Karyopharm Therapeutics Inc Research Articles

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma

Introduction - Elevated expression of XPO1 (Exportin 1) increases the nuclear export / inactivation of tumor suppressor proteins (e.g. p53, IkB, p21, FOXO) and promotes the export / translation of eIF4E-bound oncoprotein mRNAs (e.g. c-MYC, BCL-2, Cyclin D). Selinexor, the first oral Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 and has shown promising anti-cancer activity across hematological and solid tumors in Phase 1 and 2 clinical trials, including in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Considering the breadth of knowledge on selinexor ± dexamethasone (dex) in RRMM, eltanexor (KPT-8602), a second-generation oral SINE compound, was evaluated for safety and tolerability in this pt population. The primary objectives were to determine the safety, preliminary anti-MM activity, and the recommended Phase 2 dose (RP2D) of eltanexor ± dex.Methods - In this Phase 1/2 study, using a 3+3 dose escalation design, eltanexor is dosed orally (QDx5 or QoDx3 weekly) for a 28-day cycle with a starting dose of 5 mg. Pts with less than a minor response (MR) after 1 cycle or partial response (PR) after 2 cycles were permitted to add low dose dex. In some pts, dex was added from day 1. The pharmacokinetic (PK) and pharmacodynamic (XPO1 mRNA) profiles of eltanexor were evaluated.Results - As of 31-July-2017, 36 pts (23 M/13 F; median prior therapies: 7; median age: 66) with RRMM were enrolled; most with quad- or penta-refractory MM. Median duration of treatment is 76 days (range: 10 - 441). Most common drug related adverse events (AEs; >30%, any grade) are thrombocytopenia, nausea, neutropenia, anemia, leukopenia, fatigue, diarrhea, and dysgeusia. Grade ≥3 related AEs include thrombocytopenia (43%), neutropenia (26%), leukopenia (14%), and anemia (11%). Although 2 dose limiting toxicities (DLTs; >4 missed doses and Grade 4 thrombocytopenia) were observed in different cohorts, the protocol-defined maximum tolerated dose (MTD) was not reached. Further evaluation of 20 or 30 mg eltanexor QDx5 + dex is ongoing in expansion cohorts. The preliminary efficacy of eltanexor (Table 1) shows that eltanexor ± dex can induce responses and disease stabilization. A dose proportional PK profile without accumulation has been observed. Mean Cmax and AUC0-inf values for eltanexor doses of 5 - 60 mg ranged from 36.6 - 284 ng/mL and 164 - 2,581 ng*h/mL, respectively. Tmax and t½ ranged from 0.5 - 8.0 h and 4.0 - 7.1 h, respectively. For all cohorts evaluated, the fold-change maximum (Fmax) of XPO1 mRNA expression was achieved 4 - 8 h post-dose (tmax). The Fmax for XPO1 mRNA was roughly dose proportional to the Cmax of eltanexor. As expected, based on observations with other SINE compounds, the plateau for Fmax of XPO1 mRNA in treated pts was ~6 - 10-fold change and was achievable at 40 - 60 mg of eltanexor.Conclusions - Based on preliminary data, eltanexor is well tolerated and demonstrates promising activity in this heavily pre-treated RRMM population. The gastrointestinal and constitutional toxicities observed with <40 mg eltanexor QDx5 are low grade, transient, and do not limit dosing. Thrombocytopenia (with minimal clinical impact) was the most common hematologic toxicity and was expected in this population. As with selinexor, addition of low-dose dex (20 mg) twice weekly (BIW) to the eltanexor treatment regimen appeared to improve efficacy while maintaining tolerability. Of the 31 evaluable pts, 25 received dex with their eltanexor regimen. Therefore, both 20 and 30 mg eltanexor QDx5 + 20 mg dex BIW are being evaluated to clearly define the RP2D. Based on these results and anti-tumor activity previously observed with selinexor, pts with advanced colorectal cancer, castration resistant prostate cancer, and myelodysplastic syndrome are being enrolled. [Display omitted] DisclosuresRossi:Thrassos: Consultancy; Celgene: Consultancy. Baz:Sanofi: Research Funding; BMS: Research Funding; merck: Research Funding; takeda: Research Funding; celgene: Honoraria, Research Funding; karyopharm: Research Funding. Hofmeister:Roche: Research Funding; Celgene: Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding. Shustik:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Richter:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Vogl:Teva: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; GSK: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Calithera: Research Funding. Baloglu:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Phase Ib/II Trial of Selinexor Combined with Lenalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; IkB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. The combination of lenalidomide/dexamethasone (Rd) is an approved regimen in relapsed/refractory multiple myeloma (RRMM) with an overall response rate (ORR) of 70-76% and a low complete response rate. In combination with selinexor, the anticipated overlapping toxicities are fatigue, thrombocytopenia and neutropenia. We hypothesized that selinexor could be safely combined with Rd and improve efficacy.Methods - The objective of this phase 1b/2 dose escalation study (NCT02343042) was to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) of the combination of selinexor, lenalidomide (len) and dexamethasone (SRd) in RRMM. Patients (pts) with RRMM who received ≥ 1 prior therapy were enrolled. Selinexor was dosed escalated in two regimens once-weekly (QW) or twice weekly (BIW) with both dosing cohorts starting at 60 mg, len 25 mg PO daily and dexamethasone (dex) 20 mg BIW or 40 mg QW.Results - As of 15-Jul-2017, 18 pts (13 male / 5 female) were enrolled. The median age was 68 years and pts received a median of 1 (range, 1 - 7) prior treatment regimen. Thrombocytopenia was the most common side effect with 4 associated DLTs (2 pts each in the 60 mg BIW and 80 QW cohorts). One additional DLT of grade 3 anorexia was observed in the 60 mg BIW cohort. Common treatment-related grade 1/2 adverse events (AEs) included: nausea (67%), anorexia (44%), fatigue (28%), vomiting (28%), and constipation (28%). Grade 3/4 AEs include: thrombocytopenia (56%), neutropenia (39%), fatigue (11%) and anemia (6%). No DLTs were observed with selinexor 60 mg QW and long-term tolerability was observed. Fifteen pts were evaluable for response, of which 11 pts responded for an ORR of 73%. Among the len naïve pts (n=11), an ORR of 91% was seen, including 3 very good partial responses (VGPR), 7 partial responses (PR, 2 unconfirmed) and 1 unconfirmed minor response (MR). Of the len refractory/relapsed pts (n=4), there was 1 unconfirmed PR, 1 MR, and 2 stable disease (SD). Median PFS was 6.6 months with a median follow up of 4 months. Based on tolerability and anti-MM activity the RP2D of SRd is selinexor 60 mg QW, len 25 mg qd and dex 40 mg QW.Conclusions - The all oral combination of SRd has significant clinical activity in pts with MM. Importantly, in len naïve pts, the ORR was 91%. No new or unexpected toxicities were observed. The combination has no thrombotic, cardiac, pulmonary, liver or renal toxicity. The main DLT was thrombocytopenia. This phase 1 trial demonstrated that selinexor be can safely combined with Rd in RRMM with high ORR in len naïve pts. These results support the further studies in both newly diagnosed MM as well as in RRMM. DisclosuresBahlis:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Janssen, BMS, Celgene: Consultancy; Celgene: Research Funding. Sebag:Celgene, Janssen: Consultancy. Lentzsch:BMS: Consultancy; Amgen: Consultancy; Caelum Biosciences: Other: leadership position and stock. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Bayer: Research Funding. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment.

Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability. We present the results of a phase I dose escalation study of selinexor in combination with pom and dex (SPd) in RRMM.Methods - The primary objective of this phase 1b/2 study (NCT02343042) is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of SPd. Patients (pts) with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW.Results - As of 15-Jul-2017, 29 pts (14 male / 15 female) have been enrolled. The median age is 61 years, with a median of 4 (range, 2 - 9) prior treatment regimens. Twenty-five patients were IMiD refractory (15 len, 2 pom, 8 pom/len). Three dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (60 mg BIW, pom 3 mg) and 4 missed doses in Cycle 1 (100 mg QW, pom 4 mg). Common treatment related Grade 1/2 adverse events (AEs) include: nausea (55%), fatigue (48%), anorexia (48%) and diarrhea (24%). Grade 3/4 AEs include: neutropenia (48%), thrombocytopenia (31%), and anemia (28%). Doses of 60 mg QW and 80 mg QW are being evaluted to determine RP2D. Twenty-four pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. Eight pts are still on study, (range 1 - 16+ months).Conclusions - Once weekly selinexor can be safely combined with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 54% in pts with heavily pretreated MM compared to previously published data of 30% ORR. No additional toxicities over monotherapy with selinexor or the Pd combination were observed. The novel all oral combination of SPd is a well-tolerated regimen and supports further clinical development in RRMM. [Display omitted] DisclosuresChen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sebag:Celgene, Janssen: Consultancy. Bensinger:Bayer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding. Gasparetto:Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy; Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed. Lentzsch:Caelum Biosciences: Other: leadership position and stock; Amgen: Consultancy; BMS: Consultancy. Schiller:Celator/Jazz: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment. Bahlis:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Selinexor in Combination with Weekly Low Dose Bortezomib and Dexamethasone (SVd) Induces a High Response Rate with Durable Responses in Patients with Refractory Multiple Myeloma (MM)

Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Twice weekly (BIW) bortezomib in combination with dexamethasone (Vd) is an established therapy in relapsed and refractory multiple myeloma (RRMM). While the activity of bortezomib (bort) BIW in combination with other agents is efficacious, prolonged use is limited due to peripheral neuropathy (50-60%) as well as acquired resistance to bort. Strategies to identify new dosing regimes with high response rates, improved tolerability and the ability to overcome resistance are needed. Preclinical studies have shown that selinexor, when combined with bort, can restore sensitivity of bort-resistant MM, inhibiting tumor growth and increasing survival in murine MM xenografts. In this clinical trial (NCT02343042), we investigated the safety, tolerability and efficacy of the combination of selinexor, bortezomib and low dose dexamethasone (SVd) in patients (pts) with RRMM.Methods - This phase 1b/2 dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for SVd. The study enrolled pts with RRMM after ≥ 1 prior therapy. Pts with prior exposure or refractoriness to proteasome inhibitors (PI) were included, provided they were not refractory to bort as a last therapy. Selinexor was independently dosed escalated in once-weekly (QW, 80; 100 mg) or twice-weekly (BIW, 60; 80 mg) regimens. Bort (1.3 mg/m2 sc) was administered QW or BIW. Dexamethasone (dex) was given orally 40 mg QW or 20 mg BIW.Results - As of July 15th, 2017, 42 pts were enrolled; 22 pts in the dose escalation and 20 pts in the expansion (RP2D) cohort. Median age was 64 years; 55% male, median of 3 (range, 1 - 11) prior lines of therapy. The MTD was not reached. Three pts in the BIW bort cohort were dose reduced to QW bort after Cycle 1. Common treatment related grade 1/2 adverse events (AEs) included: anorexia (57%), nausea (55%), fatigue (48%), and vomiting (26%). Grade 3/4 AEs included: thrombocytopenia (40%), neutropenia (19%) and anemia (12%). Importantly, peripheral neuropathy (PN) across all pts was limited to 6 patients (14%) (G1 4pts, G2 2 pts) of which 5 had prior bort exposure. Based on tolerability and efficacy, the RP2D of SVd is selinexor 100 mg, bort 1.3 mg/m2 and dex 40 mg, all QW (40% less bort and 25% less dex compared to the standard, approved BIW schedule of Vd). Among the 18 pts with non-PI refractory MM and ≤ 3 lines of prior therapy, the ORR was 83% and CBR 89%; the median follow up was 10 months and PFS was not reached. Ten of these pts remain on study. Among the 19 pts with PI (bort, ixazomib or carfilzomib) refractory MM, the ORR was 42% and CBR 68%. The median follow up was 9.2 months and the median PFS was 9 months. Six of these pts remain on study.Conclusions - Selinexor in combination with weekly bort and dex is well tolerated and highly active in RRMM. The ORR of 83% and PN rate of 13% in PI non-refractory MM with 1-3 lines of prior therapy compares favorably to the previously reported ORR of 63% and >40% PN for Vd demonstrated in previous phase III trials. The high ORR with SVd is achieved with 40% less bort and 25% less dex and no overt major organ toxicities. Furthermore, in pts with PI refractory MM, the ORR of 42% and CBR of 68% support preclinical findings that selinexor re-sensitizes and overcomes resistance to PIs. SVd has shown durable responses regardless of prior PI sensitivity status and has an improved side effect profile. This data supports the ongoing phase 3 BOSTON study examining SVd vs Vd. [Display omitted] DisclosuresBahlis:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sutherland:Janssen: Honoraria. Sebag:Celgene, Janssen: Consultancy. Lentzsch:Amgen: Consultancy; Caelum Biosciences: Other: leadership position and stock; BMS: Consultancy. Gasparetto:Janssen, BMS, Celgene, Takeda: Honoraria; Celgene: Research Funding; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Janssen, BMS, Celgene: Consultancy. Bensinger:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Sanofi: Consultancy, Research Funding; Acetylon: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Abbvie: Honoraria.

