First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial

Abstract

SummaryBackgroundBisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma.MethodsPatients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111.Findings1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137–632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9–4·7). Zoledronic acid reduced mortality by 16% (95% CI 4–26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74–0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2–20) versus clodronic acid (HR 0·88, 95% CI 0·80–0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0–38·0 vs 17·5 months, IQR 8·5–34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]).InterpretationConsistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevent...

Limiting early mortality: Do's and don'ts in the management of patients with newly diagnosed multiple myeloma

“…Similar effect has been demonstrated with the use of zoledronic acid [93]. In fact, one randomized trial pointed to lower mortality (mostly due to reduction in early mortality) in MM patients treated with zoledronic acid when compared to patients treated with clodronic acid [94]. Radiation, typically in low doses administered in few fractions, can lead to rapid improvement in pain but should be avoided in newly diagnosed patients in nonurgent circumstances, particularly when multiple lesions are presents and large fields are required.…”

Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology

“…Zoledronic acid was reported to reduce mortality and significantly improve PFS. 167 Patients on clodronate and zoledronic acid had similar occurrence of acute renal failure and treatment-related serious adverse events. Zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw than was clodronic acid.…”

Mechanisms of multiple myeloma bone disease

“…The recent MRC Myeloma IX trial demonstrated that blocking osteoclast activity increases survival of myeloma patients. 25 Similarly, enhancing marrow stromal cell differentiation into osteoblasts decreases tumor growth and bone destruction, as well as increases bone formation. 26,27 Unfortunately, myeloma is still incurable for most patients and MMBD remains a major contributor to the morbidity and mortality of myeloma patients.…”