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Clinical Utility of Selinexor/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: A Review of Current Evidence and Patient Selection.

ABSTRACT: Multiple myeloma (MM) is one the most common hematological malignancies, and despite the survival prolongation offered by proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies, the need for novel agents is prominent. Selinexor is a first-in-class, oral, selective inhibitor of exportin-1 (XPO1), a vital protein for the exportation of more than 200 tumor suppressor proteins from the nucleus. Both in solid tumors and hematologic malignancies, selinexor-mediated inhibition of nucleus export seems to effectively lead to cancer cell death. Selinexor in combination with dexamethasone (Sd) received an accelerated FDA approval on July 2019 for heavily pretreated patients with relapsed/refractory MM (RRMM) based on the promising results of the Phase II STORM trial. The preliminary results of the randomized Phase III BOSTON trial have shown a 47% increase in progression-free survival among PI-sensitive, RRMM patients who received selinexor with bortezomib-dexamethasone compared with bortezomib-dexamethasone alone. Several different selinexor-containing triplet regimens are currently being tested in the RRMM setting in an umbrella trial, and the preliminary results seem promising. Furthermore, the addition of selinexor in other anti-myeloma agents seems to overcome drug-acquired resistance in preclinical studies. The main toxicities of selinexor are gastrointestinal disorders and hematologic toxicities (mainly thrombocytopenia); however, they are manageable with proper supportive measures. In conclusion, selinexor is a new anti-myeloma drug that seems to be effective in patients who have no other therapeutic options, including patients who have received novel cellular therapies such as CAR-T cells. Its potential role earlier in the therapeutic algorithm of MM is currently under clinical investigation.

SUBMITTER: Malandrakis P

PROVIDER: S-EPMC7335864 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Clinical Utility of Selinexor/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: A Review of Current Evidence and Patient Selection.

Malandrakis Panagiotis P Ntanasis-Stathopoulos Ioannis I Gavriatopoulou Maria M Terpos Evangelos E

OncoTargets and therapy 20200701

Multiple myeloma (MM) is one the most common hematological malignancies, and despite the survival prolongation offered by proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies, the need for novel agents is prominent. Selinexor is a first-in-class, oral, selective inhibitor of exportin-1 (XPO1), a vital protein for the exportation of more than 200 tumor suppressor proteins from the nucleus. Both in solid tumors and hematologic malignancies, selinexor-medi ...[more]

PMID: 32669858

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Project description:PurposeMelphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.Patients and methodsPatients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.ResultsOf 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.ConclusionMelflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.

Dataset Information

Clinical Utility of Selinexor/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: A Review of Current Evidence and Patient Selection.

Publications

Clinical Utility of Selinexor/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: A Review of Current Evidence and Patient Selection.

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