Selective Inhibitor Of Nuclear Export Research Articles

Digital monitoring and assessments in patients with glioblastoma.

2045 Background: Glioblastoma (GBM) is an aggressive primary tumor with poor prognosis and survival. Patients (pts) experience debilitating symptoms that have a negative effect on quality of life (QoL). A multidisciplinary approach is necessary to facilitate the reduction of morbidity, preserve QoL, and maximize benefits of treatment. Selinexor (SEL) is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 approved for use in multiple myeloma and diffuse large B-cell lymphoma and has shown activity in GBM. Digital measurements in the KING study through wearable sensors and other devices capture actionable daily data at home for improved care, symptom management, and QoL, are reported here. Methods: XPORT-GBM-029 (NCT04421378) is an ongoing phase 1 dose finding study followed by an open-label randomized phase 2, 5-arm trial to evaluate SEL in combination with standard therapies for newly diagnosed and recurrent GBM (n = 350): radiation+SEL /radiation and temozolomide; radiation and temozolomide±SEL; lomustine±SEL; bevacizumab±SEL; tumor treating field±SEL. The study is conducted at 18 sites in the US and Canada. GBM progression is assessed by standard clinical and imaging as well as QoL measurements by novel digital tools. Four parameters to determine the impact on QoL (cognitive function, lateralization, fatigue, sleep) are measured remotely by smartwatch and smartphone to continuously measure activity and sleep, and to complete a cognitive battery at baseline and before each MRI. Results: To date, pts wearing the smartwatch had higher compliance during the day for activity and gait measures compared to night for sleep measures. Younger pts had better compliance. Over the course of SEL treatment, changes were observed in balance (characterized by double support % and walking asymmetry) and activity level (characterized by step count and walking distance). Of the pts who participated in the cognitive battery (CANTAB) tests, 2 pts had a minor change in cognition measures including psychomotor and processing speed, episodic and spatial working memory, and executive function after 2 SEL treatment cycles. Overall, the CANTAB measures are stable, which align with the mRANO (MRI) results. The correlation between the CANTAB cognition measures and MRI data will be evaluated once more clinical data become available. Ongoing analyses will apply machine learning and statistical tools to determine potential correlations between digital and clinical data, such as physical examinations, AEs, Karnofsky scores, mRANO, NANO, KPS, and PRO QoL questionnaires. Conclusions: This is the first demonstration of digital measurement feasibility in a longitudinal study of pts with GBM. Digital measurements for pts with GBM could provide information on the impact of SEL-based treatment and functional outcomes in clinical trials and increase communication between clinicians and pts, thereby improving QoL and care management. Clinical trial information: NCT04421378.

A Three-Gene Signature Predicts Response to Selinexor in Multiple Myeloma.

Selinexor is the first selective inhibitor of nuclear export to be approved for the treatment of relapsed or refractory multiple myeloma (MM). Currently, there are no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aimed to characterize the transcriptomic correlates of response to selinexor-based therapy. We performed RNA sequencing on CD138+ cells from the bone marrow of 100 patients with MM who participated in the BOSTON study, followed by differential gene expression and pathway analysis. Using the differentially expressed genes, we used cox proportional hazard models to identify a gene signature predictive of response to selinexor, followed by validation in external cohorts. The three-gene signature predicts response to selinexor-based therapy in patients with MM in the BOSTON cohort. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM and additionally in an external cohort of 35 patients treated in a real-world setting outside of clinical trials. We found that the signature tracks with both depth and duration of response, and it also validates in a different tumor type using a cohort of pretreatment tumors from patients with recurrent glioblastoma. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. In this study, we present a present a novel, three-gene expression signature that predicts selinexor response in MM. This signature has important clinical relevance as it could identify patients with cancer who are most likely to benefit from treatment with selinexor-based therapy.

