Synergistic Inhibition of Myeloma Cell Growth by Combinations of Dexamethasone with Other Anti-Myeloma Agents.

During the past few years, several new agents with anti-myeloma activity have entered the clinic and improved disease outcome. In addition, inhibitors of key signal transduction pathways have shown promising results in preclinical studies. Combining novel and existing therapeutics might be essential to further improve treatment efficacy, while at the same time reducing adverse side effects. In this study, we systematically tested all possible two-fold combinations out of a repertoire of 8 anti-myeloma agents on five human maligant plasma cell lines. We included the conventional therapeutics doxorubicin and dexamethasone, the new therapeutics bortezomib and zoledronate, and the signal transduction inhibitors rapamycin (mTOR), AG490 (JAK/STAT), U0126 (MEK/MAPK) and L744.852 (farnesyltransferase). The anti-myeloma efficacy of each compound combination was tested in an MTS-based cell growth assay. Interestingly, the majority of compound combinations which blocked myeloma cell growth in a synergistic fashion included dexamethasone. The synergistic effect being mainly due to an increased sensitivity of the cell lines towards dexamethasone. In both the L363 and JK-6L cell lines, strong synergistic effects were observed if dexamethasone was combined with the mTOR inhbitor rapamycin, the MEK inhibitor U0126, the farnesyltransferase inhibitor L744.852 or, to a lesser extent, the JAK inhibitor AG490. In the INA-6 cell line, synergistic cell growth inhibition was observed if dexamethasone was combined with the MEK inhibitor U0126. No strong synergisms were found for the U266 and RPMI8226 cell lines. In the L363 cell line, we also observed strong synergistic effects between L744.852 and rapamycin, and between L744.852 and U0126, indicating that a three-fold combination of dexamethasone, L744.852 and rapamycin or U0126 could result in even more potent myeloma cell growth inhibition. Similarly, synergistic cell growth inhibition was seen in the JK-6L cell line when combining rapamycin and U0126, again suggesting that a three-fold combination including these two compounds and dexamethasone could be highly effective. In conclusion, our results offer important insights into the efficacy of combinations of anti-myeloma agents. Systematic in vitro testing could provide a first step towards finding useful combinations of agents to improve clinical outcome.