported, he said.
A second reason could be an unknown, theoretical impact of denosumab on immune function, similar to the negative effect of RANKL/-RANK on B-cell development.
Third, perhaps it was not a negative effect of denosumab as much as a positive impact of the bisphosphonate on survival. Berenson said there is clinical evidence of anticancer effects for zoledronic acid, pamidronate, and clodronate. Bisphosphonates are known to induce apoptosis, prevent prenylation of GTPases, reduce growth factors, and inhibit angiogenesis.
Addressing the issue of bisphosphonates and survival, Berenson reviewed the Medical Research Council Myeloma IX trial in the UK, which compared zoledronic acid with clodronate. Overall survival in patients treated with zoledronic acid improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health, he said.
A recent update of that study (Blood 2012;119:5374-5383) showed a continued overall survival advantage, but Berenson said this was largely restricted to patients with lytic disease at baseline. “Intriguingly, there was an increase in both complete response and very good partial response among patients treated with zoledronic acid,” he said.
Morton Coleman: Mild Case Made for Denosumab
Speaking with OT after the session, Meeting Chair Morton Coleman, MD, Clinical Professor of Medicine and Director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital-Weill Cornell Medical Center, said Berenson “made a mild case for zoledronic acid being superior to denosumab primarily based on the notion that zoledronic acid does more than just affect the bones, that it may affect the myeloma cells as well.”
Coleman noted that although zoledronic acid has been used for many years and is at the point of becoming a generic drug, “the jury is out,” regarding comparison between the two agents, and the trial now starting may answer that question.
Coleman speculated that denosumab might have an advantage over bisphosphonates with regard to osteonecrosis of the jaw. Both zoledronic acid and denosumab can cause osteonecrosis of the jaw but denosumab has a much shorter half life in the marrow, meaning that the osteonecrosis might reverse more rapidly with denosumab.