Prospective Randomized Trial of Dichloromethylene Bisphosphonate (Clodronate) in Patients with Multiple Myeloma Requiring Treatment. A Multicenter Study

Abstract

Background: Characteristic features of multiple myeloma are bone resorption, osteoporosis and osteolytic lesions. Bisphosphonates can inhibit osteoclast activity and bone resorption. In this controlled randomized multicenter trial the effect of the bisphosphonate clodronate on the progression of bone involvement in multiple myeloma was evaluated. Patients and Methods: 170 patients with multiple myeloma requiring treatment and with bone involvement were recruited and randomized. All patients received 15 mg/m² i.v. melphalan on day 1 and 60 mg/m2 p.o. predisone on days 1-4 every 4 weeks. Patients randomized to the bisphosphonate arm received 1,600 mg clodronate p.o./day for 1 year. Bone response was evaluated on the basis of X-ray controls of the skeleton at baseline, 6, and 12 months staging. In addition chemotherapy response, blood chemistry, cytology, pain, and analgesic drug consumption were documented. Results: After one year of treatment there was a higher bone response in the clodronate group (13%) when compared to the control group (6%, n.s.). The difference was mainly due to the change of the osteolytic lesions. Hypercalcemia was observed more often in the control group. The number of progressive sites was lower in the clodronate group (mean 0.49 vs. 0.66, result after one year, p = 0.09). The bone resorption index was significantly reduced in the clodronate group, but not in the control group. A reduction of pain and analgesic consumption was observed under clodronate treatment.

Bone disease in myeloma

“…Bisphosphonates have been evaluated in several large randomized trials in myeloma patients also receiving chemotherapy. Oral etidronate given daily showed no clinical benefit [2], whereas the use of oral clodronate daily produced variable clinical results in three randomized trials [11,16,17]. Oral administration of pamidronate was ineffective in reducing the skeletal complications of these patients [18].…”

“…• These agents have been evaluated alone and as adjunctive therapy to primary anti-cancer treatment in patients with cancers involving the bone, including multiple myeloma [2,[11][12][13][14][15][16][17][18][19][20]43]. Recent, large, placebocontrolled clinical trials have shown the efficacy of bisphosphonates in reducing skeletal complications in myeloma patients, suggesting that these agents may also alter the overall course of the disease.…”

Use of Bisphosphonates in Skeletal Metastasis

“…The effectiveness of bisphosphonates has been evaluated by their ability to reduce skeletal events: (1) new bone lesions (x-rays or scintigraphy) ; (2) fractures (radiologic or clinical examination) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20); (3) bone pain (analgesics, visual analogue scale, pain score, requirement of irradiation or isotope therapy) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41); (4) performance status (Karnofsky, Zubrod, ECOG) (11 -20, 31-41); (5) quality of life measures (16-20, 36, 37, 40, 41); (6) hypercalcemia (11 -21, 25, 31 -38); (7) measurements of different bone markers (11 -13, 20, 28, 30, 35 -38, 40 -44); and (8) survival (11 -13, 15, 18 -20, 34 -38, 40, 41). Study endpoints have been defined as a reduction of skeletal events and complications as well as an improvement of quality of life and pain relief.…”

“…The same applies to myeloma patients. It is now clear that bisphosphonates combined with chemotherapy are superior to chemotherapy alone in multiple myeloma (32)(33)(34)(35)(36)(37)(38). The subgroup analysis of the Finnish myeloma study showed also that patients without any bone lesion at baseline had benefited from a bisphosphonate because only 2.6% on clodronate had developed skeletal lesions after 2 years in comparison with 11.1% on placebo (p =0.03) (35).…”

Use of Bisphosphonates in Therapy and Prophylaxis of Cancer-Induced Bone Diseases

“…Side effects were similar in both groups. A second randomized trial using clodronate in patients receiving melphalan and prednisone showed a reduction of pain and analgesic consumption under bisphosphonate treatment [26]. In a trial by the British MRC group [27], 536 patients with recently diagnosed multiple myeloma were randomized to receive in addition to chemotherapy either clodronate 1,600 mg daily or a placebo.…”