Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial

Abstract

© F e r r a t a S t o r t i F o u n d a t i o n R. García-Sanz et al. 1208haematologica | 2015; 100(9)Myeloma Group (GEM/PETHEMA) in order to evaluate whether treatment with ZA delays the time to next therapy (TNT) in patients with MM in biochemical relapse, compared to the standard management with observation only. Methods Trial designIn 2010, GEM/PETHEMA activated the "Analysis of Zoledronic Acid therapy in MM in BioCHEmical relapses" (AZABACHE) trial. This randomized, prospective, open label, phase IV trial included MM patients in asymptomatic biochemical relapse after a prior response to standard therapy. Patients were randomly distributed into two groups: (i) the experimental group, in which patients received ZA, and (ii) the control group in which patients did not receive any treatment. Patients in the experimental group received zolendronic acid, 4 mg in a 15-minute intravenous infusion every 4 weeks, for a total of 12 doses, plus standard supportive care; the control group received only supportive care. The trial and all procedures were performed in accordance with the Helsinki Declaration and were reviewed and approved by the Spanish National Agency and the Ethics Committees of all the centers involved. Inclusion and exclusion criteriaAll patients had to meet the following inclusion criteria: (i) 18 years of age or older; (ii) confirmed biochemical relapse of MM after an initial response, without symptoms derived from the disease and (iii) signed informed consent to participation in the trial. Relapse was defined according to the IMWG criteria of 2006. 2Patients treated for any symptom of myeloma-related organ or tissue impairment or who had received bisphosphonates in the preceding 3 months were excluded; this meant that most patients had had a prior response longer than 24 months, which is the usual time that bisphosphonates are given in Spanish trials. 17 Variables for evaluationThe main end-point was TNT, which was calculated as the time that elapsed between inclusion in the protocol, and the moment at which new antimyeloma therapy was initiated based on the appearance of a clinical relapse or death from any cause. The appearance of a significant paraprotein relapse was not considered as a clinical relapse but it was qualified as a cause for initiating anti-myeloma when considering the TNT. Other end-points for evaluation were: (i) response rate during the follow-up period (12 months of therapy or follow-up, or until drop-out of the trial) according to the IMWG criteria; 3 (ii) time to clinical symptoms, defined as the time between inclusion in the trial and the development of a clinical (CRAB) relapse; 3 and (iii) time to a skeletal-related event, defined as the time between inclusion in the trial and the occurrence of any the following: bone fracture (vertebral and non-vertebral), requirement for bone radiotherapy, requirement for bone surgery, or hypercalcemia. The presence of osteonecrosis of the jaw and/or renal dysfunction was carefully assessed throughout the treatment and follow-up ...

Use of bone‐modifying agents and clinical outcomes in older adults with multiple myeloma

“…Our study replicates the BMA advantage in the era when most patients receive novel, highly active anti‐myeloma agents (bortezomib or lenalidomide) and lower cumulative doses of dexamethasone compared with historical practice . Other trials, conducted largely before the widespread use of bortezomib and lenalidomide, have confirmed the lower risk of SRE with BMA, whereas survival benefits have not been seen consistently . Similarly to a prior network meta‐analysis and a phase 3 trial, we did not observe differential efficacy of various BMAs, with the caveat that denosumab use was too rare to draw conclusions .…”

“…34 Other trials, conducted largely before the widespread use of bortezomib and lenalidomide, have confirmed the lower risk of SRE with BMA, whereas survival benefits have not been seen consistently. 2,4,6,35,36 Similarly to a prior network metaanalysis and a phase 3 trial, we did not observe differential efficacy of various BMAs, with the caveat that denosumab use was too rare to draw conclusions. 4,7 Early institution of BMA may be paramount to achieve benefits, as the risk of SRE peaks in the first 2 years from diagnosis and is associated with higher mortality.…”

Systematic review and meta-analysis comparing zoledronic acid administered at 12-week and 4-week intervals in patients with bone metastasis

“…Zoledronic acid is a highly effective drug that inhibits osteoclast-mediated bone resorption, and is approximately 100–1000 times more potent than other bisphosphonates [ 4 , 5 ]. Zoledronic acid has been approved for the treatment of patients with bone metastasis [ 6 , 7 ] and tumor-induced hypercalcemia [ 8 ]. Because SREs can repeatedly occur during bone metastases, the clinical guidelines of the American Society of Clinical Oncology recommend that zoledronic acid should be taken indefinitely every 3–4 weeks unless there is deterioration in the general health of patients [ 9 ].…”

Current Controversies in the Management of Myeloma Bone Disease

“…To date, this issue has been evaluated in a single small study, the recently reported AZABACHE trial. In this study, zoledronic acid did not alter biochemical myeloma response, though it did significantly reduce the risk of severe skeletal complications (progressive bone disease, spinal cord compression, and hypercalcemia) as compared to the observation group, suggesting that bisphosphonates may have utility in the setting of biochemical relapse (Garcia‐Sanz et al, ), however future studies evaluating this issue are warranted. In addition, complications associated with bisphosphonate therapy, including acute phase reactions, ARONJ, renal impairment, and the concern that long‐term bisphosphonate use may result in over‐suppression of bone turnover that can induce marked skeletal fragility must be considered and weighed against the potential treatment benefits at the time that re‐initiation of bisphosphonates is considered.…”