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Simple Summary: The chemotherapy combination rituximab, gemcitabine, and dexamethasone (R-GDP), followed by high-dose chemotherapy and autologous stem cell transplantation, is one of the standards of care for relapsed or refractory B-cell non-Hodgkin lymphoma (R/R NHL). Complete metabolic response before transplantation is the most important prognosis factor for a long duration of remission. Selinexor is an oral, selective inhibitor of the nuclear export compound (XPO1). For heavily pretreated patients with DLBCL, the single drug selinexor has previously shown an overall response rate of 29%. In this study, we evaluated selinexor in combination with RGDP for patients with R/R B-cell lymphoma. The results from our phase I clinical study indicate that weekly selinexor plus RGDP has a generally tolerable safety profile and durable efficacy in R/R B-NHL. Purpose: Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma. Patients and methods: We conducted a phase 1b, dose-escalation, and expansion trial, which enrolled patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Patients received oral selinexor according to a 3 + 3 design in combination with rituximab and dexamethasone, high-dose cytarabine, oxaliplatine (DHAOX) or gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. Results: A total of 39 patients were enrolled, 27 during the escalation phase and 12 during the expansion phase. Most patients had diffuse large B-cell lymphoma (DLBCL; 77%). Group R-DHAOX was prematurely closed to inclusion due to a recommendation from the French drug agency, independent of this trial. A recommended phase 2 dose (RP2D) of selinexor in association with R-GPD was established at 40 mg on days 1, 8, and 15 of each 21-day cycle. In a population of 18 patients treated at this dose of selinexor, the most frequent grade 3–4 adverse events were hematological. With this regimen, seven obtained a complete metabolic response and five a partial response. The median PFS was 5.8 months. Conclusions: Among the patients with R/R B-cell lymphoma, selinexor at a weekly dose of 40 mg with R-GDP is feasible for outpatients, with a generally acceptable safety profile. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the impact of prior therapies on outcomes with selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in 402 patients with relapsed/refractory multiple myeloma (RRMM) in the phase 3 BOSTON trial. Methods: Post hoc analysis of progression‐free survival (PFS), overall survival (OS), and safety for lenalidomide‐refractory, proteasome inhibitor (PI)‐naïve, bortezomib‐naïve, and one prior line of therapy (1LOT) patient subgroups. Results: At a median follow‐up of over 28 months, clinically meaningful improvements in PFS were noted across all groups with SVd. The median SVd PFS was longer in all subgroups (lenalidomide‐refractory: 10.2 vs. 7.1 months, PI‐naïve: 29.5 vs. 9.7; bortezomib‐naïve: 29.5 vs. 9.7; 1LOT: 21.0 vs. 10.7; p <.05). The lenalidomide‐refractory subgroup had longer OS with SVd (26.7 vs. 18.6 months; HR 0.53; p =.015). In all subgroups, overall response and ≥very good partial response rates were higher with SVd. The manageable safety profile of SVd was similar to the overall patient population. Conclusions: With over 2 years of follow‐up, these clinically meaningful outcomes further support the use of SVd in patients who are lenalidomide‐refractory, PI‐naïve, bortezomib‐naïve, or who received 1LOT (including a monoclonal antibody) and underscore the observed synergy between selinexor and bortezomib. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. Methods: Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. Results: Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. Conclusions: In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies. [ABSTRACT FROM AUTHOR]

The outcomes of patients with myeloma after exposed to penta-classes are extremely poor. Selinexor is the first approved exportin inhibitor for those patients, but intractable toxicities may limit its use. This retrospective study evaluated the real-world efficacy and safety of selinexor plus dexamethasone (XD) and involved 48 patients with multiple myeloma, who were treated from November 2020 to October 2022. Their median age was 64 years, and the median number of prior lines of therapy was 6. The overall response rate was 25%, and the median progression-free survival (PFS) was 2.1 months (95% confidence interval (CI), 1.7–2.5). Patients on a reduced initial dose, delayed treatment, and dose reduction had better PFS. After XD treatment failure, 17 patients received subsequent therapy and had a median PFS of 2.4 months. The median overall survival was 4.6 months (95% CI, 2.3–6.9). Among the patients, 12 (25%) and 17 (35%) experienced dose reduction and delayed treatment, respectively. Our data show that the real-world efficacy of XD treatment in heavily pretreated patients was modest and that improving treatment adherence through reducing initial doses or delaying treatments may improve patient outcomes. [ABSTRACT FROM AUTHOR]

Abstract As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019–June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients’ health.

Objective: To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd). Methods: An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials. Results: Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatmentemergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%). Conclusion: The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall riskbenefit profile favored the SPd-40 regimen. [ABSTRACT FROM AUTHOR]

As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019–June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients’ health. [ABSTRACT FROM AUTHOR]

Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor's dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug's impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson's Disease. The review emphasizes the criticality of managing Selinexor's side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor's long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders. [ABSTRACT FROM AUTHOR]

Objective To observe the effect of Selinexor (SEL) combined with Imatinib (IM) on the proliferation and apoptosis of Imatinib-resistant chronic myeloid leukemia K562/G01 (KG) cells and explore the possible mechanisms. Methods K562 cells and KG cells were treated with SEL or IM respectively or in combination. Cells viability was examined by MTT assay. Apoptosis was assessed by flow cytometry. BCR-ABL mRNA was detected by RT-PCR. XPO1 was detected by Western blotting. Results IM and SEL both inhibited the proliferation of K562 cells and KG cells; half maximal inhibitory concentration (IC50) for 48 h was 0.16 µmol/L vs. 6.48 µmol/L for IM and 132.0 nmol/L vs. 275.9 nmol/L for SEL. Compared with SEL or IM alone, SEL combined with IM significantly inhibited the proliferation of KG cells (P<0.05), induced KG cells apoptosis (P<0.05), downregulated the levels of BCR-ABL mRNA (P<0.05), and inhibited the expressions of XPO1 in KG cells (P<0.05). Conclusion SEL combined with IM can synergistically inhibit the proliferation and induce apoptosis of KG cells, and then inhibit the expressions of BCR-ABL mRNA and XPO1 to exert an anti-leukemia effect. [ABSTRACT FROM AUTHOR]

Objective: Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1 protein in these cells. Data source: A comprehensive search was done, and data showing the efficacy and safety of selinexor in relapsed/refractory multiple myeloma was collected using PubMed, Google Scholar, and clincialtrials.gov. Data summary: Results from the clinical trials STORM, BOSTON, and STOMP were included. Parts I and II of the STORM trial revealed a progression-free survival (PFS) of 4.7 and 3.7 months, a median duration of response of 6.2 and 4.4 months, and an overall survival of 7.3 and 8.4 months, respectively. BOSTON trial's SVd arm (selinexor, bortezomib, and dexamethasone) had a median follow-up period of 13.2 months and an mPFS of 13.93 months. The Vd arm (bortezomib and dexamethasone) had a median follow-up duration of 16.5 months and an mPFS of 9.46 months. The STOMP trial is still active and has limited data available. The SKd arm (selinexor, carfilzomib, and dexamethasone) reported an overall response rate of 66.7% in patients with triple refractory multiple myeloma, and 82% in patients with high-risk cytogenetics. The SPd arm (selinexor, pomalidomide, and dexamethasone) shows an overall response rate of 54.30% in pomalidomide naïve-nonrefractory, 35.70% in pomalidomide refractory and 60% in those dosed at RP2D. SRd arm (selinexor, lenalidomide, and dexamethasone) shows an overall response rate of 91.7% in lenalidomide naïve and 12.5% in lenalidomide refractory patients. SVd (selinexor, bortezomib, and dexamethasone) arm reported an overall response rate of 63% in all patients while the SDd arm (selinexor, daratumumab, and dexamethasone) showed an overall response rate of 73%. Conclusion: To improve the outcome of patients with relapsed/refractory multiple myeloma, it is critical to develop new therapies, assess potential therapeutic synergies, and overcome drug resistance by determining the efficacy of multiple myeloma therapies across multiple disease subgroups. [ABSTRACT FROM AUTHOR]

The treatment of elderly patients diagnosed with acute myeloid leukemia (AML) poses significant challenges. Currently, one promising strategy in therapeutic interventions for geriatric individuals revolves around the utilization of small molecule targeted drugs either independently or in conjunction with demethylating agents. In this report, we present the successful attainment of complete remission in an elderly female patient with relapsed AML, the patient underwent treatment with a combination of Selinexor, decitabine, and a half-dose CAG regimen for two cycles. Subsequently, the patient has sustained this remission through consolidation therapy involving a medium dose of Ara-c. This therapeutic regimen has demonstrated favorable outcomes in the management of relapsed AML in elderly individuals. Furthermore, the adverse reactions were manageable. In order to devise an efficacious treatment regimen for elderly patients suffering from relapsed and refractory acute myeloid leukemia, it is imperative to incorporate a larger cohort of cases for clinical investigation.

The article offers information on the potential expansion of nuclear export inhibitors, specifically Exportin 1 (XPO1) inhibitors, from treating hematologic malignancies to solid tumors. Topics discussed include the challenges and successes of selinexor in clinical trials for solid tumors; the need for targeted patient populations in future trials; and the exploration of second-generation XPO1 inhibitors like eltanexor and felezonexor.

