Kenneth C. Anderson, MD
Dr. Anderson indicated no relevant conflicts of interest.
Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376:1989-1999.
Bisphosphonates have demonstrated an ability to reduce skeletal-related events (SRE), including bone pain, pathologic fracture, spinal cord compression, and need for radiation to bone. As approximately 80 percent of patients with multiple myeloma (MM) have bone disease, the use of bisphosphonates has transformed the paradigm for supportive care in MM. With their long-term use, attendant complications such as renal compromise and osteonecrosis of the jaw occur in a small percentage of cases. As a result, guidelines now recommend use of aminobisphosphonates for two years in MM patients, with further use predicated upon the presence of active MM and ongoing bone disease. Importantly, bisphosphonates are now standard practice, since the benefits of their use to reduce bone-related complications and pain and improve quality of life and performance status is overwhelming.
In addition to this clinical benefit, preclinical studies in laboratory models show that bisphosphonates can induce MM cell apoptosis and inhibit cytokines including IL-6. Moreover, decreased tumor cell growth with prolonged host survival has been observed after aminobisphosphonate treatment in xenograft murine models of human MM. Prior smaller clinical studies have suggested anti-MM activity when aminobisphosphonates were added to conventional therapies for newly diagnosed MM, relapsed and refractory disease, or MM with high bone turnover. However, whether aminobisphosphonates confer clinical benefits, aside from reducing bone complications, remains controversial.
In this study by Dr. Morgan and colleagues from the United Kingdom, patients received either intensive chemotherapy (if they were candidates for high-dose therapy) and stem cell transplantation, or non-intensive chemotherapy (if they were not candidates), and were subsequently randomized to receive either zoledronic acid or clodronic acid. The primary endpoints were to determine anti-MM clinical benefits assessed by progression-free and overall survival, as well as overall response rate. Compared with clodronic acid, zoledronic acid prolonged median progression-free survival by two months and overall survival by 5.5 months, and reduced mortality by 16 percent. However, the extent and frequency of response within the intensive and non-intensive chemotherapy arms, assessed by response rates (complete/very good partial/partial), did not differ with zoledronic versus clodronic acid treatment. Adverse events were uncommon, although osteonecrosis of the jaw was more frequent with zoledronic acid (3%) than with clodronic acid (< 1%) treatment.
This study provides the strongest evidence to date of a clinically significant anti-MM effect of zoledronic acid. Zoledronic acid also reduced the proportion of patients with SRE, further confirming the benefit of aminobisphosphonates in reducing bone-related disease and complications in MM. The early separation of the survival curves in favor of zoledronic acid, coupled with the prolonged survival with zoledronic acid even after adjusting for time to first SRE, further supports its anti-MM activity. The lack of differences between zoledronic versus clodronic acid treatment in extent or frequency of response within either treatment cohort, coupled with prolonged progression-free and overall survival in both settings, is consistent with zoledronic acid’s benefit as a maintenance therapy. Both direct and indirect (targeting angiogenesis or cytokines, modulating immunity) anti-tumor effects may be contributing to this clinical outcome. In this study, patients took bisphosphonates until progression; however, they received bisphosphonates for an average of approximately one year. Since current guidelines recommend bisphosphonate therapy for two years, further studies examining duration and frequency are necessary to establish their optimal use. Importantly, the only novel therapy used in the intensive or non-intensive cohorts was thalidomide. Given that novel agents targeting the tumor cell in its bone marrow microenvironment (such as bortezomib) can also have an impact on bone, it is not surprising to confirm that therapies targeting bone such as zoledronic acid may also favorably impact MM. In the future, it will be critical to incorporate novel agents for MM with novel agents targeting bone to determine their optimal use as both induction and maintenance therapies.