Prognostic and therapeutic significance of XPO1 in T-cell lymphoma

T-cell lymphoma (TCL) is a highly heterogeneous group of invasive non-Hodgkin lymphoma with adverse prognosis and limited treatment options. The relationship between TCL and Exportin-1 (XPO1), a major nuclear export receptor, has not been established yet. We here investigated the prognostic role and therapeutic implication of XPO1 in TCL. We analyzed XPO1 expression in a cohort of 69 TCL tumors and found that XPO1 was over-expressed in 76.8% of TCL and correlated with decreased progression-free survival (PFS) and overall survival (OS). In vitro treatment of TCL cell lines with KPT-8602, the second-generation selective inhibitor of nuclear export (SINE), inhibited XPO1 expression and showed significant anti-proliferative, cell-cycle arrest and pro-apoptotic efficacy. In mechanism, KPT-8602 restored the localization of cytoplasmic FOXO3A, p27, p21, IκBα and PP2A into the nucleus, leading to AKT and NF-κB deactivation. Our data demonstrate for the first time that XPO1 could be an unfavorable prognostic factor for TCL, and provide a rationale for further investigation of the efficacy of KPT-8602 in TCL patients.

Selinexor and COVID-19: The Neglected Warden.

A novel severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) has been confirmed as the cause of the global pandemic coronavirus disease 2019 (COVID-19). Different repurposed drugs have been trialed and used in the management of COVID-19. One of these agents was the anti-cancer Selinexor (SXR). SXR is an anti-cancer drug that acts by inhibition of nuclear exportin-1 (XPO1), which inhibits transport of nuclear proteins from the nucleus to the cytoplasm, leading to the induction of cell-cycle arrest and apoptosis. XPO1 inhibitors had antiviral effects, mainly against respiratory syncytial virus (RSV) and influenza virus. SXR inhibits transport of SARS-CoV-2 nuclear proteins to the cytoplasm with further inhibition of SARS-CoV-2 proliferation. SXR has the ability to prevent the development of a cytokine storm in COVID-19 by inhibiting the release of pro-inflammatory cytokines with the augmentation release of anti-inflammatory cytokines. In conclusion, SARS-CoV-2 infection is linked with activation of XPO1, leading to the triggering of inflammatory reactions and oxidative stress. Inhibition of XPO1 by Selinexor (SXR), a selective inhibitor of nuclear export (SINE), can reduce the proliferation of SARS-CoV-2 and associated inflammatory disorders. Preclinical and clinical studies are warranted in this regard.

KPT330 improves Cas9 precision genome- and base-editing by selectively regulating mRNA nuclear export

CRISPR-based genome engineering tools are associated with off-target effects that constitutively active Cas9 protein may instigate. Previous studies have revealed the feasibility of modulating Cas9-based genome- and base-editing tools using protein or small-molecule CRISPR inhibitors. Here we screened a set of small molecule compounds with irreversible warhead, aiming to identifying small-molecule modulators of CRISPR-Cas9. It was found that selective inhibitors of nuclear export (SINEs) could efficiently inhibit the cellular activity of Cas9 in the form of genome-, base- and prime-editing tools. Interestingly, SINEs did not function as direct inhibitors to Cas9, but modulated Cas9 activities by interfering with the nuclear export process of Cas9 mRNA. Thus, to the best of our knowledge, SINEs represent the first reported indirect, irreversible inhibitors of CRISPR-Cas9. Most importantly, an FDA-approved anticancer drug KPT330, along with other examined SINEs, could improve the specificities of CRISPR-Cas9-based genome- and base editing tools in human cells. Our study expands the toolbox of CRISPR modulating elements and provides a feasible approach to improving the specificity of CRISPR-Cas9-based genome engineering tools.

Guidance for Use and dosing of Selinexor in Multiple Myeloma in 2021: Consensus From International Myeloma Foundation Expert Roundtable

Selinexor is a first in class selective inhibitor of nuclear export (SINE), blocks exportin 1 (XPO1), a protein transporter, that among other actions, shuttles cargo proteins such as tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and oncoprotein messenger RNAs (mRNAs) across the nuclear membrane to cytoplasm. By blocking XPO1, selinexor facilitates nuclear preservation and activation of TSPs, and prevents mRNA translation of the oncoproteins leading to induction of apoptosis. The therapeutic value of selinexor in combination with dexamethasone has been successfully demonstrated in treating relapsed and/or refractory myeloma (RRMM), leading to the Food and Drug Administration (FDA) approval of selinexor in combination with dexamethasone in 2019 for the treatment of adult patients with RRMM who received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (mAb) – a pentarefractory myeloma. More recently, selinexor in combination with bortezomib and dexamethasone was approved by the FDA in December 2020, based on the BOSTON study among RRMM patients who had received at least one prior line of therapy. With more available safety and efficacy data supporting the increased interval between dosing of selinexor (and lesser cumulative weekly dosing) and schedule, contrary to the originally approved dose of 160 mg per week, the supportive care guidelines needed to be revisited. The current manuscript summarizes the supportive care solutions with weekly dosing of selinexor and identifies the ideal potential patient for selinexor treatment.

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Simple SummaryDiffuse large B-cell lymphoma (DLBCL) is a complex disease. A combination of immunotherapy and chemotherapy is used to treat DLBCL at initial diagnosis. Additional treatments are available when DLBCL does not respond to initial treatment; however, for many patients, DLBCL will stop responding to treatment (relapse) or may not respond at all (refractory). Selinexor is a novel, oral medication that belongs to a class of drugs called selective inhibitors of nuclear export, and it works by killing cancer cells in patients with DLBCL that has relapsed after or is refractory to at least two treatments. When deciding on a course of treatment, it is useful for physicians to know which frequently described clinical characteristics of DLBCL affect the activity and tolerability of selinexor. We found that selinexor showed similar activity and tolerability across most of the frequently described clinical characteristics assessed.Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients < 65 vs. ≥ 65 years, and for those with lymphocyte counts ≥ 1000/µL vs. < 1000/µL or lactate dehydrogenase ≤ ULN vs. > ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL.

Open-label phase 1/2 study evaluating the tolerability and antitumor activity of selinexor and pembrolizumab in colorectal cancer.

110 Background: Single agent selinexor, an oral selective inhibitor of nuclear export (SINE), showed activity against heavily pretreated CRC with RAS mutations (mut) or wildtype (wt) in 2 clinical studies. In preclinical studies, selinexor showed superior potency in KRAS mut over wt with improved activity in combination with PD-1/PD-L1 blockade. A phase 1b study (NCT02419495) showed the safety and antitumor activity of combined selinexor and a PD-1/PD-L1 inhibitor. This phase 1/2 open-label study is evaluating selinexor with pembrolizumab in patients with microsatellite instability (MSI)-stable CRC. Methods: The study enrolled patients with advanced/metastatic CRC who progressed after prior chemotherapy (1-3 lines for RAS wt, 1-2 for RAS mut) and are ineligible for anti-PD-1/PD-L1 therapy. Patients received weekly oral selinexor 80 mg and pembrolizumab 200 mg IV every 3 weeks. Antitumor activity, safety and tolerability were assessed. Results: Thirty-four patients, median age 57.5 years, male 59%, RAS mut 53%, median prior lines 2, are enrolled. At data cutoff (1-SEP-21) median treatment duration was 57 days (range: 1-246) and 25 patients were evaluable for response. Best response was stable disease in 8/13 patients with RAS mut CRC (62%) and in 3/12 patients with RAS wt CRC (25%). Median overall survival (months) has not been reached for the overall population (95% CI: 6.3, NE), for RAS mut (95% CI: 7.6, NE), and for the RAS wt (95% CI: 6.1, NE). Median progression-free survival is 3.0 and 1.4 months for patients with CRC with RAS mut and wt, respectively (p=0.04; HR: 0.43 [959% CI: 0.18, 1.01]). Thirty patients (88%) discontinued therapy, mostly due to progressive disease (44%). The most common treatment-emergent adverse events (TEAEs) (total; Grade ≥3) were nausea (77%; 3%), vomiting (41%; 0%), fatigue (41%; 12%), decreased appetite (35%; 0%), diarrhea (32%; 0%). Nine patients (26%) had serious treatment-emergent adverse events. Conclusions: Combined selinexor with pembrolizumab demonstrated higher disease control rates and prolonged overall survival in patients with chemotherapy-refractory advanced/metastatic CRC with RAS mut vs RAS wt tumors. These patients would not have been eligible for anti-PD-1 mAb therapy because their tumors were not MSI-high, suggesting that the combination may be active in RAS mut CRC. Therapy was well tolerated with no unanticipated adverse events. Further investigation of this combined treatment is warranted, particularly in patients with CRC with RAS mut. Clinical trial information: NCT04256707.