Best practice (BP) in cancer care consists of a multifaceted approach comprising individualized treatment plans, evidence-based medicine, the optimal use of supportive care and patient education. We investigated the impact of a BP program in patients with relapsed/refractory multiple myeloma (RRMM) receiving selinexor. Features of the BP program that were specific to selinexor were initiating selinexor at doses ≤80 mg once weekly and the upfront use of standardized antiemetics. Study endpoints included time to treatment failure (TTF), duration of therapy, dose limiting toxicities and overall survival. Comparative analysis on TTF and duration of therapy was conducted using a log-rank test and multivariate Cox proportional hazard regression. Over the ensuing 12-month post-BP period, 41 patients received selinexor-based therapy compared to 68 patients who received selinexor-based therapy pre-BP implementation. Patients treated in the post-BP period had reductions in TTF (hazard ratio [HR] = 0.50; 95% CI: 0.27 to 0.92). Patients in the pre-BP period were four times more likely to stop therapy than those in the post-period (odds ratio [OR] = 4.0, 95% CI: 1.75 to 9.3). The findings suggest a BP program tailored to selinexor could increase the time to treatment failure, increase treatment duration and lower the incidence of drug limiting toxicities.

Acute myeloid leukemia(AML) is a hematological malignancy characterized by clonal proliferation of bone marrow progenitor cells in bone marrow and blood. Although researchers have continuously proposed new treatment options, the overall prognosis of patients has not improved significantly. The nuclear export protein 1(XPO1) inhibitor plays an important role in cancer by inhibiting the key substances leading to tumorigenesis through the nuclear membrane of cancer cells. It can promote cell cycle arrest and apoptosis in AML cells, and has a wide range of anti-cancer effects and good safety in combination with other targeted drugs or chemotherapy regimens. This article mainly reviewed the research progress of XPO1 inhibitor selineror in the treatment of AML. [ABSTRACT FROM AUTHOR]

Selinexor (Seli) is a first-in-class, oral selective inhibitor of the nuclear export protein, exportin-1 (XPO1). Seli exhibits its antitumor effect through the blockage of XPO1, which increases nuclear retention of tumor suppressor proteins (TSPs), including p53, thereby limiting the translation of oncogenes, triggering cell cycle arrest and the death of malignant cells. Multiple Myeloma (MM) patients with del17p are deficient in TP53 and have a particularly poor prognosis. Given its unique mechanism of action, we investigated whether Seli has increased efficacy in RRMM patients with del17p compared to other high-risk cytogenetics (OHRC). This is an IRB-approved observational study of RRMM patients with high-risk cytogenetics (del17p, t (4;14), t (14;16) or gain 1q) or standard-risk cytogenetics treated at the Levine Cancer Institute (LCI) with a Seli-based regimen between January 2019 and December 2022. Time-to-event endpoints (PFS, OS) were evaluated using Kaplan–Meier (KM) methods. Log-rank tests compared time-to-event endpoints between cohorts [del17p vs. OHRC vs. standard risk]. We identified 40 RRMM patients with high-risk cytogenetics, including 16 patients with del17p and 24 patients with OHRC, as well as 20 with standard-risk cytogenetics. The median age was 62.5 vs. 69 vs. 65.5 years (del17p group vs. OHRC vs. standard risk). The median prior line of therapies was five (range: 3–16) with similar rates of prior autologous stem cell transplant in all arms (68.8% vs. 62.5% vs. 70.0%). The most frequently used regimens were Seli–Pomalidomide–dexamethasone(dex) or Seli–Carfilzomib–dex (Seli-Kd) in the del17p group and Seli-Kd in the OHRC and standard-risk groups. The median time to start the Seli-based regimen after initial MM diagnosis was 5.6 years for the del17p group, 4.1 years in OHRC, and 4.8 years in the standard-risk group. The median follow-up time after the start of the Seli-based regimen was 10.5 months (mos) in the del17p group, 8.4 mos in OHRC, and 10.3 mos in the standard-risk group. In the del17p group, 50% had an objective response, 41.7% in the OHRC, and 35% in the standard-risk group (p = 0.71). Depth of response was also similar across the arms (12.5% vs. 12.5% vs. 10.0% VGPR p = 0.99). The median OS was 10.9 mos in the del17p group, 10.3 mos in the OHRC, and 10.3 mos in the standard-risk group (p = 0.92). The median OS was 15.5 mos for patients who received Seli as a bridging therapy versus 9 mos for Seli use for other reasons rather than as a bridge. Overall, Seli-based regimens showed promising responses even in this heavily pretreated population. Our analysis suggests that Seli-based regimens lead to similar outcomes among RRMM patients with del17p, OHRC, and standard-risk cytogenetics. This contrasts with previously reported outcomes using combinations of novel therapies in this population, where the del17p patients often have a poorer prognosis. Interestingly, our data suggest that Seli is a particularly effective bridging modality for patients preparing for CAR-T cell therapies in our population. Further investigation into this population is warranted, including in earlier lines of therapy, in hopes of seeing a more durable response. [ABSTRACT FROM AUTHOR]

