The role of bisphosphonate therapy in the global management of multiple myeloma

In this issue of Leukemia and Lymphoma, D'Arena and colleagues provide final results of a long-term phase III study that compared pamidronate to observation in 177 patients with multiple myeloma, and reconfirmed a reduction of skeletal-related events from 72.7% in controls to 39.2% in pamidronate-treated patients. There was no impact on median time to progression or overall survival [1]. The use of parenterally administered bisphosphonates has been the standard for supportive care management of multiple myeloma for the past 15 years. When patients with Durie–Salmon stage III multiple myeloma and at least one lytic lesion were randomized to placebo or 90 mg of pamidronate over 4 h, the proportion of patients who had a skeletal-related event, defined by the need for surgery on bone, radiation therapy, hypercalcemia, or a pathologic fracture, was reduced from 41% in the placebo group to 24% in the pamidronate group [2]. In a subsequent study, powered for non-inferiority, zoledronic acid in two doses of 4 or 8 mg was compared with pamidronate in patients with breast cancer or multiple myeloma. The median time to first skeletal-related event was 1 year in each treatment group, suggesting that zoledronic acid at 4 mg was as effective as pamidronate 90 mg [3]. However, because the infusion time of zoledronic acid was only 15 min versus the 4 h pamidronate infusion, zoledronic acid rapidly became the standard of care for prevention of myeloma skeletal-related events.

The benefits of bisphosphonates, however, did not come without toxicity. Subsequent reports of dose- and infusion rate-dependent effects on renal function, serum creatinine rise, and proteinuria rapidly appeared [4]. The recognition of the development of osteonecrosis of the jaw related to bisphosphonates appeared shortly thereafter. With data censored at 36 months, the estimated incidence among patients receiving zoledronic acid was 10%, and those receiving pamidronate was 4% [5]. Dental surgery may exacerbate osteonecrosis of the jaw in those in whom the condition has developed during bisphosphonate therapy. This compares with only a very small proportion of patients developing bisphosphonate-related osteonecrosis of the jaw receiving oral bisphosphonates [6]. Recognition of bisphosphonate toxicities led to the development of consensus guidelines by the Mayo Clinic, American Society of Clinical Oncology, and National Comprehensive Cancer Network regarding bisphosphonate therapy. These consensus criteria were designed to try and optimize the benefits of bisphosphonates while reducing the risk of osteonecrosis. At Mayo Clinic, our recommendation included discontinuation of bisphosphonates after 2 years of therapy for patients who achieved a complete response or a stable plateau. For patients whose disease was active or with threatening bone disease beyond 2 years, therapy frequency was reduced to every 3 months [7]. Studies have suggested that antibiotic prophylaxis prior to dental procedures could reduce the risk of osteonecrosis of the jaw. In one non-randomized study [8], only one antibiotic-treated patient developed osteonecrosis of the jaw not related to a dental procedure. Eight patients with osteonecrosis were seen, all in a group that did not receive antibiotic prophylaxis, which was predominantly amoxicillin clavulanic acid. It was concluded that antibiotic prophylaxis had a protective effect.

One study compared 504 patients randomly assigned to pamidronate 30 or 90 mg. The median time to the first skeletal-related event in patients who had such an event was 9.2 months in the 90 mg pamidronate group and 10.2 months in the 30 mg pamidronate group. In retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group, suggesting that dose reduction lowers the risk of jaw osteonecrosis. Furthermore, patients who received pamidronate at a dose of 30 mg had a trend for fewer renal toxic events than did those who received pamidronate 90 mg. The incidence of osteonecrosis of the jaw was 3.2% vs. 0.8% in the pamidronate 90 mg and pamidronate 30 mg groups, respectively. Pamidronate monthly infusion of 30 mg became the new recommended dose [9].

The first suggestion that the consequences of myeloma bone disease could have an impact on survival came from a multivariable analysis of 282 patients with multiple myeloma. Five significant prognostic factors for the first skeletal-related event were identified: weight, race, high N-terminal cross-linked telopeptide of type I collagen (NTx), high pain score, and need for narcotics [10]. High NTx was the only variable associated with elevated risks of both first skeletal-related event and death. The possibility that managing myeloma bone disease might have an impact on overall mortality was reported in abstract form in 2010, at the American Society of Hematology. With a median follow-up of 3.7 years and 1960 evaluable patients, there was a trend for more patients with a complete response, fewer early deaths, and improved overall survival for patients receiving zoledronic acid versus clodronate, an oral bisphosphonate [11]. As expected, skeletal-related event risk was significantly reduced with zoledronic acid. However, in each treatment arm in this study, the zoledronic acid group had higher rates of complete and very good partial response compared to clodronate (p = 0.03), and zoledronic acid reduced the risk of death by 17%. Zoledronic acid provided benefits beyond clodronate in improving overall survival, response status, and preventing skeletal-related events, which is in distinct contrast to the article published in this issue of Leukemia and Lymphoma. This suggests that the benefit seen with zoledronic acid may not occur in pamidronate-treated patients, therefore requiring zoledronic acid therapy to achieve a survival benefit. Consensus guidelines are now undergoing rapid revision to accommodate this recently reported information. Monthly zoledronic acid should be the standard for all patients with multiple myeloma, continued at least until disease progression.

These results applied to patients who did not have myeloma skeletal disease by plain radiographs at study entry, and bisphosphonate use should not be limited to those who have proven bony disease. In conclusion, zoledronic acid, 4 mg monthly, appears to be a standard until such time as lower-intensity bisphosphonates are shown to have a survival advantage.

Potential conflict of interest: A disclosure form provided by the author is available with the full text of this article at www.informahealthcare.com/lal.