Recent advances in diagnosis and treatment of multiple myeloma

Multiple myeloma (MM) is a stem cell malignancy arising from a single plasma cell clone that secretes a monoclonal immunoglobulin. Clinical outcome depend on multiple risk factors which include performance status, age, international stage and cytogenetics including mutated and translocated oncogenes. The Mayo clinic's risk-stratification tool (mSMART) based on cytogenetic markers categorizes patients into low, intermediate, and high risk that guides initial therapy. Despite the addition of newer and more effective therapeutic options for MM, the disease remains incurable. The goal of therapy is focused on improving overall survival, progression free survival, duration of complete response, and quality of life. This is largely due to novel agents, combination therapies, better targeting of the tumor microenvironment and autologous stem cell transplantation. Currently FDA approved therapeutic options include immunomodulatory (iMiDs) drugs, proteaosome inhibitors, alkylators, anthracycline, vinca alkaloid, and steroids. Bortezomib and lenalidomide have become the backbone for transplant eligible patients with induction therapy in combination with other agents. Various combinations exist; bortezomib and dexamethasone with lenalidomide, thalidomide, cyclophosphamide, or liposomal doxorubicin. In transplant ineligible patients induction therapies overlap but include mephalan plus dexamethasone with bortezomib, lenalidomide, or thalidomide. As knowledge of the molecular pathways in combination of whole exome sequencing continues to expand, novel therapies will be matched to underlying biology. We discuss these exciting drugs, their mechanism of action, pathways, and their incorporation into ongoing clinical trials to improve overall syrvival. Examples of cell surface and extracellular targets include EGFR, CS-1, IGF-1R, CD40, CD38, CD138, PD-1 and PDL1 respectively. Of the novel agents, a humanized IgG1 monoclonal antibody to CD38 SAR650984 (SAR) showed a favorable toxicity profile and encouraging single agent activity in an early phase clinical trial. OSI-906 an oral IGF-1R kinase inhibitor in combination with bortezomib was cytotoxic to MM cell lines in a dose-dependent manner suggesting a high degree of synergy for combination therapy. A phase I trial evaluating OSI-906 in combination with bortezomib plus dexamethasone is underway. Of the intracellular targeted agents novel proteosome inhibitors, Bcl2 inhibitors, HSP90 inhibitors, AKT inhibitors, mTOR inhibitors, p38 MAPK inhibitors, autophagy inducers, HDAC inhibitors, aurora kinase and CDK inhibitors have shown promising in vivo activity. TGO2 a multi-kinase inhibitor of CDK 1, 2, 9, JAK2, FLT3, in addition to MAPK, ERK5 in MM cell lines resulted in arrest and rapid apoptosis. TGO2 is under evaluation in phase I clinical trials alone or in combination with carfilzomib. Finally, chimeric antigen receptors (CARs) which are synthetic trans-membrane proteins are being utilized to redirect autologous T-cells with specificity for surface antigens on MM cells. Current targets are the Kappa light chain, CD138, and Lewis Y antigen. CARs targeting BCMA, CS1, and CD38 are in pre-clinical investigation. Initial CARs therapy would focus on R/R MM, while consolidation strategies after first-line therapy or in conjunction with autologous stem cell transplantation are promising.