Zoledronic acid improves survival in multiple myeloma patients versus the UK and European standard treatment of clodronic acid (sodium clodronate) in patients with multiple myeloma. Since overall survival in patients given zoledronic acid improved independently of prevention of skeletal-related events, the study shows that zoledronic acid has treatment benefits beyond bone health. These findings from the MRC Myeloma IX study are published in an upcoming Lancet, and were presented at the 2010 American Society of Hematology meeting in Orlando, Florida. The research was carried out by Professor Gareth J Morgan, The Institute of Cancer Research, London, UK, and Professors Walter M Gregory and J Anthony Child, Clinical Trials Research Unit, University of Leeds, UK, and colleagues.

Bisphosphonates are a standard aspect of care for prevention of skeletal-related events in patients with advanced cancer. In multiple myeloma, malignant plasma cells in the bone marrow induce destruction of bone putting patients at high risk of fractures with severe consequences. Previous work has suggested that some bisphosphonates, including zoledronic acid and clodronic acid—may also cause destruction of cancer cells in addition to protecting bone health. Zoledronic acid ,in particular,has shown potential anticancer effects in preclinical and clinical studies. Bisphosphonates break the cycle of bone destruction and cancer growth that can result in skeletal-related events. Yet despite strong consensus that antimyeloma therapies  should be given to symptomatic patients with multiple myeloma, no optimal regimen has emerged. In this study, the largest and most  comprehensive yet undertaken in myeloma, the authors compared zoledronic acid and clodronic acid in multiple myeloma patients.


In this randomised controlled trial, 1960 patients were assessed: 981 receiving zoledronic acid, with 555 on intensive chemotherapy and 426 on non-intensive chemotherapy; and 979 receiving clodronic acid, with 556 on intensive chemotherapy and 423 on non-intensive chemotherapy. Patients spent a median time of 350 days on bisphosphonate treatment before disease progression, with a median of 3.7 years’ follow-up.

The researchers found that zoledronic acid reduced mortality by 16% versus clodronic acid, and extended median overall survival by 5·5 months (50 months versus 44.5 months). Zoledronic acid also significantly improved progression-free survival by 12% versus clodronic acid, and increased median progression-free survival by 2·0 months (the 2.0 months result being of borderline statistical significance). Rates of complete, very good partial, or partial response did not differ significantly (statistically) between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (78% vs 76%) or non-intensive induction chemotherapy (50% vs 46%).


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 (4%) than was clodronic acid (<1%). This complication, with destruction of jaw bone, ulceration and potentially serious dental problems was, however, at a relatively low level (in particular compared with some US studies).


The authors say: “The improvement in overall survival with zoledronic acid remained significant after adjustment for the reduction in risk of skeletal-related events. These data add to growing clinical evidence supporting anticancer benefits with zoledronic acid in patients with newly diagnosed cancers. Although we have not definitively identified the underlying mechanism of action, the early improvement in overall survival with zoledronic acid compared with clodronic acid supports early use of zoledronic acid in multiple myeloma.”


In a linked comment, Dr S Vincent Rajkumar, Mayo Clinic, Rochester, MN, USA, said that many caveats need to be emphasised. Including that in most countries outside the UK, pamidronic acid rather than clodronic acid is the usual alternative to zoledronic acid. Compared with zoledronic acid, pamidronic acid is ten times less expensive, seems to be equivalent in terms of prevention of skeletal-related events, has a lower reported risk of osteonecrosis of the jaw in many studies, and has not shown any significant survival disadvantage in randomised trials. He also notes that it is unclear whether the subset of patients who entered Myeloma IX without bone disease (about 30% of the sample) derived any significant survival benefit.


He concluded that most groups recommend 2 years of bisphosphonate therapy, and that Myeloma IX should not be used to justify indefinite therapy: “Besides the cost and inconvenience, long-term treatment with high-potency bisphosphonates can lead to several complications, including renal failure, osteonecrosis of the jaw, and atypical fractures of the femur. Further study is needed to establish the best dose and duration of therapy, and investigate primary prevention in early asymptomatic stages.”

Watch an ecancer interview with Gareth Morgan here

Source: Lancet