Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma

Oral clodronate (1600 mg/d) has been shown to significantly reduce the inci dence of skeletal complications in multiple myeloma. Preliminary analysis o f a double-blind placebo-controlled trial of this treatment indicated that clodronate might prolong survival in patients without vertebral fractures a t presentation. This issue was re-examined after further follow-up of the p atients recruited into the Medical Research Council (MRC) VIth Myeloma Stud y. The trial examined the effects of clodronate on the natural history of s keletal disease in multiple myeloma; 619 patients were randomized between T une 1986 and May 1992 commencing 15 d after the start of ABCM [adriamycin, BCNU (carmustine), cyclophosphamide, melphalan] chemotherapy or 43 d after ABCMP (ABCM + prenisolone); 535 patients who received clodronate or placebo were included in the analysis. The presence or absence of spinal fractures was assessed centrally from spinal X-rays; longbone fractures were assesse d locally. With a median followup of 8.6 years, there was no overall signif icant difference in survival between the two treatment groups (O/E, chi (2) = 0.78, P = 0.38). Among the subgroup of 153 patients with no skeletal fra ctures at presentation there was a significant survival advantage (O/E, chi (2) = 7.52, P = 0.006) in favour of the 73 patients receiving clodronate, with median survivals being, respectively 59 months (95% CI 43-71 months) a nd 37 months (95% CI 31-52 months), and 5-year survivals being 46% and 35%. The original analysis of this study shows that there is a benefit in takin g 1600 mg clodronate daily for patients with myelomatosis to prevent the de velopment of new skeletal disease. Bearing in mind the limitations of subgr oup analysis, the present study indicates that treatment may prolong surviv al in patients without overt skeletal disease at diagnosis. These observati ons, however, require confirmation in prospective clinical trials.