title: Novel generation of agents with proven clinical activity in multiple myeloma.
abstract: The activity observed with proteasome inhibitors and immunomodulatory drugs (IMIDs) in multiple myeloma (MM) has prompted the development of second- and third-generation agents with similar, but not exactly the same, mechanisms of action as their predecessors. This review summarizes the mechanism of action and the available data on the clinical activity of novel proteasome inhibitors (carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs (pomalidomide), stressing the similarities and differences with bortezomib, and with thalidomide and lenalidomide, respectively. In summary, these novel agents have shown clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their parental drugs; moreover, they may even overcome resistance, indicating that there are some differences in their mechanisms of action and resistance. These data indicate that both the inhibition of the proteasome and the modulation of the immune system are good strategies to target MM tumor cells and this, along with the absence of complete cross-resistance observed among these drugs, open new avenues to optimize their use through the most appropriate sequencing and combinations.
authors.affiliation: Haematology Department, University Hospital of Salamanca, Cancer Research Center (IBMCC-CSIC), University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Spain. Electronic address: mvmateos@usal.es.
authors.forename: María-Victoria
authors.initials: MV
authors.lastname: Mateos
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007783:Lactones / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use; D061988:Proteasome Inhibitors / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D012008:Recurrence; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D007783:Lactones; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011758:Pyrroles; D013792:Thalidomide; C475865:marizomib; C524865:carfilzomib; C467566:pomalidomide