Yi-Chang Liu, Susann Szmania, Frits van Rhee

Although the introduction of novel drugs has improved outcome significantly in multiple myeloma (MM), many patients still eventually relapse. Monoclonal antibodies (mAbs) targeting MM-related antigens can complement currently available therapies. CS1 (also known as CD2 subunit 1, SLAMF7, CD319, and CRACC), a cell surface glycoprotein receptor that is a member of the signaling lymphocytic activation molecule (SLAM) family, is highly and nearly uniformly expressed in myeloma cells at the gene and protein level, but not expressed in other tissues, including hematopoietic stem cells, making CS1 a compelling target for the design of immunotherapies directed at MM. Elotuzumab (formerly HuLuc63), which is a humanized IgG1 mAb recognizing the extracellular region of human CS1, has been shown to be effective in preclinical and early stage clinical investigations, and its efficacy and safety will be further validated in ongoing Phase III trials. Integration of elotuzumab into multidrug therapeutic paradigms seems logical, as elotuzumab is more effective when combined with other agents, such as immunomodulatory drugs or proteasome inhibitors. The functional role of CS1 in MM pathogenesis and the consequences of elotuzumab on normal immune cells should be further investigated. Identification of potential biomarkers and exploration of resistance mechanisms are important issues for elotuzumab-based therapies, as is determining the best clinical placement of elotuzumab, not only in the relapsed/refractory setting but also in upfront therapy for high-risk frank MM, smoldering MM at high-risk of progression, and in maintenance regimens. This review will cover the biological characteristics of CS1 in normal immune cells and MM cells, the efficacy profile and mechanisms of action of elotuzumab from preclinical and clinical investigations, and its potential impact on the treatment of MM.