Zoledronic acid plus standard therapy offers anticancer effect in multiple myeloma

ABSTRACT: Combined with first-line chemotherapy, intravenous delivery therapy also confers a survival benefit over oral bisphosphonates.

Zoledronic acid (Zometa) should be considered for early integration into treatment regimens in patients with newly diagnosed multiple myeloma, according to British researchers. Treatment with the intravenous bisphosphonate prevented skeletal-related events and improved survival when combined with first-line chemotherapy.

“For my money, zoledronic acid is a new standard of care for patients with myeloma.”- GARETH MORGAN, MD, PHD

"For my money, zoledronic acid is a new standard of care for patients with myeloma," said lead investigator Gareth J. Morgan, MD, PhD, a professor of hematology at the Institute of Cancer Research and the Royal Marsden Hospital in London.

The phase III Medical Research Council Myeloma IX study included 1,960 patients from 121 centers in the UK. Newly diagnosed patients with stage I, II, or III multiple myeloma were treated with either an intensive high-dose treatment with stem cell support when appropriate, or, if they were older and less fit, standard-dose chemotherapy. All patients were randomized to receive either zoledronic acid or clodronate (Bonefos or Loron) on a 1:1 basis. After induction and consolidation therapy, all patients received either thalidomide maintenance or no maintenance therapy on a 1:1 basis. All patients continued bisphosphonate therapy with zoledronic acid or clodronate (American Society of Clinical Oncology [ASCO] 2010 abstract 8021).

According to the results, the addition of IV zoledronic acid (4 mg every 3 to 4 weeks) to induction chemotherapy improved overall survival by 16% or 5.5 months (P = .0118) and progression-free survival by 12% or two months when compared with oral clodronate (1,600 mg daily). Patients who took IV zoledronic acid were followed for a median of 3.7 years and experienced fewer skeletal-related events (27%) than those who took oral clodronate (35.3%; P = .0004).

The investigators adjusted for time to first skeletal-related event in a Cox model and found that the survival benefit conferred by adding zoledronic acid to chemotherapy was independent of its effects on skeletal complications (P = .0178).

"This study adds to evidence that support the antitumor effects of zoledronic acid," Dr. Morgan said. He noted that previous preclinical and clinical studies have indicated that zoledronic acid induces apoptosis in myeloma cells, inhibits angiogenesis, and stimulates gamma-delta T-cells.

Both bisphosphonates were well-tolerated and renal function values were similar in those who received either drug. Concerns have been raised about osteonecrosis of the jaw in zoledronic acid patients, and Dr. Morgan noted that the incidence of this complication was higher in the zoledronic acid arm: 3.5% vs 0.3%. "Yet the cases (of osteonecrosis of the jaw) in those who received zoledronic acid were mild-grade 1-and did not need surgical intervention," he said.

Dr. Morgan said that the investigators of the Myeloma IX study planned to do further statistical analysis to reveal the effects of zoledronic acid vs clodronate on subgroups in the study, such as those who achieved a complete response after initial chemotherapy vs those who did not (ASH 2010 abstract 311).

VANTAGE POINT Results favor use of IV zoledronic acid over oral bisphosphonate

SAGAR LONIAL, MD

The use of bisphosphonates in myeloma management stems from both clinical and preclinical data demonstrating the intricate relationship between the malignant plasma cell, the surrounding bone marrow microenvironment, and bone.

"It is well known that myeloma activates osteoclasts and inhibits osteoblasts via cytokines, thereby resulting in the presence of lytic bone disease that can often be noted on routine x-rays," said Dr. Lonial, an associate professor of hematology and medical oncology at Atlanta's Emory University School of Medicine and director of the Translational Research B-cell Malignancy Program at the university's Winship Cancer Institute.

A randomized trial demonstrated that zoledronic acid was as effective as pamidronate (Aredia) at reducing skeletal-related events and had a more convenient infusion schedule (Cancer 98:1735-1744, 2003). This led to the widespread adoption of long-term bisphosphonates as standard therapy for patients with myeloma, Dr. Lonial said.

More recently there has been discussion of the optimal duration of bisphosphonate therapy and cost, he said. The use of bisphosphonates appears to be associated with a higher rate of osteonecrosis of the jaw. The reported rate of this complication has varied, but most large studies report a frequency of less than 5%. Nonetheless, the duration of bisphosphonate therapy has more recently been limited to two years. These observations form the basis of the current state of the art of bisphosphonate therapy in myeloma.

In the Myeloma IX trial, one of the questions was, can zoledronic acid improve OS, PFS, and reduce skeletal-related events? The results showed improvement in all three areas, favoring the use of IV zoledronic acid over an oral bisphosphonate. In addition, he said, the results showed an anticancer effect that was separate from the effects on bone. This anticancer effect has also been noted in the breast cancer literature.

Further evaluation and analysis are needed before these results can be widely adopted, Dr. Lonial said, but a longer duration of bisphosphonate therapy may improve bone health and reduce and control tumor burden in multiple myeloma patients.