Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1-mediated nuclear export.

Chromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin-1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose-limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein-labeled HIV-1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1-mediated export, can be followed by co-culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110α, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110α partially relies on CRM1-dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1-independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor.

Selinexor With Anti-PD-1 Antibody as a Potentially Effective Regimen for Patients With Natural Killer/T-Cell Lymphoma Failing Prior L-Asparaginase and PD-1 Blockade.

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.

Real-world outcome of patients with extensively pretreated multiple myeloma who were treated with selinexor and dexamethasone: a Korean multicenter retrospective analysis.

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.

Impact of prior treatment on selinexor, bortezomib, dexamethasone outcomes in patients with relapsed/refractory multiple myeloma: Extended follow-up subgroup analysis of the BOSTON trial.

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.

Selinexor for the treatment of patients with relapsed or refractory multiple myeloma.

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.

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non-small cell lung cancer.

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.

Phase 1b study of combined selinexor and eribulin for the treatment of advanced solid tumors and triple-negative breast cancer.

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination. METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort. RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m2 eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose-escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose-expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing). CONCLUSIONS: Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients. PLAIN LANGUAGE SUMMARY: Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.

Synthetic lethal targeting of TET2-mutant haematopoietic stem and progenitor cells by XPO1 inhibitors.

TET2 inactivating mutations serve as initiating genetic lesions in the transformation of haematopoietic stem and progenitor cells (HSPCs). In this study, we analysed known drugs in zebrafish embryos for their ability to selectively kill tet2-mutant HSPCs in vivo. We found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively kill tet2-mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murine Tet2-deficient Lineage-, Sca1+, Kit+ (LSK) cells, and also TET2-inactivated human acute myeloid leukaemia (AML) cells. Selective killing of TET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased γH2AX expression. The finding that TET2 loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of the selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment of TET2-mutant haematopoietic malignancies, and to suppress clonal expansion in age-related TET2-mutant clonal haematopoiesis.

A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma.

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.

Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy.

Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.

Selinexor in combination with weekly paclitaxel in patients with metastatic solid tumors: Results of an open label, single-center, multi-arm phase 1b study with expansion phase in ovarian cancer.

OBJECTIVE: Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound which blocks Exportin-1 (XPO1). Our objective was to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. METHODS: This was an open label, single-center, multi-arm phase 1b study utilizing a "3 + 3" design and a "basket-type" expansion in recurrent solid tumors. Selinexor (60 mg or 80 mg twice weekly orally) and weekly paclitaxel (80 mg IV 2 week on, 1 week off) were one of 13 parallel arms. Efficacy was evaluated using RECIST version 1.1. RESULTS: All 35 patients treated were evaluable for toxicity and 31 (88%) were evaluable for response. Patient diagnoses included platinum-resistant/refractory ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Patients had a median of four prior therapies (range 1-10), and 47% had a prior taxane in the recurrent setting. There were no DLTs and 60 mg was chosen as the RP2D due to long-term tolerability. Ninety-seven percent of patients had at least one treatment-emergent adverse event (TEAE), and the most common grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), and nausea (21%). Among 24 evaluable patients with ovarian cancer, response rate was 17%, CBR was 58%, and median PFS was 6.8 months (95% CI 3.7, not reached (NR)). CONCLUSIONS: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies.

Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.

Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease's five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common. This review focuses on the current pipeline, along with the contemporary roles and future prospects for small molecules in MM therapy. While small molecules offer prospective benefits in terms of oral bioavailability, cellular penetration, simplicity of preparation, and improved cost-benefit considerations, they also pose problems of toxicity due to off-target effects. Highlighted in the discussion are recent developments in the applications of alkylating agents, immunomodulators, proteasome inhibitors, apoptosis inducers, kinesin spindle protein inhibitors, blockers of nuclear transport, and drugs that affect various kinases involved in intracellular signaling pathways. Molecular and cellular targets are described for each class of agents in relation to their roles as drivers of MM.

Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor (MARCH): a phase II, single-arm study.

BACKGROUND: Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM. METHODS: The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses. RESULTS: A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients. CONCLUSIONS: With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019).

Selinexor synergizes with azacitidine to eliminate myelodysplastic syndrome cells through p53 nuclear accumulation.

