BARCELONA, SPAIN—Median survival among patients randomized to receive zoledronic acid with their primary chemotherapy for newly diagnosed multiple myeloma was five months longer than in those who received clodronate plus chemotherapy, according to data reported here at the European Hematology Association Congress.
The results from the MRC Myeloma IX trial of 1,960 patients followed for a median of 3.7 years were reported by Gareth Morgan, MD, Professor of Haematology at the Royal Marsden Hospital, who said that zoledronic acid may have “clinically meaningful” anticancer effects when combined with chemotherapy.
Furthermore, there was a 26% relative reduction in skeletal-related events (SREs) with zoledronic acid as compared with clodronate; median progression-free survival was prolonged by two months; and use of zoledronic acid halved the incidence of new osteolytic bone lesions compared with clodronate: while rates of renal failure were reported to be “low” in both groups—about 6% for each regimen.
“Treatment with zoledronic acid is now the new gold standard against which new bone agents need to be compared—not only against SRE-reduction but also in having an impact on survival,” Dr. Morgan said in an interview after his talk.
The improvement in overall survival with zoledronic acid was independent of the effects of other therapy—“so it would seem that this agent is an effective anti-myeloma drug that actually contributes to improving outcome in patients,” he said.
Randomization between zoledronic acid and clodronate within the MRC IX trial was done because historically 50% of patients with multiple myeloma have been observed to get skeletal problems during the course of their disease—within nine to 21 months according to one key study, Dr. Morgan said. “It was obvious we needed to do something to prevent this.”
An earlier UK study had already found benefits from adding bone-targeted therapy to chemotherapy—adding clodronate not only reduced SREs but also seemed to extend survival in a subgroup of patients, he said. Also laboratory experiments had shown in mouse models of myeloma that disease progression can be slowed and that there can be an “active effect against the disease.” The hope was that the new generation bisphosphonate—zoledronic acid—could be even more potent; so the British team decided to randomize it head-to-head with clodronate.
The overall purpose of the MRC IX study was to compare primary therapy regimens in patients with newly diagnosed multiple myeloma. The schedules—based on current guidelines—included intensive chemotherapy plus transplant and non-intensive regimens, with or without thalidomide. All patients were randomized between clodronate and zoledronic for their bone-targeted therapy. The aim was to compare disease outcomes, SREs, safety, and survival between the two agents.
Patients received intravenous zoledronic acid at 4 mg (dose adjusted based on renal function, every 3-4 weeks) or daily oral clodronate at 1600 mg, plus antimyeloma therapy. A diagnosis of myeloma bone disease was not a study requirement, and so bisphosphonate was used off-label in some patients.
The hoped-for benefit was to reduce skeletal disease and to increase overall survival—“and we hit both of those endpoints,” Dr. Morgan said. “And this reduction of events was present in both patients with bone disease at presentation and those who lacked bone disease at presentation.”
He recommended that all myeloma patients be treated with zoledronic acid at presentation—which was continued until disease progression in the MRC trial. And he suggested that this policy was justified by the 50% reduction observed of new lytic lesions at disease progression.
Low Rate of Osteonecrosis of the Jaw
The regimen was safe, Dr. Morgan said, pointing to the low (3%) observed rate of osteonecrosis of the jaw and virtually “no renal signal.”
Regarding the suitability of combining zoledronic acid with other novel agents, Dr. Morgan said that since the MRC study had demonstrated the agent's shafety when added to a thalidomide-containing regimen there was “some sense” in combining it with bortezomib which affects osteoblasts—while zoledronic acid affects osteoclasts—so there should be synergy between zoledronic acid and bortezomib.
The study also indicates that zoledronic acid could safely be combined with lenalidomide as well—“I think it's compatible with all of these agents,” he said.
Dr. Morgan said that this treatment should be useful for all myeloma patients, not just those who have bone disease at presentation—“We saw a significant effect in people who didn't have bone disease at presentation. So across the board it seems to work.”
But in patients with compromised creatinine clearance, he warned, “care needs to be taken.”
Robert Coleman, MBBS, MD, Professor of Clinical Oncology at Weston Park Hospital in Sheffield, UK, commented that he agreed that the MRC IX study gives evidence of direct anticancer activity, and urged oncologists who had not practiced in the era before bisphosphonate therapy became available to consider all patients for bone-targeted treatment.
But Dr. Coleman had some reservations about the MRC trial: “I would like to know whether the benefit is greater with one particular type of chemotherapy or with a particular subset of patients; or whether it's generalizable across all patients,” he said.
Still, it is a very important result, he said. “It's not just improvement in overall survival—this [benefit] was being driven by an improvement in complete remission rates.” This is important in myeloma because it led to increased overall survival, as seen in the trial.
Dr. Morgan was asked in the question-and-answer period after his talk if the difference in survival was apparent in both the elderly and the intensive therapy groups. Yes, it was consistent across the study, he said, and although the analysis is incomplete, “my suspicion is that a lot of benefit will be in the older patients.”
Another audience member wanted to know if there were subsets of patients with greater benefit from zoledronic acid. Dr. Morgan said that although the full data analysis was lacking, “if you don't achieve a complete response, you may have a greater benefit,” so his interim recommendation was that all patients should be treated with zoledronic acid.