Selinexor: Targeting a novel pathway in multiple myeloma

Abstract

Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin‐1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor‐based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor‐dexamethasone approved in the later‐relapse setting for penta‐refractory patients and selinexor‐bortezomib‐dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor‐based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

Mezigdomide—A Novel Cereblon E3 Ligase Modulator under Investigation in Relapsed/Refractory Multiple Myeloma

“…For example, triplet standards of care as second-line therapy include daratumumab or isatuximab in combination with carfilzomib or pomalidomide and dexamethasone, as well as elotuzumab plus lenalidomide or pomalidomide and dexamethasone [ 7 , 13 , 14 , 16 ]. Regimens incorporating novel targeted agents are also recommended as RRMM treatment, including the exportin-1 (XPO1) inhibitor selinexor plus bortezomib and dexamethasone (Vd) [ 17 ] and, in Europe, the cytotoxic drug–peptide conjugate melflufen plus dexamethasone [ 18 ]. More recently, novel immune-based therapies have been approved and are being investigated early in the RRMM treatment algorithm [ 4 , 16 , 19 , 20 , 21 ], including the chimeric antigen receptor (CAR) T-cell therapies idecabtagene vicleucel (ide-cel) [ 22 , 23 ] and ciltacabtagene autoleucel (cilta-cel) [ 24 , 25 ]; the bispecific antibodies/T-cell engagers teclistamab [ 26 ], talquetamab [ 27 ], and elranatamab [ 28 ]; and, in Europe, the antibody–drug conjugate belantamab mafodotin [ 29 ].…”