• Hematology Disease Site Group. Imrie K, Stevens A, Makarski J, Esmail R, Meharchand J, Meyer R. The role of bisphosphonates in the management of skeletal complications for patients with multiple myeloma [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Mar 30. 21 p. (Practice guideline report; no. 6-4). [28 references]

Skeletal complications of multiple myeloma, including lytic bone lesions, osteopenia, osteoporosis, vertebral and non-vertebral fractures, spinal cord compression, hypercalcemia, and bone pain

Assessment of Therapeutic Effectiveness
Management
Prevention
Treatment

Hematology
Oncology

Physicians

To evaluate if there is evidence that the use of bisphosphonates in patients with active multiple myeloma:

• Improves survival
• Improves quality of life
• Reduces bone pain
• Reduces or delays the development of skeletal complications

Adult patients with active plasma cell myeloma (symptomatic stage 1 or greater)

Use of bisphosphonates (oral clodronate, intravenous pamidronate, or intravenous zoledronate) for prevention and treatment of skeletal complications of multiple myeloma

Note: Other bisphosphonates (etidronate, ibandronate) were considered but not recommended for use. Oral pamidronate was also not recommended.

• Overall survival
• Vertebral and non-vertebral fractures
• Hypercalcemia
• Pain
• Gastrointestinal symptoms
• Treatment-related toxicities

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Sixteen fully published reports were reviewed. One was a systematic review that included a meta-analysis, one was a practice guideline, and the other 14 reports described 12 randomized trials

Expert Consensus (Committee)

Not applicable

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

It was decided not to pool the results of randomized controlled trials (RCTs) because of the availability of an up-to-date, published systematic review that included a meta-analysis of the available randomized controlled trials evaluating the efficacy and safety of bisphosphonates in multiple myeloma.

Expert Consensus

The members of the Disease Site Group (DSG) felt that the routine use of a bisphosphonate is recommended for patients with myeloma who have bone disease. The DSG members concluded that a number needed to treat (NNT) of 10 to prevent one patient with a vertebral fracture and a number needed to treat of 11 to prevent bone pain in one patient were clinically meaningful benefits. There was considerable discussion about the following issues:

1. Patients without bone disease: There was debate over the strength of the draft recommendation for using a bisphosphonate in patients without bone disease. Some members felt that a bisphosphonate should be recommended for these patients because a subset analysis of results of one trial detected benefits that were consistent with those seen in patients with bone disease and included a possible advantage in overall survival. Another view expressed was that while the use of a bisphosphonate would be reasonable and should be discussed with patients, available data were derived from a small number of patients described in a subset analysis and were insufficient to warrant "recommending" this treatment to all patients. The DSG therefore concluded that the wording of this practice guideline should be to "offer" treatment to these patients.
2. Choice of bisphosphonate: In the absence of compelling data detecting the superiority of one agent over others, the DSG members concluded that oral clodronate and intravenous pamidronate or zoledronate are all reasonable choices of therapy. Etidronate, oral pamidronate, and ibandronate should not be used. The DSG expressed a preference for intravenous pamidronate, as monthly intravenous infusions were perceived to be better tolerated, but unlike the American Society of Clinical Oncology (ASCO) expert panel, did not feel that the evidence clearly favoured pamidronate or zoledronate over clodronate.
3. Duration of therapy: Both the clodronate and pamidronate trials suggest that a prolonged duration of therapy (at least 24 months) is beneficial. Given the mechanism of action of bisphosphonates, the DSG felt it was reasonable to continue treatment until the myeloma becomes refractory to therapy. At this point, there may still be benefits in providing treatment with a bisphosphonate in order to palliate pain associated with progressive bone disease.
4. Autologous stem cell transplantation: Although no trials were performed specifically in patients undergoing autologous stem cell transplantation, DSG members concluded that it was reasonable to generalize recommendations to this setting.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Practitioner feedback was obtained through a mailed survey of 115 practitioners in Ontario (58 medical oncologists and 57 hematologists). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The practitioner feedback survey was mailed out on June 26, 2003. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Hematology Disease Site Group (DSG) reviewed the results of the survey.