Background: The intricate relationship between Forkhead box O1 (FOXO1), a well-established tumor suppressor, and breast cancer (BC) remains partially elucidated. This study aims to investigate the mechanistic role of FOXO1 nuclear localization in the context of BC. Methods: In vitro experiments employed BC cell lines MCF-7 and MDA-MB-175 treated with LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling, and selinexor, an exportin 1 inhibitor. Nuclear accumulation of FOXO1, its interaction with β-catenin, and expressions of key proteins like V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), cyclin D1 and apoptosis markers were assessed. In vivo, the effects of LOM612 and selinexor were studied using MCF-7 cell-derived xenografts (CDX). Results: Treatment with LOM612 exhibited a significant enhancement in nuclear accumulation of FOXO1 within BC cells. This effect coincided with suppressed migratory behavior and heightened apoptosis susceptibility in these cells. Mechanistically, LOM612 orchestrated FOXO1 to compete with transcription factors (TCF) for binding to β-catenin in the nucleus, leading to reduced c-Myc and cyclin D1 expressions, along with elevated levels of apoptosis-related proteins. Similar trends were observed in CDX models, where LOM612 effectively suppressed tumor growth, increased FOXO1 nuclear localization, and downregulated c-Myc and cyclin D1 expressions. Importantly, selinexor synergistically reinforced the therapeutic effects of LOM612 both in vitro and in vivo. Conclusions: Collectively, this study underscores the potential of combining LOM612 and selinexor as an efficacious anti-BC strategy. The underlying mechanism involves FOXO1's nuclear translocation, which disrupts TCF-β-catenin interactions, thus indirectly inhibiting the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations. [ABSTRACT FROM AUTHOR]

Background: Atypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported. Case description: In this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML. Conclusion: Our case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT. [ABSTRACT FROM AUTHOR]

Best practice (BP) in cancer care consists of a multifaceted approach comprising individualized treatment plans, evidence-based medicine, the optimal use of supportive care and patient education. We investigated the impact of a BP program in patients with relapsed/refractory multiple myeloma (RRMM) receiving selinexor. Features of the BP program that were specific to selinexor were initiating selinexor at doses ≤80 mg once weekly and the upfront use of standardized antiemetics. Study endpoints included time to treatment failure (TTF), duration of therapy, dose limiting toxicities and overall survival. Comparative analysis on TTF and duration of therapy was conducted using a log-rank test and multivariate Cox proportional hazard regression. Over the ensuing 12-month post-BP period, 41 patients received selinexor-based therapy compared to 68 patients who received selinexor-based therapy pre-BP implementation. Patients treated in the post-BP period had reductions in TTF (hazard ratio [HR] = 0.50; 95% CI: 0.27 to 0.92). Patients in the pre-BP period were four times more likely to stop therapy than those in the post-period (odds ratio [OR] = 4.0, 95% CI: 1.75 to 9.3). The findings suggest a BP program tailored to selinexor could increase the time to treatment failure, increase treatment duration and lower the incidence of drug limiting toxicities. [ABSTRACT FROM AUTHOR]

Background Natural killer/T-cell lymphoma (NKTCL) is a rare and heterogeneous tumor type of non-Hodgkin's lymphoma (NHL) with a poor clinical outcome. There is no standardized salvage treatment failing l -asparaginase-based regimens. Here we report our retrospective results of the combined use of selinexor and PD-1 blockade (tislelizumab) in 5 patients with NKTCL who had exhausted almost all available treatments. Patients and methods A total of 5 patients with relapsed/refractory(R/R) NK/T-cell lymphomas failing prior l -asparaginase and anti-PD-1 antibody were retrospectively collected. They were treated with at least one cycle of XPO1 inhibitor plus the same anti-PD-1 antibody. Anti-PD-1 antibody (Tislelizumab) was administrated at 200 mg on day 1 every 3 weeks and selinexor doses and schedules ranged from 40 mg weekly for 2 weeks per 21-day cycle to 60 mg weekly per cycle. Results Five patients with relapsed NKTCL with extensive organ involvement including 4 central nervous system (CNS) infiltration patients were included. Four patients achieved objective responses including 3 complete responses (CR) and 1 partial response (PR). After a median follow-up time of 14.5 (range, 5-22) months, 1 patient was still in remission with CR, and the other 4 patients discontinued due to disease progression with a median progression-free survival (PFS) of 6 months and median overall survival (OS) of 12 months. Four patients with CNS involvement achieved a median OS of 8 months. Our data suggest that selinexor in combination with an anti-PD-1 antibody is a promising small molecule and immunotherapy combination regimen for patients with relapsed or refractory NKTCL. [ABSTRACT FROM AUTHOR]

ObjectiveTo identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd).MethodsAn analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials.ResultsTwenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%).ConclusionThe all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.

Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor’s dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug’s impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson’s Disease. The review emphasizes the criticality of managing Selinexor’s side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor’s long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders.

The outcome of AL amyloidosis remains poor, particularly in patients with advanced organ involvement which takes long time to recovery. We conducted an observational study of two patients with AL amyloidosis treated with SDd regimen. Both patients successfully achieved significant hematological and organ responses without severe adverse events, and the time to organ response was remarkably shorter than previously reported. Notably, an over 15% reduction in interventricular septal thickness (IVST) was observed in patient#2 within 6 months. Up to now, SDd therapy has not been previously reported in AL amyloidosis and may be a promising option for these patients.

Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B‐cell lymphoma (PMBL) and classical Hodgkin's lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1E571K. To understand the impact of mutation on protein function, we studied the response of PMBL and cHL cells to selinexor, a SINE, and ibrutinib, an inhibitor of Bruton tyrosine kinase. XPO1 mutation renders lymphoma cells more sensitive to selinexor due to a faster degradation of mutant XPO1 compared to the wild‐type. We further showed that a mistrafficking of p65 (RELA) and p52 (NFκB2) transcription factors between the nuclear and cytoplasmic compartments accounts for the response toward ibrutinib. XPO1 mutation may be envisaged as a biomarker of the response of PMBL and cHL cells and other B‐cell hemopathies to SINEs and drugs that target even indirectly the NFκB signaling pathway.

Jiqian Jiang,1 Yan Wang,1 Dan Liu,1 Xiaoyu Wang,1 Yingqiao Zhu,1 Juan Tong,1 Erling Chen,1 Lei Xue,1 Na Zhao,1 Tingting Liang,2 Changcheng Zheng1 1Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 2The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng Zheng, Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of China, Tel/Fax +86-551-62284476, Email zhengchch1123@ustc.edu.cnIntroduction: The BCL-2 inhibitor venetoclax has been widely used in the treatment of acute myeloid leukemia (AML); however, AML patients treated with venetoclax gradually develop resistance. The exportin-1 (XPO1) inhibitor selinexor can synergistically promote the antileukemia activity of venetoclax, but the mechanism remains unclear.Methods and Results: Annexin V/7-aminoactinomycin D assays were used to examine the effects of a combination of venetoclax and selinexor (VEN+SEL) on AML cell lines and primary AML cells. RNA sequencing and oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) determinations by a Seahorse XF analyzer were employed to investigate the molecular mechanism of the toxicity of the VEN+SEL combination to AML cells. The cytotoxicity of NK cell combined with VEN+SEL combination was assessed in vitro using flow cytometry. VEN+SEL enhanced the apoptosis of AML cells (KG-1A and THP-1) and primary AML samples in vitro. The ECAR and OCR results demonstrated that the VEN+SEL combination significantly inhibited glycolytic function. RNA sequencing of THP-1 cells demonstrated that DNA replication-related genes were downregulated after treatment with the VEN+SEL combination.Conclusion: This study indicated that selinexor can synergistically enhance the antileukemia activity of venetoclax in AML cells in vitro by inhibiting glycolytic function and downregulating DNA replication-related genes. Based on our experimental data, combining selinexor with venetoclax is an appropriate advanced treatment option for AML patients.Keywords: venetoclax, selinexor, acute myeloid leukemia, glycolytic function, DNA replication-related genes

Abstract Background Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report. Methods Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines. Results After infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro. Conclusions The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.

Purpose: Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma. Patients and methods: We conducted a phase 1b, dose-escalation, and expansion trial, which enrolled patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Patients received oral selinexor according to a 3 + 3 design in combination with rituximab and dexamethasone, high-dose cytarabine, oxaliplatine (DHAOX) or gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. Results: A total of 39 patients were enrolled, 27 during the escalation phase and 12 during the expansion phase. Most patients had diffuse large B-cell lymphoma (DLBCL; 77%). Group R-DHAOX was prematurely closed to inclusion due to a recommendation from the French drug agency, independent of this trial. A recommended phase 2 dose (RP2D) of selinexor in association with R-GPD was established at 40 mg on days 1, 8, and 15 of each 21-day cycle. In a population of 18 patients treated at this dose of selinexor, the most frequent grade 3–4 adverse events were hematological. With this regimen, seven obtained a complete metabolic response and five a partial response. The median PFS was 5.8 months. Conclusions: Among the patients with R/R B-cell lymphoma, selinexor at a weekly dose of 40 mg with R-GDP is feasible for outpatients, with a generally acceptable safety profile.

Background: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. Methods: Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. Results: Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. Conclusions: In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.

UNLABELLED: The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell cycle markers, KRAS and NF-kB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models. SIGNIFICANCE: In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m2), the maximum tolerated dose was 30 mg/m2. The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML. [ABSTRACT FROM AUTHOR]

Most tumor suppressor and growth-regulating proteins are transported via the plasmic nuclear transporter exportin 1 (XPO1). Many malignancies have excessive XPO1 expression, which is associated with disease progression and resistance to therapy. A novel class of anticancer medication called selective inhibitor of nuclear export (SINE) can down-regulate the levels of a number of antigenic proteins in the cytoplasm, activate tumor suppressor and other growth regulating proteins, and promote the nuclear retention and apoptosis of tumor cells. This article discusses the function of XPO1 in drug resistance and tumor development as well as the advancement of XPO1 inhibitor research for the treatment of hematological cancers. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) remains an incurable disease despite advances in treatment options. Recently, selinexor has shown promising efficacy for relapsed/refractory multiple myeloma (RRMM), whereas its optimal timing and drug combination remain unclear. In order to assess the various regimens that incorporate selinexor, a systematic review and meta-analysis was conducted. Clinical trials and real-world studies involving MM patients treated with selinexor were included. Pooled risk ratio (RR) was calculated to compare the rates, along with a 95% confidence interval (CI) and concurrent p-value assessment. A random-effects model was employed to provide a more conservative evaluation. A total of 16 studies enrolling 817 patients were reviewed. The usage of selinexor as the fifth-line or prior therapy achieved a higher objective response rate (ORR) (65.9% versus 23.4%, p < 0.01) and longer pooled progression-free survival (PFS) (median: 12.5 months versus 2.9 months, p < 0.01) than those after the fifth-line usage. In addition, early usage also resulted in a consistent trend of pooled overall survival (median: 22.7 months versus 8.9 months, p = 0.26), compared with post-fifth-line usage. Selinexor and dexamethasone (Xd) plus either protease inhibitors (PIs) or immunomodulatory drugs (IMiDs) achieved better ORRs than the Xd-only regimen for RRMM, with ORRs of 56.1%, 52.5% and 24.6%, respectively (p < 0.01). In conclusion, using selinexor as the fifth-line or prior therapy had a beneficial impact on RRMM. The regimen of Xd plus PIs or IMiDs was recommended. [ABSTRACT FROM AUTHOR]

Background: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods: Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results: Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls (p <.05). Immunohistochemical analysis of residual KPC tumours showed re‐organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase‐like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'‐kinase‐Akt (PI3K‐AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel‐GemPac‐treated mice tumours including the CD44+ stem cell population. Conclusion: Taken together, these results demonstrate that the Sel‐GemPac treatment caused broad perturbation of PDAC‐supporting signalling networks in the KPC mouse model. Highlights: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac).Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse derived cell line and enhanced the survival of mice.Digital spatial profiling shows that Sel‐GemPac causes broad perturbation of PDAC‐supporting signalling in the KPC model. [ABSTRACT FROM AUTHOR]

Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B‐cell lymphoma (PMBL) and classical Hodgkin's lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1E571K. To understand the impact of mutation on protein function, we studied the response of PMBL and cHL cells to selinexor, a SINE, and ibrutinib, an inhibitor of Bruton tyrosine kinase. XPO1 mutation renders lymphoma cells more sensitive to selinexor due to a faster degradation of mutant XPO1 compared to the wild‐type. We further showed that a mistrafficking of p65 (RELA) and p52 (NFκB2) transcription factors between the nuclear and cytoplasmic compartments accounts for the response toward ibrutinib. XPO1 mutation may be envisaged as a biomarker of the response of PMBL and cHL cells and other B‐cell hemopathies to SINEs and drugs that target even indirectly the NFκB signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report. Methods: Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines. Results: After infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro. Conclusions: The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma. [ABSTRACT FROM AUTHOR]

