[5286] The Effect of Bortezomib (Velcade) on Bone Disease in Multiple Myeloma. Session Type: Publication Only
Evangelos Terpos, Marianna Politou, Laurraine Armstrong, Catriona Henderson, Edward Kanfer, Jane F. Apperley, John M. Goldman, Amin Rahemtulla Department of Haematology, Faculty of Medicine Imperial College London, London, United Kingdom
Bone resorption is increased in multiple myeloma (MM) due to increased osteoclastic activity and suppressed osteoblast function; thus, leading to the development of osteoporosis and osteolytic lesions. Receptor activator of nuclear factor-kappa B ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) are implicated in the differentiation and survival of osteoclasts. It has been reported recently by our group that the ratio RANKL/OPG is increased and correlates with the extent of bone disease, bone resorption, and survival in MM patients (Terpos et al, Blood 2003). The effect of RANKL on osteoclasts is through many pathways, including the activation of nuclear factor kappa-B (NF-B). Bortezomib (VELCADE) is a proteasome inhibitor, which is effective in patients with refractory MM. Its major effect is thought to be through the inhibition of NF-B. The aim of this study was to evaluate, for the first time in humans, the effect of bortezomib on bone disease and on markers of osteoclast function and bone resorption in patients with relapsed/refractory MM. We studied 11 patients (7M/4F; median age 59.5 years) who had received more than 2 lines of previous treatment, including high dose therapy with stem cell support. Eight patients had IgG MM, while one patient had IgA, one non-secretory and one light-chain MM. All patients had more than 3 lytic lesions and/or fractures on plain radiographs at the time of treatment initiation. Bortezomib was given at a dose of 1.3mg/m2, iv, in 3-week cycles, on days 1, 4, 8, and 11 of each cycle, for 8 cycles. All patients received zoledronic acid both pre-and post-bortezomib administration. Bone pain was clinically evaluated at baseline and on the first day of each cycle. Skeletal survey was performed at baseline, and after the 4th and 8th cycle of treatment. Markers of osteoclast function and bone resorption, such as soluble RANKL (sRANKL), OPG, and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), were measured at baseline and on day 1 of each cycle. The above markers were also measured in 12 healthy, gender and age matched, controls. Five out of 11 patients had achieved a partial response, while 3 patients had a minimal response, and 3 patients had not responded to bortezomib, according to EBMT criteria. All patients experienced dramatic improvement in bone-related pain after the 3rd cycle of treatment (p<.01). In particular, 3 patients who had grade III bone-related pain, according to Common Toxicity Criteria, achieved complete pain relief after 3 cycles of treatment. At baseline, OPG serum levels were very decreased compared to controls (p<.001). On the contrary, there was no difference in serum levels of sRANKL and TRACP-5 between patients and controls, possibly due to the long-term administration of zoledronic acid prior to bortezomib treatment. Administration of bortezomib produced no significant alteration in the levels of the above biochemical parameters. These data are in keeping with the recently published report that NF-B expression is not required for RANKL or OPG production by osteoblasts in murine models (Xing et al, J Bone Miner Res 2003) and suggest that bortezomib is very effective in controlling bone-related pain in myeloma patients independent of the RANKL/OPG pathway.
Abstract #5286 appears in Blood, Volume 102, issue 11, November 16, 2003
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