Guidelines on the Diagnosis and Management of Multiple Myeloma

Recommendations for Bisphosphonates (December 2002 Revision; amended March 2003 with additional minor amendments July 2003)

Based on existing data the UKMF guidelines 2001 recommended the long-term use of either oral clodronate or intravenous pamidronate for all patients requiring treatment for myeloma. A Cochrane review published in 2001 and updated in 2002 reached similar conclusions (Djulbegovic et al, 2001, 2002). Subsequently, two additional randomised controlled trials of long-term bisphosphonate therapy in MM have been published, one comparing zoledronic acid and pamidronate, and one comparing ibandronate with placebo. There have also been some reports of renal toxicity with newer nitrogen-containing bisphosphonates. In the light of these publications the UKMF Guidelines Working Group has updated the previous recommendations for bisphosphonate therapy.

[NB the following review of the recent evidence is intended to supplement and not replace the information contained in the main guideline.]

Cochrane Review

The Cochrane Review included data from 10 placebo-controlled studies of clodronate, pamidronate, or etidronate and from a preliminary report of the ibandronate study. The zoledronic acid versus pamidronate study had not been published at that time. The meta-analysis demonstrated:

• a highly significant reduction in the incidence of pathological vertebral fractures (25% vs. 35%, P=0.0001) during treatment with a bisphosphonate. The reduction in absolute risk of 10% equates to a number needed to treat (NNT) of 10 for vertebral fracture (i.e. for every 10 patients treated with bisphosphonates one patient will avoid a vertebral fracture).
• a reduction in incidence of bone pain from 51% to 42% with bisphosphonate usage (OR 0.59, p=0.00005). Thus, on average, for every 11 patients treated with bisphosphonate, one patient will not experience pain.
• a reduction in incidence of hypercalcaemia from 10.1% to 8% (OR 0.76, p=0.07).
• the meta-analysis did not show any overall significant effect of bisphosphonates on non-vertebral fracture risk (OR 1.05, p=0.7). However, some heterogeneity was noted among the trials with clodronate showing a non-significant benefit and pamidronate and ibandronate non-significant adverse effects.

The conclusions of the Cochrane Review were that adding bisphosphonates to the treatment of multiple myeloma reduces vertebral fracture, probably pain, and possibly the incidence of hypercalcaemia.

Ibandronate versus Placebo

A randomised placebo controlled trial of intravenous ibandronate 2mg in approximately 200 patients with advanced myeloma observed no benefit of ibandronate (Menssen et al, 2002). The incidence of SRE's and the time to first SRE were not significantly different between the 2 groups, and there were no differences in quality of life or survival. It is possible that the dose chosen was sub-optimal, but at present there is no evidence to support the use of ibandronate in myeloma.

Zoledronic acid versus Pamidronate

Rosen et al (2001) reported the results of a direct comparative study of long-term pamidronate and zoledronic acid in a study including both women with breast cancer and patients with multiple myeloma. They were randomised to receive pamidronate 90mg, zoledronic acid 4mg or zoledronic acid 8mg, monthly, for a period of 12 months. A total of 1,648 patients were enrolled, including 513 patients with Durie-Salmon stage III myeloma and at least one osteolytic bone lesion. The incidence of skeletal events (excluding hypercalcaemia) over the 12 months of treatment was similar in all 3 treatment groups (47%, 49% and 49% of patients experiencing events for 4mg zoledronic acid, 8mg zoledronic acid and 90mg pamidronate respectively).

The median times to first event were also similar (373 days vs. 363 days for zoledronic acid 4mg and pamidronate respectively) and there were no detectable differences in pain scores, analgesic use or performance status.

The 8mg dose of zoledronic acid was discontinued because of effects on renal function. There were also some problems with renal function in initial patients receiving zoledronic acid 4mg which led to extension of the infusion time to 15 minutes. Except for the differing effects on renal function the side effect profiles of zoledronic acid 4mg and pamidronate 90mg were similar.

This study concluded that zoledronic acid (4mg) via 15-minute intravenous infusion was as effective and well tolerated as 90mg of pamidronate in the treatment of osteolytic lesions in patients with advanced breast cancer or multiple myeloma. Zoledronic acid has subsequently been licensed for the treatment of metastatic bone disease. The main advantage of zoledronic acid over pamidronate is the shorter infusion time. Care needs to be taken in routine clinical practice to ensure that the infusion time for the 4mg dose is not faster than recommended. Renal function should be monitored in all patients.

The ASCO Guidelines

The American Society of Clinical Oncology have since published guidelines on the role of bisphosphonates in multiple myeloma (Berenson et al, 2002). They also concluded that the available evidence indicated that clodronate, intravenous pamidronate and intravenous zoledronic acid are superior to placebo.

Nitrogen-containing Bisphosphonates and Renal Function

[please refer to the original guidelines for recommendations on dosage of clodronate and pamidronate in renal failure].

1. Pamidronate

The schedule recommended by the UKMF guidelines for intravenous pamidronate administration is 90mg monthly. The development of nephrotic syndrome has recently been reported in 5 patients receiving pamidronate at a higher dose or frequency (Desikan et al, 2002). Renal biopsy was performed in 2 patients and showed focal segmental glomerulosclerosis. The authors felt that a similar risk was likely with other nitrogen containing bisphosphonates including ibandronate and zoledronic acid.

2. Zoledronic acid

As discussed above, zoledronic acid has been shown to affect renal function at higher doses or with the 4mg dose if given over a period shorter than 15 minutes. Zoledronic acid is not currently recommended for patients with serum creatinine of 400 µmol/l or above. The manufacturers indicate that dose reduction is not required in patients with moderate renal impairment (serum creatinine below 400 µmol/l). Such patients should, however, be closely monitored for changes in renal function.

Recently a marked increase in creatinine was reported in 2 of 3 patients with myeloma receiving thalidomide who were changed from regular pamidronate to zoledronic acid 4mg by 15 minute infusion (Jones et al, 2002), suggesting a possible drug interaction, but the significance of this is as yet uncertain.

Revised Recommendations [additions from 2001 are highlighted]

 

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