Selective Inhibition of Nucleocytoplasmic Transport Overcomes Ruxolitinib Resistance in Myelofibrosis

Myelofibrosis (MF) is a stem cell-derived hematopoietic malignancy characterized by constitutive activation of JAK/STAT signaling through mutations in JAK2, calreticulin or MPL. MF patients have reduced life expectancy due to cytopenias, progression to acute myeloid leukemia and thromboembolic events. JAK kinase inhibitors such as ruxolitinib reduce constitutive symptoms but are not curative, with persistence of malignant cells. Allogeneic stem cell transplant remains the only curative therapy for MF, but is associated with considerable morbidity and mortality, defining an urgent need for new therapies that induce more profound and durable responses.We used a barcoded lentiviral shRNA library to identify survival-critical genes for MF in HEL cells (homozygous for JAK2V617F), established from a patient with erythroleukemia. shRNAs targeting RAN and binding protein (RANBP) were significantly depleted, implicating nucleocytoplasmic transport (NCT) as one of the top survival-critical pathways. RAN is a small GTPase, whose cycling between GTP- and GDP-bound forms provides the engine for NCT. We previously presented results showing that shRNA-mediated knockdown of RAN, significantly reduced proliferation and induced apoptosis in HEL and SET-2 cells (harboring heterozygous JAK2V617F). Additionally, KPT-330 (selinexor, Karyopharm Therapeutics), an inhibitor of CRM1, the core component of NCT, also inhibited proliferation of HEL and SET-2 cells and colony formation by primary MF CD34+ cells, but not cord blood (CB). Importantly, inhibition of NCT was effective at reducing colony formation in samples from ruxolitinib-refractory MF patients, regardless of mutation status. A clinical trial to evaluate KPT-330 in ruxolitinib-refractory MF is in preparation.KPT-8602 is a second-generation inhibitor of CRM-1. Unlike KPT-330, KPT-8602 does not cross the brain-blood barrier, resulting in minimal anorexia, malaise, and weight loss [Etchin et al., Leukemia, 2017 Jan;31(1):143-150]. To determine the efficacy of KPT-8602 in MF, we tested KPT-8602 in cell lines, patient samples, and a mouse model of MF, along with ruxolitinib as comparison.In cell proliferation assays, KPT-8602 was five-fold more potent than ruxolitinib against HEL cells (IC50: 83 nM vs. 437 nM) and as potent as ruxolitinib in SET-2 cells (IC50: 95 nM vs. 85 nM). In clonogenic assays, KPT-8602 showed selectivity toward primary MF vs. CB CD34+ cells (IC50: 25 nM for MF vs. 258 nM for CB) and, in combination with ruxolitinib, resulted in a 95% reduction in colony formation. KPT-8602 inhibited colony formation by CD34+ cells from all MF patients tested, including ruxolitinib-refractory cases, irrespective of mutation status (including triple negative).To evaluate the possible use of KPT-8602 in vivo, we used a mouse transduction/transplantation model of JAK2V617F - positive myeloproliferative neoplasm (MPN). In this model, mice develop MPN resembling polycythemia vera that progresses to MF [Bumm et al., Cancer Res., 2006, 1;66(23):11156-65]. MPN was evident based on elevated blood counts and blood GFP+ cells (representing JAK2V617F allelic burden). MPN mice were randomized into four groups: vehicles, KPT-8602 (initial dose 15 mg/kg daily, orally), ruxolitinib (initial dose 50 mg/kg twice daily, orally) or combined ruxolitinib with KPT-8602 at these same concentrations, and treated for 28 days. KPT-8602 as a single agent reduced red blood cells (RBC), white blood cells (WBC), BM GFP+ cells, peripheral blood (PB) GFP+ cells and spleen size to the same extent as ruxolitinib, and the combination was no more effective than either single agent (Table 1). Spleen cytoarchitecture was fully restored by KPT-8602, but bone marrow fibrosis was not rectified in any treatment group. Mice in all groups, including the combined vehicle controls, still experienced weight loss and lethality, suggesting that toxicity may be due to vehicles, and that optimization of drug formulations and dosing is warranted.Overall, these results indicate that NCT is critical for MF survival, and that NCT inhibition may provide therapeutic benefit for MF patients. KPT-8602 is being tested in a clinical trial (NCT02649790) for refractory multiple myeloma. The results of our study provide strong rationale for a clinical trial in patients with refractory MF. [Display omitted] DisclosuresBaloglu:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Deininger:Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Celgene: Research Funding; ARIAD: Consultancy; Gilead: Research Funding; BMS: Consultancy, Research Funding.

