Introduction: Glucocorticoids have been widely used in the treatment of multiple myeloma, both as single agents and combined with conventional and novel agents. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. Blockade of IL-6 signaling seems to be essential for dexamethasone-induced cell death because apoptotic pathways activated by dexamethasone can be abrogated by IL-6. The dipeptide boronic acid analogue bortezomib is a potent, highly selective, and reversible proteasome inhibitor that targets 26S proteasome complex and inhibits its function. Preclinical in vitro and in vivo studies show remarkable anti-multiple myeloma activity of the proteasome inhibitor bortezomib even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide.
Purpose of the study: In these studies, we have examined the effects of combining dexamethasone, melphalan, bendamustine, doxorubicin and thalidomide with bortezomib in the chemotherapy refractory cell line RPMI-8226 and the chemotherapy sensitive human multiple myeloma cell line OPM-2. >Methods: The sensitivity of the different cell lines against the tested chemotherapeutic drugs was assessed using the MTT test system. The therapeutic index was calculated from isobologram analyses. >Results: Comparing two cell lines from multiple myeloma (IgG lambda type), the RPMI-8226 line was much more resistant to the tested conventionally used drugs doxorubicin (resistance factor (RF) = 2), melphalan (RF = 15), bendamustine (RF = 1.5), thalidomide (RF = 2.5) and dexamethasone (RF = 300) compared to the OPM-2 cell line. Relative resistance to bortezomib of the RPMI-8226 cell line in this comparison was determined to a RF of 3. Isobologram analysis of cytotoxicity assays revealed that there is a strong synergistic interaction between dexamethasone and bortezomib in both cell lines. In general, a sequence of short time exposure (1 h) of conventional cytostatics (ctx) to the tested cell lines prior to the administration of bortezomib shows a higher therapeutic index than the sequence bortezomib prior to ctx. >Conclusion: Our findings of a strong synergistic interaction between dexamethasone and bortezomib give evidence for a combination therapy in patients suffering multiple myeloma even in a dexamethasone resistant situation.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA