CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.
After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.
The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.
"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.
Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.
"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."
The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).
Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.
The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.
Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.
Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.
The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.
Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.
The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.
Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.
Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.
The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.