A Phase 1b Study to Assess the Combination of Selinexor and Daratumumab in Patients with Relapsed / Refractory Multiple Myeloma Previously Exposed to Proteasome Inhibitors (PI) and Immunomodulatory Drugs (IMiDs)

Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor, as a single agent, or in combination with PIs or IMiDs, has shown anti-MM activity in patients (pts) with relapsed or refractory multiple myeloma (RRMM). Daratumumab, an anti-CD38 monoclonal antibody, is approved for the treatment of RRMM. In this study, we aim to explore the safety and efficacy of selinexor in combination with daratumumab and low dose dexamethasone (SDd) in pts with RRMM.\\Methods - This is a phase 1b/2 dose escalation study using a standard 3+3 design. The primary endpoint is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) for SDd. Pts were eligible if they had RRMM and had received ≥ 3 prior therapies, including a PI and IMiD. Selinexor was independently dosed escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg) regimens. Daratumumab (16 mg/kg IV) was administered QW and dexamethasone (dex) was given orally 40 mg QW or 20 mg BIW.Results - As of 15-Jul-2017, 6 pts (4 males / 2 females) have been enrolled. Three pts each have been enrolled into the 100 mg QW and 60 mg BIW cohorts. Pts have a median age of 66 years and a median of 3 (range, 3 - 7) prior treatment regimens. Adverse events include: nausea, thrombocytopenia, and anemia. Three pts in the 100 mg QW cohort tolerated the regimen well with no DLT. The 3 pts in the 60 mg BIW cohort have not yet completed DLT evaluation. Based on preliminary tolerability and efficacy, an additional 3 pts will be enrolled in the 100 mg QW cohort to establish the RP2D dose. All 3 pts from the 100 mg QW cohort had a partial response (2 unconfirmed) after C1 and remain on study.Conclusions - Selinexor 100 mg QW, can be combined safely with daratumumab and dex. The activity observed in the first 3 pts is promising with all 3 pts responding to therapy. Enrollment is ongoing and updated data from 100 mg QW cohort, 100 mg QW expansion, and full phase 1 will be updated and presented. DisclosuresGasparetto:Celgene: Research Funding; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Consultancy. Lentzsch:Amgen: Consultancy; BMS: Consultancy; Caelum Biosciences: Other: leadership position and stock. Bensinger:Bayer: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; BMS: Consultancy, Research Funding. Bahlis:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sebag:Celgene, Janssen: Consultancy. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Abbvie: Honoraria. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment.

XPO1 Inhibitor Selinexor Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma Via Nuclear Retention of IκB

Background: B-cell receptor signaling (BCR) plays a central role in mantle cell lymphoma (MCL) and inhibition of BCR signaling through the BTK inhibitor, ibrutinib, has generated remarkable responses in patients. However, approximately one-third of the patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. Selinexor is a first-in-class selective inhibitor of nuclear export. It binds and inhibits exportin XPO-1, which mediates the nuclear export of proteins and mRNAs. Inactivation of XPO-1 increases the retention of tumor suppressors in the nuclei to enhance suppression of tumor cell growth. Inactivation of exportin also decreases the the expression of oncogenes of which translation is eIF4E-dependent. Since many of the oncogenes and tumor suppressor genes in MCL also shuttle between nuclei and cytoplasm, we speculate that selinexor would be active in MCL. As selinexor acts on a cellular process rather than a particular molecular target, we thus postulate selinexor may have the potential to act broadly in both ibrutinib-sensitive and -resistant mantle lymphoma cells. In this study, we compared and contrasted the intrinsic cellular response of MCL cells to ibrutinib versus selinexor. We aim to identify molecular mechanisms underlying differential cellular response to these two drugs in order to obtain a deeper understanding of what underlies tumor cells' susceptibility to drug intervention.Methods: We first determined the sensitivity of six MCL cell lines to both ibrutinib and selinexor in a cell-based MTT assay, which measures cellular metabolic activity, and then tested the effects of the drugs on cell growth. Next, we examined the effects of both inhibitors on apoptosis and proliferation to further delineate the differential sensitivity of MCL cells to ibrutinib and selinexor. We performed RNA-seq analyses to identify signaling pathways that underlie differential cellular response to these two drugs. Lastly, we validated the major findings in both cell lines and primary MCL tumors using a variety of assays including Flowsight analysis.Results: We found that selinexor had a broader anti-tumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib were sensitive to selinexor. We showed that selinexor induced apoptosis in addition to causing cell cycle arrest. Further, inhibition of NF-kB gene expression signature, as opposed to BCR signature, was a common feature that underlies the response of MCL cell lines to both selinexor and ibrutinib while unchanged NF-kB signature was associated exclusively with ibrutinib resistance. Using Flowsight, we showed that selinexor increased nuclear retention of IκB that was accompanied by the reduction of NF-kB DNA binding activity. In primary MCL tumor cells, we further demonstrated that the number of cells with IκB nuclear retention was linearly correlated with the degree of cellular apoptosis.Conclusions: Together, our results show that inhibition of NF-κB transcription via IκB nuclear retention is an important action of selinexor in MCL tumor cells. Selinexor is effective MCL cells with intrinsic resistance to ibrutinib and has the potential to prevent and overcome ibrutinib resistance. Our study warrants further clinical investigation of this compound in MCL. DisclosuresKadri:Portola Pharmacueticals, Inc.: Research Funding. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Landesman:Karyopharm Therapeutics: Employment. Lu:Portola Pharmacueticals, Inc.: Research Funding.

Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High-Risk Cytogenetic Risk Planned Subgroup Analyses from the Phase 3 Boston Study

Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High-Risk Cytogenetic Risk Planned Subgroup Analyses from the Phase 3 Boston Study

Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 Boston Study

Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 Boston Study

Selinexor in Combination with Pomalidomide and Dexamethasone (SPd) for Treatment of Patients with Relapsed Refractory Multiple Myeloma (RRMM)

Selinexor in Combination with Pomalidomide and Dexamethasone (SPd) for Treatment of Patients with Relapsed Refractory Multiple Myeloma (RRMM)

Selinexor, Lenalidomide and Dexamethasone (SRd) for Patients with Relapsed/Refractory and Newly Diagnosed Multiple Myeloma

Selinexor, Lenalidomide and Dexamethasone (SRd) for Patients with Relapsed/Refractory and Newly Diagnosed Multiple Myeloma

A Six-Protein Activity Signature Defines Favorable Response to Selinexor Treatment for Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: Selinexor is an oral selective inhibitor of XPO1 that was recently approved by the US FDA for treatment of adult patients with relapsed or refractory DLBCL, after at least two lines of systemic therapy. Approval was based on results of the Phase 2b SADAL study, which had an overall response rate of 29% in the primary analysis population (clinicaltrials.gov: NCT02227251). We herein investigated molecular markers of response to selinexor from patients treated on the SADAL study. Methods: Exome sequencing was performed on pre-selinexor treatment biopsies from 55 patients and used to compare mutation frequencies between 21 responder patients (best overall response of complete response [CR], 6; and partial response [PR], 15) and 34 non-responder patients (stable disease [SD], 8; and progressive disease [PD], 26). Additionally, RNA sequencing was performed on a subset of 33 patients and gene expressions were used to infer activities of regulatory proteins with the VIPER algorithm. Differences in inferred protein activities between responder and non-responder patients were assessed using four machine learning algorithms: linear regression (LR), linear discriminant analysis (LDA), ridge regression (RR) and random forest (RF). Model performance was estimated using leave-one-out cross-validation (LOOCV). A separate comparison was performed in the subset of 12 patients with germinal B-cell like (GCB) DLBCL. Results: Our analysis of genes commonly mutated in DLBCL revealed that non-responder patients more frequently harbored mutations in KMT2D (35% non-responders, 14% responders). Examination of the specific types of KMT2D mutations showed that the vast majority were loss-of-function frameshift or nonsense mutations (13 of 15 mutations), indicating they could have functional relevance to disease biology. The activities of 5,742 regulatory proteins were successful inferred from RNA sequencing performed on 33 patients. Unsupervised clustering identified two outlier samples that were removed from further analysis. The remaining 31 patients consisted of 16 responders (CR, 5; and PR, 11) that were compared to 15 non-responders (PD, 15). Dimension reduction of the 5,742 protein activities (filtering proteins with low variation, poor VIPER imputation, and strong linkage) resulted in 680 independent informative regulatory protein activities used for predicting selinexor response. Different numbers of regulatory proteins were iteratively input into the machine learning models to compare responders and non-responders. The best performance model was achieved using only six proteins (ASH1L, ZNF471, RRN3, CD248, ZNF750, INHBA) (Figure 1A), and had an area under the receiver operating characteristic curve (AUC) of 0.917, 0.925, 0.883, and 0.875, for the LDA, LR, RF and RR, models, respectively (p &amp;lt; 0.05, permutation test) (Figure 1B). A final integrated model combining the four methods achieved an AUC = 0.929 (p &amp;lt; 0.05, permutation test, AUC 95% CI: [0.831-1] DeLong non-parametric method) (Figure 1C). Similar results were obtained using 5-fold cross validation with the six-protein activity signature (integrated model AUC = 0.858, AUC 95% CI: [0.72-0.997]). Finally, we focused separately on 12 patients with germinal B-cell like (GCB) DLBCL, (6 responder patients, and 6 non-responder patients). Using LOOCV with the top three protein activities associated with selinexor response in GCB-DLBCL (COL1A1, INHBA, and CNOT2) resulted in remarkably high accuracy, with an integrated model AUC = .972 (p &amp;lt; 0.05, permutation test, AUC 95% CI: [0.895-1]). Discussion and Conclusions: The six proteins used for defining the DLBCL selinexor response signature are not typically associated with a role in DLBCL but have been implicated in cancer biology in other contexts. Notably, INHBA was found as predictor of response in the full set and also the GCB subtype patients, suggesting that activin/inhibin signaling could be important for response to selinexor in patients with DLBCL, especially the GCB subtype. Our results produced a protein activity signature that could be useful for identifying patients with DLBCL likely to respond well to selinexor treatment, which will be validated in a larger independent sample set. Figure 1 Disclosures Walker: Vigeo Therapeutics: Consultancy; Karyopharm: Current Employment, Current equity holder in publicly-traded company. Alvarez:DarwinHealth, Inc: Current Employment, Current equity holder in private company. Chang:Karyopharm Therapeutics Inc: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents &amp; Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Califano:DarwinHealth, Inc: Consultancy, Current Employment, Current equity holder in private company, Other: Founder. Landesman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company.

Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study

Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study

Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study

Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study

Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone

Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone

Selinexor in Combination with Carfilzomib and Dexamethasone, All Once Weekly (SKd), for Patients with Relapsed/Refractory Multiple Myeloma

Selinexor in Combination with Carfilzomib and Dexamethasone, All Once Weekly (SKd), for Patients with Relapsed/Refractory Multiple Myeloma

Effect of Age on the Efficacy and Safety of Single Agent Oral Selinexor in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Pivotal Study

Effect of Age on the Efficacy and Safety of Single Agent Oral Selinexor in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Pivotal Study

Selinexor Efficacy and Safety Are Independent of Renal Function in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis from the Pivotal Phase 2b Sadal Study

Selinexor Efficacy and Safety Are Independent of Renal Function in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis from the Pivotal Phase 2b Sadal Study

CRISPR/Cas9 Chemogenetic Profiling Identifies Candidate Biomarker Genes That Modulate Sensitivity to Selinexor

Introduction Selinexor (KPT-330) is a first-in-class selective inhibitor of XPO1-mediated nuclear export that has recently been approved by the US FDA for the treatment of relapsed/refractory multiple myeloma and relapsed diffuse large B-cell lymphoma. Additionally, the drug is being evaluated in ongoing clinical trials (phase I to III) on late-stage haematological and solid tumours. To improve outcomes and personalize therapeutics, specific biomarkers and underlying mechanisms of response to treatment need to be uncovered. Material and method We performed genome-wide CRISPR/Cas9-mediated loss-of-function genetic screening in two multiple myeloma (KMS-28-BM and SK-MM-1) and one chronic myeloid leukemia (HAP1) cell lines. After transduction with a knockout library, cells were divided and subsequently cultured into three parallel groups (control, IC20 and IC50) for at least 20 cell doublings. This setup allows monitoring of subtle relative changes between groups. After DNA extraction, sequencing of guide RNAs and statistical analysis, we identified genes that upon disruption confer either increased susceptibility or resistance to selinexor. Results and discussion For the multiple myeloma cell lines, the TGF-β/SMAD4 signalling pathway stood out as an important mediator of resistance to selinexor. Besides SMAD4 as a major hit in both cell lines, we identified five other genes from this pathway leading to resistance in KMS-28-BM cells, suggesting that downregulation of this pathway is a potential biomarker of response to SINE treatment in multiple myeloma. In addition, screens revealed significant variability across cell lines with hit genes involved in mRNA processing, proteasomal degradation and cell cycle regulation. Interestingly, we could simultaneously uncover resistance and sensitivity genes involved in the same pathway, suggesting that these have antagonistic effects. Notably, we identified knockout of the poorly characterized gene ASB8 as a strong, common sensitizer between the three cell lines. Conclusion Until now, most chemogenetic CRISPR/Cas9 knockout screens have focused on determining resistance genes, and few have employed the technique to screen for genes that enhance cell kill. We performed such screens with selinexor and found a number of general and cell type-specific hits. Genes identified to confer increased resistance are candidate biomarkers while genes inducing increased susceptibility represent new targets for drug combination therapies. Disclosures Kwanten: Karyopharm Therapeutics Inc.: Patents &amp; Royalties: employees of KULeuven. KULeuven has a license agreement (royalties) with Karyopharm Therapeutics on XPO1 inhibitors (selinexor). Landesman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Daelemans:Karyopharm Therapeutics Inc.: Patents &amp; Royalties: employees of KULeuven. KULeuven has a license agreement (royalties) with Karyopharm Therapeutics on XPO1 inhibitors (selinexor).

