We are of the opinion that, although RSK2 is the bottleneck output hub of RAS/RAF/ERK pathway [39,40], the therapeutic effect of single targeting of RAS or RAF might be hampered by the PDPK1-mediated constitutive active status of RSK2, which is independent of RAS/RAF/ERK activity in myeloma cells, while the blockade of AKT alone has only cytostatic effects but no major cell killing effect, as was found in this study in myeloma cells. This evidence concerns the gene RPS6KA3 and plasma cell myeloma.