The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval. Nine of 13 members of the PGCC returned ballots. One member did not review the report for approval as this individual is a member of the Hematology DSG. Five PGCC members approved the practice guideline report as written, two members approved the guideline and provided suggestions for consideration by the Hematology DSG, and one member approved the guideline conditional on the Hematology DSG addressing specific concerns.

No changes were made to the guideline in response to the comments made by the PGCC.

The practice guideline reflects the integration of the draft recommendations with feedback obtained from the external review process. It has been approved by the Hematology DSG and has been approved by the Practice Guidelines Coordinating Committee.

• It is recommended that all patients with myeloma who have lytic bone lesions, osteopenia, or osteoporosis receive a bisphosphonate.
• For patients with myeloma who do not have lytic bone lesions, osteopenia, or osteoporosis, health care providers should inform patients of the potential benefits and risks of therapy and offer treatment with a bisphosphonate to these patients.
• Evidence exists to support the use of clodronate (800 mg orally twice daily), pamidronate (90 mg intravenously every four weeks), or zoledronate (4 mg intravenously every four 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.

None provided

The recommendations are supported by randomized controlled trials and meta-analyses.

• In the systematic review, 11 trials that included 2,183 patients compared the use of a bisphosphonate with placebo or no treatment. Outcomes assessed included overall survival, vertebral and non-vertebral fractures, hypercalcemia, pain, and gastrointestinal symptoms. Of these outcomes, vertebral fractures (Peto odds ratio 0.59; 95% confidence interval 0.45 to 0.78; p = 0.0001) and pain (Peto odds ratio 0.59; 95% confidence interval 0.46 to 0.76; p = 0.00005) were significantly reduced in patients receiving bisphosphonates. These results translate to a number-needed-to-treat value of 10 (95% confidence interval 7 to 20) in order to avoid one patient with a vertebral body fracture and 11 (95% confidence interval 7 to 28) in order to avoid pain in one patient. The authors of the review suggest that clodronate and pamidronate might be the preferred agents.
• In a randomized trial comparing intravenous zoledronate with intravenous pamidronate in 510 patients with multiple myeloma and 1,130 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, or treatment-related toxicities.

• Gastrointestinal symptoms (grade III/IV) were the most commonly reported adverse effects in all trials.
• Renal function is an important consideration when using a bisphosphonate to treat patients with myeloma. Clodronate, pamidronate, and zoledronate are excreted unchanged by the kidneys, and nephrotoxicity has been reported with each of these agents.

Clodronate is contraindicated in patients with a serum creatinine value greater than 440 micromoles/L. Limited experience exists with pamidronate and zoledronate in patients with severe renal impairment; these agents may be used with careful monitoring of renal function.

• Twenty-four hour urinary protein levels and serum creatinine values should be monitored in patients with myeloma who are receiving a bisphosphonate. Patients with new unexplained albuminuria or an increasing serum creatinine should have the bisphosphonate withheld pending additional evaluation. 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 micromoles/L. Limited experience exists with pamidronate and zoledronate in patients with severe renal impairment; 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.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness
Patient-centeredness

• Hematology Disease Site Group. Imrie K, Stevens A, Makarski J, Esmail R, Meharchand J, Meyer R. The role of bisphosphonates in the management of skeletal complications for patients with multiple myeloma [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Mar 30. 21 p. (Practice guideline report; no. 6-4). [28 references]

Not applicable: The guideline was not adapted from another source.

2004 Mar 30

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Practice Guidelines Initiative (PGI) is the main project of the Program in Evidence-based Care (PEBC), a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Hematology Disease Site Group

Members of the Hematology Disease Site Group (DSG) disclosed potential conflict of interest information.

None available

This NGC summary was completed by ECRI on June 30, 2004. The information was verified by the guideline developer on July 19, 2004. This summary was updated by ECRI on May 20, 2005, following the U.S. Food and Drug Administration advisory on Aredia (pamidronate disodium) and Zometa (zoledronic acid).