A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies

Purpose:This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies.Experimental Design:A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m2.Results:In our Asian patient cohort, dosing at 40 mg/m2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin’s lymphoma and thymic carcinoma patient, respectively.Conclusion:Selinexor is tolerated by Asian patients at 40 mg/m2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia.

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.

Nuclear export proteins such as exportin-1 (XPO1) transport tumor-suppressor proteins and other growth-regulatory proteins from the nucleus to the cytoplasm. Overexpression of XPO1 has been observed in several cancers and correlates with shorter event-free and overall survival in multiple myeloma. Selinexor was developed as an oral first-in-class selective inhibitor of nuclear export (SINE) that inhibits XPO1. Preclinical studies in tumor cell lines and mouse models have demonstrated the efficacy of selinexor both as a single agent and in various combinations with known active antimyeloma agents. Results from the pivotal phase II STORM trial led to the US FDA approval of selinexor with dexamethasone in penta-refractory myeloma. Because of the feasibility of combining selinexor with other active antimyeloma agents, the multiarm STOMP trial was initiated and is ongoing, with impressive response rates reported in some of the combination arms thus far. The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. The toxicity profile of selinexor is wellestablished and predictable and may be significant unless managed aggressively and preemptively. The most common side effects are thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. Hyponatremia and cataracts seem to be class effects. Other SINE compounds are now being studied in efforts to discover agents that will potentially be better tolerated. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM.

Overview of systemic therapy options in liposarcoma, with a focus on the activity of selinexor, a selective inhibitor of nuclear export in dedifferentiated liposarcoma.

Liposarcoma (LPS) is a common soft tissue sarcoma that encompasses diverse subtypes of well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic LPS. There is heterogeneity among the various LPS types with regard to prognosis, molecular pathogenesis, and response to treatment. Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) are most common types, which share common genetic alteration of chromosome 12q13-15 amplification resulting in amplification of oncogenes, including MDM2 (Mouse double minute 2), CDK4 (cyclin-dependent kinase 4), and HMGA2 (High mobility group protein AT-hook 2). Despite sharing the same molecular alteration, DDLPS has a worse prognosis, with a higher recurrence rate and higher propensity for metastases compared to WDLPS. Here we provide an overview of the LPS treatment landscape focusing on recent developments in the treatment of DDLPS with a focus on selinexor. Selinexor, a selective inhibitor of XPO1, was recently evaluated in a phase 3 trial, the first prospective randomized trial in DDLPS, and we discuss its efficacy in context of other available agents for DDLPS.

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma.

The therapeutic options available for patients with multiple myeloma have greatly expanded over the past decade and incorporating these novel agents into routine clinical practice has significantly improved outcomes. The next generation of therapeutics is available for relapsed and refractory patients either as standard of care or in clinical trial, and these drugs represent a generational paradigm shift. Patients now have access to a multitude of novel immunotherapeutics, including monoclonal antibodies, an antibody–drug conjugate, chimeric antigen receptor T-cells (CAR-T), and bispecific T-cell redirecting antibodies, and novel oral therapies including selinexor (selective inhibitor of nuclear export) and venetoclax (bcl-2 inhibitor). While these drugs have the potential to be highly efficacious in certain subsets of patients when used as single agents or in combination regimens, they are each associated with unique toxicity profiles. It is imperative to understand these potential adverse events to ensure patient safety. Appropriate supportive care management is paramount to maximize drug exposure and therapeutic efficacy. The following review focuses its discussion on drugs and combination regimens that are currently FDA-approved and those that continue to be investigated in clinical trials, highlights the clinically relevant toxicity profiles for each of the different agents, and provides practical considerations for the treatment team.

Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients

BackgroundProteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM).MethodsThe safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib.ResultsThirty-two patients, median prior therapies 4 (range, 1–8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months.ConclusionsWeekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

CTNI-17. A PHASE 1 WITH DOSE EXPANSION/PHASE 2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D &amp; E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.

Comparison of Salvage Autologous Hematopoietic Cell Transplantation with Outcomes Following Selinexor Combinations Among Double/Triple Refractory Myeloma Patients

Introduction: A vast majority of multiple myeloma (MM) patients requires subsequent lines of therapy following relapses. The choice of regimen following relapse is influenced by response, tolerance to prior therapies, as well as by disease and patient features. Treatment options are limited for those who develop triple-class refractory disease. In this setting, the role of a salvage autologous stem cell transplantation (sAHCT) is controversial. This unmet need has driven the development of new therapies with novel mechanisms of action. Selinexor, an oral selective inhibitor of nuclear export (SINE) compound, was recently approved by the FDA and EMA for use in heavily pretreated relapse refractory (RRMM) patients, including triple-class refractory RRMM and FDA has also approved the agent in patients with first relapse. In the absence of head-to-head studies, comparison of treatment options among triple-class treated patients is based on real world experience. Here we performed a retrospective comparison between outcomes following sAHCT versus Selinexor combinations administered among RRMMs.Patients & Methods: Between January 2015 and April 2021, 22 patients at our center underwent sAHCT for treatment of refractory relapse. A transplant was defined as salvage if the patient had already received one prior AHCT and underwent a further AHCT after evidence of disease progression not responding to second generation proteasome inhibitors (PI), İmmunomodulating agents (IMID) or antiCD38 monoclonal antibody. We compared the outcomes of these patients with 10 RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive Selinexor, dexamethasone in combination with either bortezomib (n=7) (XVd) or carfilzomib (n=3) (XCd) as a part of a Karyopharm Expanded Access Program (KEAP). Selinexor was administered 80-100 mg po weekly in combination. Response and disease progression were assessed according to the IMWG criteria.Results: Patients' characteristics and the outcome of treatments are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 6 prior lines of therapy (4-9) and 2 out of 10 carried high-risk cytogenetics in SVd group. Seven (31.8%) patients with high-risk cytogenetics underwent sAHCT. All patients were treated with or refractory to immunomodulators and proteasome inhibitors. Five patients responded to DCEP bridging therapy prior to sAHCT. Five patients received Selinexor after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In sAHCT group, 68.2% of patients relapsed within a median of 6.3 months (Figure-1). Figure-2 shows the impact of the prior lines of therapy and selinoxor on PFS.Adverse events on selinexor regimens included fatigue, nausea, thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. Two patients eventually transitioned to new therapies, while 4 still remain on SVd due to continued response.Conclusion: Our results based on a small number of patients, compared with outcomes post sAHCT reflects comparable duration of response and disease control rates with Selinexor-PI regimens among selected patients. Hospitalization and prolonged infusions are not required with the selinexor regimens, and prolonged treatment is possible with advance in lines of therapy duration of response lessens with any treatment modality. Despite of a DCEP bridging therapy prior to sAHCT, Selinexor combos have achieved similar PFS even among triple class refractory MM patients. For countries where CAR-T therapies are not accessible, sAHCT and Selinexor combinations may be considered as a valid clinical option after failing CD38 monoclonal antibodies, PI and IMIDs. These data support the use of selinexor-based regimens in the treatment of relapsed MM, and given the potency of the combinations, in earlier lines of therapy including in patients who have received anti-CD38 mAbs. [Display omitted] DisclosuresKashyap: Karyopharm: Current Employment. Niblock: Karyopharm: Current Employment. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. OffLabel Disclosure:Selinexor has not been approved for myeloma patients in Turkey. It could be used as a part of Karyopharm Expanded Access program (KEAP).

A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor in Patients with Myelofibrosis Refractory or Intolerant to JAK Inhibitors

▪Background:Selinexor is an oral, small molecule, selective inhibitor of nuclear export (SINE) compound that specifically blocks the karyopherin protein exportin 1 (XPO1, CRM1). In an shRNA library screen, we discovered that the survival of JAK2V167F mutant HEL cells is dependent on XPO1-mediated nuclear-cytoplasmic transport. Selinexor selectively suppressed primary myelofibrosis (MF) cells as compared with normal progenitor cells and induced hematologic responses in an MPN mouse model.Methods:An open label, prospective, investigator-initiated single center study is ongoing in adults with primary or secondary MF with resistance or intolerance to JAK inhibitor (JAKi) therapy with platelets > 30 K/μL and neutrophils > 500/μL. Selinexor was given orally once a week. Spleen volume was assessed by MRI at week 12 and week 24. The study was amended to include additional MRIs every 12 weeks in the year 1 and 24 weeks in the year 2. Primary end point is spleen response, defined as ≥ 35% spleen volume reduction (SVR) by MRI or CT, where applicable) at week 24. Bone marrow was evaluated at baseline and at week 24. The projected sample size of 24 will provide 83% power to reject a response rate of 15% and allow for up to a 25% dropout rate. We provide an interim report after completing 50% enrollment.Results:Between May 2019 and February 2021, 12 patients (pts) were enrolled. JAK2, CALR and MPL mutations were present in 7 (58.3%), 4 (33.3%) and 1 (8.3%) pts respectively. Eight pts (66.6%) had at least one high molecular risk mutation at baseline (Table 1). Median duration of prior JAKi therapy was 22 months (0.5 to 96 months) and 11 out of 12 were refractory to ruxolitinib at study enrollment. Median baseline spleen volume was 1454 cm 3(range 835 to 5792). Selinexor starting dose was 80 mg weekly in the first 6 pts and 60 mg for subsequent pts. At data cutoff, median duration of selinexor therapy was 36 weeks (range 11-114 weeks). One pt was not response evaluable and died due to liver abscess at week 12 (unrelated). One pt discontinued selinexor at week 18 due to grade 3 fatigue and was not evaluable for the primary end point. Of the 11 pts who had week 12 MRI or CT, 6 showed ≥ 10% SVR, 3 showed ≥ 25% SVR and 1 pt had early progression (Figure 1). At week 24, 5/9 (56%) pts had ≥ 25% SVR and 2/9 (22%) had ≥ 35% SVR (Figure 1). In 9 pts who had ≥24 weeks of selinexor, SVR ≥ 25% and ≥ 35% occurred at any point during study treatment in 4 (44%) and 3 (33%) pts, respectively. Two pts were red cell transfusion dependent at baseline; 1 became transfusion independent after 36 weeks of treatment, has not required transfusion for 49 weeks and remains on study treatment to date (114 weeks). Six pts (50%) discontinued selinexor. Reasons for treatment discontinuation are death in 1 pt, progressive disease in 1 pt, alternative treatment in 2 pts, and toxicity in 2 pts. Ten pts required dose reduction due to fatigue (1pt), anemia (1 pt), thrombocytopenia (2 pts), abdominal pain (1pt) and weight loss (5 pts). The most common treatment related adverse event was weight loss (grade 2 in 4 pts and grade 3 in 1 pt). This was manageable with treatment interruption and dose reduction, except in one pt who discontinued selinexor. As yet no changes in reticulin fibrosis MF grade were observed among 9 patients who received at least 24 weeks of treatment.Conclusions:Once weekly, oral selinexor showed single agent activity with sustained spleen responses in pts with JAKi refractory MF. Long-term administration of selinexor was well tolerated over time in MF pts. Correlatives studies including circulating inflammatory cytokine levels and mutant allele burden, as well as clonality studies by X-chromosome inactivation studies in woman, are underway and will be presented. [Display omitted] DisclosuresTantravahi: BMS: Research Funding; Novartis: Research Funding; CTI BioPharma: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Patel: Stemline: Research Funding; Genentech: Research Funding; Roche: Research Funding. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. George: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding.

Once Weekly Oral Selinexor, Pomalidomide, and Dexamethasone in Relapsed Refractory Multiple Myeloma

Once Weekly Oral Selinexor, Pomalidomide, and Dexamethasone in Relapsed Refractory Multiple Myeloma

Efficacy and Safety of Selinexor-Containing Regimens in Patients with Multiple Myeloma Previously Treated with Anti-CD38 Monoclonal Antibodies (αCD38 mAb)

Efficacy and Safety of Selinexor-Containing Regimens in Patients with Multiple Myeloma Previously Treated with Anti-CD38 Monoclonal Antibodies (αCD38 mAb)

Selinexor-Based Regimens in Patients with Multiple Myeloma after Prior Anti-B-Cell Maturation Antigen Treatment

Selinexor-Based Regimens in Patients with Multiple Myeloma after Prior Anti-B-Cell Maturation Antigen Treatment

Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents

Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents