Lenalidomide and bortezomib induce osteoclast cytotoxicity and decrease BAFF secretion in osteoclasts in human multiple myeloma: Clinical implications

Abstract

7606 Background: Myeloma bone disease is caused by an enhanced osteoclast (OCL) activation, leading to osteolytic bone lesions. OCL have recently been reported to produce abundant B-cell activating factor (BAFF) in the bone marrow microenvironment that is important for myeloma cell growth and survival (Blood 106, 1021–30, 2005; ASH2005, #627). The proteasome inhibitor bortezomib (PS341, Velcade) has potent anti-myeloma activity with impressive clinical responses. A recent study indicated that bortezomib has inhibitory effects on OCL (ASH 2005, #2488). Lenalidomide (CC-5013, Revlimid) is an immunomodulatory derivative of thalidomide that has shown promising anti-myeloma effects in patients with relapsed or refractory multiple myeloma (MM) (ASH 2005, #6 & #1565). However, the effect of lenalidomide on human OCL lineage is unknown. Therefore, the aim of this study is to investigate the effect of lenalidomide and bortezomib on human OCL. Methods: OCL formation from healthy donors and MM patients were stimulated with RANKL (50ng/ml) and GM-CSF (10ng/ml) in 20% FBS/RPMI. Cells were incubated with lenalidomide 2μM or bortezomib 2nM, alone and in combination, for two weeks followed by [3H]thymidine uptake assay to measure growth inhibition of OCL. Similar experiments were also performed in cocultures of CD138-purified cells from MM patients with OCL, in the presence or absence of lenalidomide and bortezomib. In addition, ELISA was performed to measure cytokine release of BAFF produced by OCL in these cultures. Results: OCL growth was decreased by lenalidomide (n=6) (median 49.2%, range 20–62.5%; coculture: 53% and 35%) as well as bortezomib (96 and 49%; coculture 63 and 59%) and by the combination of both drugs (95 and 55%; coculture 42 and 44%). BAFF secretion was dramatically decreased in cultures treated with lenalidomide 2μM (n=3) (median 72%, range 61–75.9%). Conclusions: These results indicate that lenalidomide and bortezomib inhibit OCL growth and survival. Importantly, lenalidomide and bortezomib also block growth and survival of MM cells cocultured with OCL, suggesting that lenalidomide may inhibit OCL growth and survival through inhibition of BAFF and may prevent development of osteolytic lesions in MM. No significant financial relationships to disclose.