Characterization of Synergistic Selinexor Combinations of Dexamethasone, Pomalidomide, Elotuzumab and Daratumumab in Primary MM Samples Ex Vivo

Introduction. Multiple myeloma (MM) is an incurable plasma cell malignancy with a growing list of anti-MM therapeutics. However, the development of predictive biomarkers has yet to be achieved for nearly all MM therapeutics. Selinexor (SELI), a nuclear export inhibitor targeting exportin 1 (XPO1), has been approved with dexamethasone (DEX) in penta-refractory MM. Clinical studies investigating promising SELI- 3 drug combinations are ongoing. Here, we have investigated potential synergistic combinations of SELI and anti-MM agents in terms of ex vivo sensitivity, as well as paired RNAseq and WES to identify companion biomarkers. Methods. MM cells isolated from fresh bone marrow aspirates were tested for drug sensitivity in an organotypic ex vivo drug sensitivity assay, consisting of co-culture with stroma, collagen matrix and patient-derived serum. Single agents were tested at 5 concentrations, while two-drug combinations were tested at fixed ratio of concentrations. LD50 and area under the curve (AUC) were assessed during 96h-exposure as metrics for drug resistance. Drug synergy was calculated as a modified BLISS model. Matching aliquots of MM cells had RNAseq and WES performed through ORIEN/AVATAR project. Geneset enrichment analysis (GSEA) was conducted using both AUC and LD50 as phenotypes for single agents and combinations. Both curated pathways (KEGG and cancer hallmarks) and unsupervised gene clustering were used as genesets. Student t-tests with multiple test correction were used to identify non-synonymous mutations in protein coding genes associated with single agent or combination AUC. Results. For this analysis, a cohort of specimens from 103 patients (48% female, 4% Hispanic, 11% African American) was tested with SELI and/or DEX. with a median of 2 lines of therapy (0-12). A smaller cohort of 37 have been examined with SELI, pomalidomide (POM), elotuzumab (ELO) and daratumumab (DARA). Within this cohort we observed synergy between SELI and DEX, POM and ELO as shown in Figure 1. The volcano plot illustrates the number of samples, maximum drug concentration, as well as magnitude (x- axis) and significance (y- axis) of synergy. Although the SELI-DARA combination trended toward synergy, statistical significance was not achieved. To identify molecular mechanisms and biomarkers associated with sensitivity to SELI and SELI- combinations, we investigated paired RNAseq and WES with ex vivo sensitivity. Initially, we conducted GSEA on two cohorts of primary MM samples tested with SELI alone at 5µM (n=53) and 10µM (n=50). Cell adhesion (KEGG CAMS), inflammatory cytokines (KEGG ASTHMA), and epithelial mesenchymal transition (HALLMARK EMT) were associated with resistance in both cohorts, while the HALLMARK MYC TARGETS was associated with sensitivity (FWER p&amp;lt;0.05). Mutational analysis identified 46 gene mutations associated with SELI resistance and 100 associated with sensitivity at 5µM, and 87 and 27 mutations associated with SELI resistance and sensitivity, respectively, at 10µM. Two gene mutations were identified in both cohorts: BCL7A, involved in chromatin remodeling, was associated with sensitivity and CEP290, a microtubule binding protein, associated with resistance (p&amp;lt;0.05). Analysis of both gene sequences (NetNES 1.1) identified nuclear export signal (NES) residues suggesting these may be XPO1 cargo. Additionally, translocation t(11;14) was associated with SELI resistance in the 5µM cohort (p=0.037). The completed set of 50 specimens ex vivo, RNAseq and WES analysis will be mature and updated for the potential presentation at ASH. Conclusions. We observed ex vivo synergy between SELI and DEX, POM and ELO. Molecular analysis of matched ex vivo drug sensitivity, transcriptome and mutational profile identified environment-mediated drug resistance pathways positively correlated with SELI single agent resistance, as well as MYC regulated genes associated with ex vivo sensitivity. We also identified a list of mutations associated with SELI drug resistance and sensitivity, with special emphasis on two novel NES-containing genes, CEP290 and BCL7A. The next step of this project is to analyze transcriptional and mutational patterns associated with ex vivo synergy in the combinations here described, as putative biomarkers for future clinical investigation. Disclosures Shain: Amgen: Speakers Bureau; Adaptive: Consultancy, Honoraria; Karyopharm: Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; AbbVie: Research Funding. Kulkarni:M2GEN: Current Employment. Zhang:M2GEN: Current Employment. Hampton:M2GEN: Current Employment. Argueta:Karyopharm: Current Employment. Landesman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Siqueira Silva:AbbVie: Research Funding; NIH/NCI: Research Funding; Karyopharm: Research Funding.