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impressive clinical responses and improve prognoses, MCL remains an incurable disease with frequent relapses. Additional therapeutic interventions are therefore unmet medical needs for the management of patients with MCL. Methods: Cell viability and apoptosis assays were employed to analyze the therapeutic interaction of venetoclax combined with selinexor in MCL cells. Western blot was used to investigate the potential mechanism of action for the synergy of venetoclax in combination with selinexor in MCL cells. Results: In this study, we revealed that both blastoid and classical MCL cells were vulnerable to the cytotoxic effects of selinexor, a well-established XPO1 inhibitor, manifested by loss of cell viability and induction of cell apoptosis. Moreover, our data indicated that the addition of venetoclax to selinexor showed synergistically decreased cell viabilities and increased cell deaths in blastoid and classical MCL cells compared to each single drug treatment. Either selinexor or venetoclax treatment alone decreased MCL1 expressions and increased BAX levels in MCL cells, and these effects were further enhanced by their combined regimen. Mechanistically, our findings demonstrated that induction of DNA damage and inactivation of DNA damage response were involved in the synergistic interaction of the drug combination regimen. Conclusion: Collectively, this study might provide a potential attractive therapy option for the treatment of MCL. However, the conclusion needs additional experimental validation in in vivo models and clinical evaluations are mandatory. [ABSTRACT FROM AUTHOR]

Abstract Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS (ULMS) is an aggressive tumor with poor prognosis and a high risk of recurrence and death, regardless of the stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that reversibly binds to exportin 1 (XPO1), thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. In this study, we evaluated the effects of selinexor in combination with doxorubicin and eribulin in the LMS tumor model in vitro and in vivo. Treatment of selinexor combined with eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 LMS-derived xenografts. Immunohistochemical assessment of the tumor tissues showed a significantly reduced expression of proliferation (Ki67) and XPO1 markers following combination therapy compared to the control group. Global transcriptome analyses on tumor tissue revealed that the combination therapy regulates genes from several key cancer-related pathways that are differentially expressed in ULMS tumors. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of selinexor and eribulin in vivo. Results from this study further warrant clinical testing a combination of chemotherapy agents with selinexor to reduce the morbidity and mortality from ULMS.

BackgroundExportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor).ResultsWe report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.

Triple negative breast cancer (TNBC) is a deadly disease with limited treatment options. Selinexor is a selective inhibitor of nuclear export that binds covalently to exportin 1 thereby reactivating tumor suppressor proteins and downregulating expression of oncogenes and DNA damage repair (DDR) proteins. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved for the treatment of patients with breast cancer harboring BRCA mutations. We examined the effects of co-treatment with selinexor and olaparib in TNBC cell lines. BRCA1 wildtype (BRCA1-wt) and BRCA1 mutant (BRCA1-mut) TNBC cell lines were treated with selinexor and/or olaparib and effects on cell viability and cell cycle were evaluated. The effects of treatment were also evaluated in mouse xenograft models generated with BRCA1-wt and BRCA1-mut TNBC cell lines. Treatment with selinexor inhibited cell proliferation and survival of all TNBC cell lines tested in vitro. This effect was enhanced following treatment of the cells with the combination of selinexor and olaparib, which showed synergistic effects on tumor growth inhibition in MDA-MB-468-derived (BRCA1-wt) and MDA-MB-436-derived (BRCA1-mut) xenografts. As co-treatment with selinexor and olaparib exhibits anti-tumor activity regardless of BRCA1 mutation status, the clinical implications of the combination warrant further investigation.

Exportin 1 (XPO1) is a crucial molecule of nucleocytoplasmic transport. Among others, it exports molecules important for oncogenesis from the nucleus to the cytoplasm. The expression of XPO1 is increased in numerous malignancies, which contributes to the abnormal localization of tumor suppressor proteins in the cytoplasm and subsequent cell cycle dysregulation. Selective inhibitors of nuclear export (SINEs) are novel anticancer agents that target XPO1, arrest tumor suppressor proteins in the nucleus, and induce apoptosis in cancer cells. Selinexor, a first-in-class SINE, has already been approved for the treatment of relapsed/refractory multiple myeloma and relapsed/refractory diffuse large B cell lymphoma not otherwise specified. It has also been proven effective in relapsed/refractory and previously untreated acute myeloid leukemia patients. In addition, numerous studies have yielded promising results in other malignancies of the hematopoietic system and solid tumors. However, future clinical use of selinexor and other SINEs may be hampered by their significant toxicity.

