Abstract
Background: Prophylactic bisphosphonates are used worldwide in multiple myeloma patients, and two randomised studies have shown significant effect of i.v. pamidronate 90 mg once a month (N Engl J Med 1996 Feb 22;334(8):488–931) and of oral clondronate 1600 mg daily compared to placebo (Br J Haematol 2001 Jun;113(4):1035–43). However, no larger clinical study has addressed the dose-efficacy question, which is of increasing importance in view of recent reports on the risk of renal toxicity and osteonecrosis of the jaw (ONJ). In 2000 we started a randomised double blind trial with i.v. pamidronate 30 mg versus 90 mg monthly for at least 3 years.
Design: Patients with newly diagnosed symptomatic multiple myeloma were allocated to one of the two doses. Patients were stratified according to planned high dose therapy or conventional therapy and to the level of beta-2-microglobulin. Primary end-point was physical functioning at 12 months as measured by the EORTC QLQ-C30 quality of life questionnaire (QLQ), while secondary end-points were time to first objective skeletal event, cost-utility analysis, response of myeloma disease, response duration and survival, fatigue and pain determined by the QLQ. The patients were followed every third month with respect to skeletal event, toxicity and response, while the QLQ was mailed directly to the patients every third month. Skeletal x-rays were routinely performed before, and 9 and 24 months after start of pamidronate therapy.
Results: 505 patients were randomised. Median age was 63,4 years (range: 35–92). Sixty percent of the patients were treated with high-dose therapy and 40 percent with melphalan-prednisone (MP) regimes. The median follow up time was 3,7 years (1.1 to 5.7 years). There was no significant difference between the two treatment arms with respect to age, proportion of high-dose treated patients, skeletal involvement, stage (both international staging system (ISS) and Durie and Salmon), or b-2-microglobulin. The initial analysis of QLQ data shows improvement of global health status, pain, fatigue and physical functioning after myeloma treatment in accordance with earlier publication (Eur J Haematol 2001 May;66(5):328–36), but no significant difference regarding the primary end-point between the two pamidronate dose groups. Time to first skeletal event was not different in the two arms. The results from the blinded review of all skeletal x-rays will be presented together with the final analysis of toxicity data (renal failure and ONJ).
Conclusions:The initial analysis of the first prospective double blind trial on different doses of pamidronate as prophylactic treatment in multiple myeloma shows no significant difference between monthly infusions of 30 and 90 mg with respect to quality of life and time to first skeletal event. The final analysis will show whether the doses have any impact on the toxicity of the bisphosphonates. We recommend that the dose and type of bisphosphonate should be reconsidered in the prophylactic treatment of newly diagnosed myeloma patients. # ClinicalTrials.gov Identifier: NCT00376883
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