The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio E Terpos 1,2 , D Mihou 3 , R Szydlo 2 , K Tsimirika 3 , C Karkantaris 1 , M Politou 2 , E Voskaridou 4 , A Rahemtulla 2 , MA Dimopoulos 5 and K Zervas 3 1 Department of Hematology, 251 General Airforce Hospital, Athens, Greece; 2 Department of Hematology, Faculty of Medicine Imperial College London, Hammersmith Hospital, London, UK; 3 Department of Hematology, ‘Theageneion’ Cancer Center, Thessaloniki, Greece; 4 Thalassemia Center, Laikon Hospital, Athens, Greece; and 5 Department of Clinical Therapeutics and Internal Medicine, University of Athens School of Medicine, Athens, Greece The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/ Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post- treatment soluble receptor activator of nuclear factor-jB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a sig- nificant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. b 2 -microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio. Leukemia (2005) 19, 1969–1976. doi:10.1038/sj.leu.2403890; published online 4 August 2005 Keywords: multiple myeloma; thalidomide; bone markers; receptor activator of nuclear factor-kB ligand (RANKL); osteoprotegerin; osteopontin Introduction Multiple myeloma (MM) is a neoplastic disease of the bone marrow plasma cells, which remains, unfortunately, incurable with current treatment. 1,2 Thalidomide has been shown to have a significant antimyeloma activity in both refractory/relapsed and newly diagnosed MM patients. 3–5 In the first report by Singhal et al, 3 thalidomide was given at a starting dose of 200 mg/day, increasing in 200 mg increments every 2 weeks to a maximum dose of 800 mg/day. 3 However, the optimal dose of thalidomide remains uncertain. 6,7 Thalidomide produces a response rate of 30–35% in patients with refractory/relapsed disease, which is increased to almost 50% when it is combined with dexamethasone. 8,9 When thalidomide is given together with dexamethasone, the dose of 400–600 mg/day is usually used. There is very little information for the role of the combination of intermediate dose of thalidomide with dexa- methasone in the clinical course of the disease in patients with refractory/relapsed myeloma. Bone disease in MM remains a difficult problem to manage. It mainly includes osteolytic lesions due to an increased osteoclas- tic activity, which is not accompanied by a comparable increase in bone formation. 10 Cytokines produced locally by stromal or myeloma cells are responsible for the osteoclast activation. 11,12 The receptor activator of nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system has a major role in osteoclastogenesis, as RANKL directly induces osteoclast differ- entiation and proliferation by binding to its receptor RANK on the surface of osteoclast precursors. OPG is the soluble decoy receptor for RANKL and one of the most potent antiresorptive agents known. 13 In MM, the ratio of RANKL/OPG is increased due to an increase in RANKL production and a decrease in OPG production by stromal cells. 14 Furthermore, the ratio of soluble RANKL (sRANKL)/OPG has been found to be elevated in the serum of patients with MM at diagnosis and correlates with the extent of bone disease and survival. 15,16 The possible presence and production of RANKL by myeloma cells may explain the major role of this pathway in the biology of myeloma bone disease as well as tumor growth and survival. 17 To our knowl- edge, there is no information in the literature regarding the effect of thalidomide on bone turnover in myeloma patients. The aim of this study was to evaluate the effect of the combination of intermediate dose of thalidomide with dexa- methasone on disease course and bone remodeling in patients with refractory/relapsed MM who receive zoledronic acid. We have also evaluated the role of pretreatment characteristics of patients in survival and investigated if there is any correlation between markers of bone turnover and response to treatment. Patients and methods Patients In all, 35 patients (23M/12F) with refractory or relapsed myeloma were entered into this study. All patients met the eligibility criteria of the protocol that included relapsed or refractory myeloma, age p80 years, no previous treatment with thalidomide, acceptable cardiac (ejection fraction 440%), pulmonary (diffusion capacity for carbon monoxide 450% of normal) and hepatic (bilirubin and transaminases o2  upper limit) function. Poor performance status due to MM was not an Received 3 March 2005; accepted 21 June 2005; published online 4 August 2005 Correspondence: Dr E Terpos, Department of Hematology, 251 General Airforce Hospital, 3 Kanellopoulou Street, GR-11525, Athens, Greece; Fax: þ 30 210 7464648; E-mail: e.terpos@imperial.ac.uk; eterpos@hotmail.com Leukemia (2005) 19, 1969–1976 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu