Role of bisphosphonates in the management of skeletal complications in patients with multiple myeloma

Questions: For patients with active multiple myeloma, is there evidence that the use of bisphosphonates improves survival? improves quality of life? reduces bone pain? reduces or delays the development of skeletal complications? Perspectives: In the literature, bisphosphonates are reported to be potent inhibitors of osteoclastic activity. They are widely used to treat the hypercalcaemia and pain associated with malignancies that involve bone. The role of bisphosphonates in preventing bone resorption provides a rationale for using bisphosphonates to delay or prevent progressive bone disease in patients with myeloma. Emerging data reporting the potential effectiveness of bisphosphonate use in patients with myeloma and a perception of variation in practice across Ontario influenced the decision to develop this practice guideline. In addition, the acquisition costs of bisphosphonate agents are substantial and could present barriers to use of those agents. Outcomes: Outcomes of interest were overall survival, skeletal-related survival, quality of life, bone pain, pathologic fractures (non-vertebral or vertebral), progression of bone disease (osteolytic lesions), hypercalcaemia, and treatment-related toxicity. Methodology: The MEDLINE, CANCERLIT, and Cochrane Library databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1997-2002) and the American Society of Hematology (1999-2001) were systematically searched for evidence relevant to the present practice guideline report. An Internet search for ongoing trials was also performed. Evidence was selected and reviewed by two reviewers. Articles were eligible for inclusion in the systematic review of the evidence if they were fully published reports or published abstracts of systematic reviews or practice guidelines that evaluated bisphosphonate use in patients with multiple myeloma, or if they were randomised controlled trials (RCTS) or meta-analyses of RCTS that compared one bisphosphonate agent with another, or a bisphosphonate with placebo or no treatment in patients with multiple myeloma. Results: Quality of Evidence: One systematic review containing a published-data meta-analysis, one practice guideline, and reports of twelve RCTS form the basis of evidence for this practice guideline report. One trial compared two bisphosphonate agents (zoledronate and pamidronate). The remaining trials compared a bisphosphonate agent (etidronate, clodronate, pamidronate, or ibandronate) with placebo or no treatment. The systematic review included eleven of the twelve trials identified. Benefits: In the systematic review, eleven trials that included 2183 patients compared the use of a bisphosphonate with placebo or no treatment. The outcomes assessed included overall survival, vertebral and non-vertebral fractures, hypercalcaemia, pain, and gastrointestinal symptoms. Of those outcomes, vertebral fractures [Peto odds ratio (OR): 0.59; 95% confidence interval (95% CI 0.45 to 0.78; p = 0.0001] and pain (Peto OR: 0.59; 95% CI: 0.46 to 0.76; p = 0.00005) were significantly reduced in patients receiving bisphosphonates. Those results translate to a number-needed-to-treat value of 10 (95% CI: 7 to 20) to avoid 1 patient experiencing a vertebral body fracture and of 11 (95% CI: 7 to 28) to avoid pain in 1 patient. No difference in gastrointestinal symptoms was detected. The authors of the review suggested that clodronate and pamidronate might be the preferred agents. In a randomised trial comparing intravenous zoledronate with intravenous pamidronate in 510 patients with multiple myeloma and 1130 patients with breast cancer, no significant differences were detected in overall or progression-free survival, total or specific skeletal events, incidence of pain or analgesic use, and treatment-related toxicities. Harms Among the other trials included in the present practice guideline, no harms with bisphosphonate were reported. Practice Guideline: These recommendations apply to adult patients with active plasma-cell myeloma (symptomatic stage 1 or greater). Bisphosphonate treatment is recommended for all patients with myeloma who have lytic bone lesions, osteopoenia, or osteoporosis. For patients with myeloma who do not have lytic bone lesions, osteopoenia, or osteoporosis, health care providers should inform patients of the potential benefits and risks of therapy and offer treatment with a bisphosphonate to those patients. Evidence exists to support the use of clodronate (800 mg orally twice daily), pamidronate (90 mg intravenously every 4 weeks), or zoledronate (4 mg intravenously every 4 weeks). Patient preference, tolerance, and convenience will influence the choice of agent. Patients who are unable to tolerate the initial agent should be offered an alternative agent. Qualifying Statements: In patients with myeloma who are receiving a bisphosphonate, 24-hour urinary protein levels and serum creatinine values should be monitored. Pending additional evaluation, bisphosphonate should be withheld in patients with new, unexplained albuminuria or an increasing serum creatinine level. Reintroduction of bisphosphonate therapy at a slower infusion rate (for intravenous formulations) can be considered for patients demonstrating resolution of the progressive albuminuria or increasing serum creatinine. Clodronate is contraindicated in patients with a serum creatinine value greater than 440 μmol/L. Experience with pamidronate and zoledronate in patients with severe renal impairment is limited; these agents may be used with careful monitoring of renal function. No dose modification of pamidronate or zoledronate is required for patients with renal dysfunction.