Guidelines on the Diagnosis and Management of Multiple Myeloma

*** See also December 2002 revision ***

7. Bisphosphonates

Bone pain, hypercalcaemia and pathological fractures are a major cause of morbidity and mortality in patients with multiple myeloma. Randomised placebo-controlled studies with both pamidronate and clodronate have shown a significant benefit for bisphosphonate treatment (Delmas et al, 1982; Lahtinen et al, 1992; Berenson et al, 1996; Berenson et al, 1998; McCloskey et al, 1998). Long-term therapy with bisphosphonates has been shown to reduce skeletal morbidity, improve quality of life and reduce the need for surgery and radiotherapy.

Three randomised studies have compared oral clodronate with placebo. In 30 patients, Delmas et al (1982) reported a reduction in bone pain and progression of skeletal lesions. The Finnish clodronate study randomised patients to clodronate 2400 mg daily or placebo (Lahtinen, 1992; Laakso et al, 1994). There was a reduction in biochemical markers of bone turnover and a 50% reduction in the incidence of new osteolytic lesions in the clodronate group. No significant effect was seen on progression of vertebral and non-vertebral fractures. Vertebral fractures were reduced (38 vs 55%, p=0.01) and a decrease in non-vertebral fractures (6.8 vs 13.2%, p=0.04) observed in the UK MRC clodronate trial in which 536 patients were randomised between clodronate 1600mgs p.o. and placebo (McCloskey et al, 1998). Height loss was less and the incidence of hypercalcaemia reduced in patients who received clodronate; similarly analgesic usage was reduced and at 24 months back pain and poor performance status were improved for clodronate treated patients.

Subgroup analysis in both the Finnish and MRC studies showed that patients without overt skeletal disease at entry benefited from bisphosphonate treatment, and in the MRC study these patients benefited most, supporting the use of bisphosphonates early in the evolution of the disease.

Pamidronate is also effective in myeloma. Berenson et al (1996; 1998) evaluated the efficacy of pamidronate 90mgs i-v monthly in 392 patients with stage III myeloma that had been stable for over 3 months on chemotherapy. This study showed a significantly reduced incidence of bone pain, analgesic usage, fewer skeletal events together with less deterioration in performance status in patients who were randomised to receive pamidronate. Subgroup analysis of those patients undergoing chemotherapy of first relapse suggested a possible survival advantage for those who received pamidronate.

There have been no randomised studies comparing different doses of clodronate or comparing clodronate with pamidronate. Oral pamidronate has not been shown to be effective (Brincker et al, 1998). Oral etidronate is ineffective in myeloma and may cause demineralisation (Belch et al, 1991). There are no data on the effectiveness in myeloma of any other oral bisphosphonate.

Zoledronate is a new, more potent bisphosphonate in vitro. It is given intravenously and requires only a 10-minute infusion [NB: the recommended infusion time has subsequently been increased to 15mins - see December 2002 update], in comparison with 90 minutes for pamidronate. It is currently undergoing clinical trial evaluation. It has been shown to be more effective than pamidronate in the treatment of tumour related hypercalcaemia (Major et al, 2001) and to be as effective as pamidronate in reducing skeletal-related events in patients with osteolytic lesions due to myeloma or breast carcinoma (Berenson et al, 2001).

Health economic data on long-term bisphosphonate use are conflicting. In the Finnish study clodronate did not increase overall cost of treatment (Laakso et al, 1994), whereas analysis of data from the MRC trial suggested a 17% overall increase in treatment costs with the additional costs of clodronate set against the reduction in cost due to skeletal-related events (Bruce et al, 1999). Formal quality of life data are lacking in all studies but the evidence for reduction in bone pain and analgesic usage as well as fewer skeletal related events would suggest that quality of life is improved.

Recommendations:

*** See also December 2002 revision ***