One of the most frequently used and effective drugs against multiple myeloma is the alkylating drug melphalan. However, the treatment is often hampered by development of drug resistance. Eventually, nearly all patients develop resistance, and mean survival time is about 3 years. Several factors have been suggested to contribute to drug resistance, including modulated drug transport and metabolism, enhanced DNA repair and decreased apoptotic signalling1,2,3. Major common determinants associated with melphalan resistance, however, remain elusive. To further identify potential protein biomarkers and/or pathways involved in elevated drug tolerance, SILAC-based quantitative protein profiling was performed using the multiple myeloma cell line RPMI 8226 (sensitive) and its derivative RPMI 8226-LR5 (adapted to growth in melphalan). By this approach, 2827 proteins were identified and 1163 were quantified by using both Mascot Distiller and MaxQuant. Comparison as well as grouping into appropriate networks and pathways of identified proteins was performed by Ingenuity Pathway Analysis software. Preliminary analyses indicate that a large fraction of the differentially expressed proteins are involved in DNA replication, recombination and repair, in cell cycle regulation as well as in cancer- and cell death pathways. Further in-depth analysis of selected candidate proteins is now underway.