In conclusion, our study revealed that the dual blockade of RSK2 and AKT exhibits anti-tumor effects in myeloma cells via the regulation of multidirectional cell-intrinsic and extrinsic molecular mechanisms for various critical molecules and biologic processes in myeloma development and progression, and, thus, is an attractive candidate of new therapeutic strategy for MM with diverse molecular backgrounds. This evidence concerns the gene RPS6KA3 and plasma cell myeloma.