Abstract Background The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls (p

ABSTRACTObjectives Multiple myeloma (MM) remains an incurable disease despite advances in treatment options. Recently, selinexor has shown promising efficacy for relapsed/refractory multiple myeloma (RRMM), whereas its optimal timing and drug combination remain unclear. In order to assess the various regimens that incorporate selinexor, a systematic review and meta-analysis was conducted.Methods Clinical trials and real-world studies involving MM patients treated with selinexor were included. Pooled risk ratio (RR) was calculated to compare the rates, along with a 95% confidence interval (CI) and concurrent p-value assessment. A random-effects model was employed to provide a more conservative evaluation.Results A total of 16 studies enrolling 817 patients were reviewed. The usage of selinexor as the fifth-line or prior therapy achieved a higher objective response rate (ORR) (65.9% versus 23.4%, p

Simple Summary: Ovarian cancer is frequently discovered in the later stages. Current treatment for advanced disease ovarian cancer is inadequate and survival is poor. Our goal was to investigate how treatment with targeted therapy decitabine and/or selinexor could improve ovarian cancer in mice, when compared with experimental controls. Mice were administered ovarian cancer cells. About one week later, they were administered experimental treatment decitabine followed by selinexor. Disease outcome or improvement with single or combination treatment was studied by analyzing pathology changes in several organs to determine tumor spread and in biological experiments conducted on cells obtained from mice to investigate how treated mice developed anti-tumor immune responses to fight ovarian cancer. This study is of great significance as it may lead to new clinical trials with combination decitabine and selinexor and potentially to future therapies with these agents, which may prolong the life of women diagnosed with ovarian cancer. Background. High-grade serous ovarian cancer is a lethal gynecologic disease. Conventional therapies, such as platinum-based chemotherapy, are rendered inadequate for disease management as most advanced disease patients develop resistance to this therapy and soon relapse, leading to poor prognosis. Novel immunotherapy and targeted therapy are currently under investigation as treatment options for ovarian cancer, but so far with little success. Epigenetic changes, such as aberrant DNA methylation, have been reported in resistance to platinum-based therapy. Decitabine is a hypomethylating agent which is effective against platinum-resistant disease and also exhibits several anti-tumor immune functions. Selinexor is a selective inhibitor of nuclear protein export. It restored platinum sensitivity in patient-derived ovarian cancer cell lines and is currently in clinical trials for the treatment of platinum-resistant ovarian cancer. We hypothesized that these two agents used in combination could elicit more potent anti-tumor immune responses in vivo than either agent used alone. Methods. These studies were designed to investigate the efficacy of these two agents used in combination to treat ovarian cancer by assessing murine models for changes in disease pathology and in anti-tumor responses. Results. Decitabine priming followed by selinexor treatment significantly limited ascites formation and tumor size. This combination of agents also promoted T cell effector function as measured by granzyme B secretion. Treatment of mice with decitabine and selinexor led to the significant release of a broader range of macrophage and T cell cytokines and chemokines above control PBS and vehicle and above decitabine or selinexor treatment alone. Conclusions. These results reveal crucial information for the design of clinical trials which may advance therapy outcomes in ovarian cancer. [ABSTRACT FROM AUTHOR]

Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS (ULMS) is an aggressive tumor with poor prognosis and a high risk of recurrence and death, regardless of the stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that reversibly binds to exportin 1 (XPO1), thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. In this study, we evaluated the effects of selinexor in combination with doxorubicin and eribulin in the LMS tumor model in vitro and in vivo. Treatment of selinexor combined with eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 LMS-derived xenografts. Immunohistochemical assessment of the tumor tissues showed a significantly reduced expression of proliferation (Ki67) and XPO1 markers following combination therapy compared to the control group. Global transcriptome analyses on tumor tissue revealed that the combination therapy regulates genes from several key cancer-related pathways that are differentially expressed in ULMS tumors. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of selinexor and eribulin in vivo. Results from this study further warrant clinical testing a combination of chemotherapy agents with selinexor to reduce the morbidity and mortality from ULMS. [ABSTRACT FROM AUTHOR]

Background: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell‐cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non–small cell lung cancer (mNSCLC). Methods: The primary objective of this prospective investigator‐initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression‐free survival duration. Results: A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti–PD‐1/programmed death‐ligand 1 (PD‐L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti–PD‐1/PD‐L1 therapy and in patients with activating driver mutations. The median overall survival and progression‐free survival were 11.4 months (95% CI, 3.4–19.8 months) and 3.0 months (95% CI, 1.7–5.7 months), respectively. The overall response rate was 18% and the 6‐month disease control rate was 24%. Conclusions: Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti–PD‐1/PD‐L1 therapy. The therapy‐related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. Trial registration: ClinicalTrials.gov identifier: NCT02419495. Plain language summary: New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor‐suppressing pathways and induce potent immunomodulatory activities.This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non–small cell lung cancer. New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and the first‐in‐class oral selective nuclear export inhibitor selinexor in the treatment of metastatic non–small cell lung cancer. [ABSTRACT FROM AUTHOR]