Myelodysplastic syndromes (MDS) are clonal malignancies of multipotent hematopoietic stem cells, characterized by ineffective hematopoiesis leading to cytopenia. Hypomethylating agents, including azacitidine, have been used for treating MDS with some success; however, the overall survival rate remains poor and, therefore, finding new therapies is necessary. Selinexor, which exerts anticancer effects against some hematologic tumors, is a nuclear export protein inhibitor that blocks cell proliferation and induces apoptosis in various cancer cell lines. We investigated the effects of combined selinexor and azacitidine administration on two MDS cell lines, namely SKM-1 and MUTZ-1. Cells were subjected to a proliferation assay, and the effects of each drug alone, and in combination, were compared. Changes in apoptosis and the cell cycle between groups were also analyzed. Western blotting was conducted to identify the underlying mechanism of action of combined selinexor and azacitidine therapy. The results revealed that the combination of selinexor and azacitidine synergistically inhibited MDS cell proliferation and arrested the cell cycle at the G2/M phase. This combination also promoted MDS cell apoptosis and enhanced p53 accumulation in the nucleus, thereby allowing p53 to be activated and to function as a tumor suppressor. Overall, our results indicate that the combination of selinexor and azacitidine may be a promising approach for treating MDS.

Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study.

BACKGROUND: Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies. METHODS: This was a single-center, multi-arm phase Ib study utilizing a "basket type" expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible. RESULTS: Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks. CONCLUSION: The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. CLINICALTRIALS: gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ).

Efficacy and safety of selinexor-based regimens for relapsed/refractory multiple myeloma: a systematic review of literature.

With the incorporation of novel agents in earlier lines of therapy, an increasing number of multiple myeloma patients are refractory to traditional classes of drugs. Selinexor in combination with dexamethasone has emerged as a viable option for heavily pretreated triple-class relapsed and refractory multiple myeloma (RRMM). In this systematic review, we analyzed available literature on the role of selinexor in RRMM. The Boston trial demonstrated that selinexor when combined with dexamethasone and bortezomib is associated with a better depth and duration of response without excessive toxicity, compared with bortezomib and dexamethasone alone. Similarly, selinexor in combination with carfilzomib and dexamethasone was found to have a durable response and tolerable safety profile in both carfilzomib-naive and carfilzomib refractory RRMM patients. Selinexor in combination with IMiDs (lenalidomide and pomalidomide) as well as CD38 monoclonal antibodies (daratumumab) also have promising results. Selinexor combination therapy is both safe and effective for patients with pretreated RRMM.

Treatment horizon in multiple myeloma.

OBJECTIVES: This paper reviews current and emerging therapies for multiple myeloma (MM). METHODS: Narrative review. RESULTS: MM is a complex, heterogenous condition, and in recent years there has been an expansion in the number and range of treatments. Several new treatment approaches, including enhanced monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen-T-cell therapy are under development. CONCLUSIONS: The emergence of new treatments that aim to tackle MM-associated immune dysfunction has led to improvements in overall survival.

Targeting XPO1-Dependent Nuclear Export in Cancer.

Nucleocytoplasmic transport of macromolecules is tightly regulated in eukaryotic cells. XPO1 is a transport factor responsible for the nuclear export of several hundred protein and RNA substrates. Elevated levels of XPO1 and recurrent mutations have been reported in multiple cancers and linked to advanced disease stage and poor survival. In recent years, several novel small-molecule inhibitors of XPO1 were developed and extensively tested in preclinical cancer models and eventually in clinical trials. In this brief review, we summarize the functions of XPO1, its role in cancer, and the latest results of clinical trials of XPO1 inhibitors.

Overview of Ocular Side Effects of Selinexor.

BACKGROUND: The aim of this review is to elucidate the type and frequency of ocular adverse events associated with selinexor with a goal to quantify the occurrence of these events in our investigator-initiated trial. METHODS: We retrospectively reviewed medical records of 174 patients treated with at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents between July 2015 and July 2020 at a comprehensive cancer center in the U.S. All reported ocular adverse events were assessed. RESULTS: A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents in our cohort of patients with advanced malignancies. A total of 34 (19.54%) patients experienced 37 ocular adverse events. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.64%) patients. The most frequently reported treatment-related adverse event was dry eye syndrome reported in 21 (12.1%) patients, and 19 (10.9%) of them were diagnosed with mild dry eye. The second most common treatment-related adverse event was the progression of age-related nuclear sclerosis (cataract) reported in 7 (4.0%) patients. None of the ocular adverse events required therapy discontinuation. CONCLUSION: Our findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation. IMPLICATIONS FOR PRACTICE: Patients receiving selinexor in combination with multiple standard chemotherapy or immunotherapy agents were reviewed, with a total of 34 patients experiencing 37 ocular adverse events. Findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.

FDA Approval Summary: Selinexor for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee-assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22-38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL. IMPLICATIONS FOR PRACTICE: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, in the third-line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.