Abstract: Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter’s transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.

Abstract: Background: The nuclear export protein XPO1 is overexpressed in all types of hematological malignancies. The SINE selinexor (KPT-330) is a novel, first-in-class, slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over tumor suppressor proteins (TSPs) such as p53, IkB, FOXO and p21. Forced nuclear retention of TSPs leads to their reactivation, which can counteract a multitude of oncogenic pathways that perpetuate the neoplastic phenotype. In addition, XPO1 inhibition prevents the eIF4e-mediated export of messenger mRNA for a variety of oncoproteins (FLT3, c-KIT, cyclin D1, c-MYC, Bcl2), leading to decreased expressed to further provide anti-cancer activity. An ongoing Phase 1 (NCT01607892) open label, dose escalation, multi-center study in hematological malignancies was designed to evaluate the safety and tolerability of selinexor as well as response rate as the secondary objective. A maximum tolerated dose (MTD) was not identified yet in this study, but based on the ongoing Phase1 study of selinexor in pts with solid tumors, a MTD of 65 mg/m2 twice weekly was determined. The goal of the analyses reported here was to identify the recommended Phase 2 dose (RP2D) based on both tolerability and efficacy in patients with heavily pretreated hematological malignancies. Methods: A subset (N=157) of the Phase 1 patient population received oral selinexor twice weekly (8 doses/28-d cycle). General clinical observations suggested that doses of selinexor 〉 35 mg/m2 ( 〉 ~60 mg flat dose) are associated with suboptimal tolerability. Therefore, based on the actual dose administered, patients were divided into groups receiving 45-65 mg (median 60 mg; N=59) and 〉 65 mg (70-160 mg; median 90 mg, N=98) for comparison of safety and efficacy endpoints. The majority of the patients have heavily pretreated myeloma, NHL, and AML. Results: 157 pts received 45-160 mg selinexor twice weekly (89 M/68 F, median age 66 yr; median 4 prior regimens). The most common adverse events (AEs) were fatigue (66%), nausea (64%), anorexia (55%), vomiting (38%), which were mostly gr 1/2, and thrombocytopenia (44%), which was mostly grade 3/4. Incidence of certain selinexor-related high grade (3/4) adverse events was greater in pts receiving 〉 65 mg selinexor vs those receiving 45-65 mg (Table 1). Grade 3 nausea (4%), anorexia (3%), vomiting (3%) and hypokalemia (3%) were observed in the 〉 65 mg group but were not seen in the 45-65 mg group. Grade 3 and 4 anemia were 19% vs 14% and 4% vs 2% for the 〉 65 mg vs 45-65 mg groups, respectively. Grade 3 and 4 thrombocytopenia was similar in both groups, but slightly higher in the 〉 65 mg group, with 8% and 24 % in the 45-65 mg group vs 12% and 27% in the 〉 65 mg group. Neutropenia was also very similar in Grade 3 and 4 toxicity for both groups with 10% and 12% in the 45-65 mg group vs 11% and 10% in the 〉 65 mg group. In contrast, high grade cataract was only seen in the 45-65 mg group (8%; 3 gr 3, 1 gr 4). Selinexor-induced weight loss, as compared to baseline, was maximal by the end of cycle 2 in both dose groups, without further loss through at least cycle 4, but the 〉 65 mg group lost on average 〉 5-fold more weight (average of 3.8 ± 1.1 kg vs 0.7 ± 0.1 kg in the 65 mg group from 56 d- 126 d; p 〈 0.001). Also, pts in the 45-65 mg group remained on study longer (average of 101 d vs 69 d in the 〉 65 mg group; p=0. 05). In contrast, overall efficacy in the two dose groups was comparable, with 5 complete responses (CRs, 10%) and an overall response rate (ORR) of 23% in the 45-65 mg group and 4 CRs (5%) and ORR of 24% in the 〉 65 mg group. A listing of all responses for both groups can be seen in Table 2. Conclusions: While efficacy is comparable, doses of selinexor from 45-65 mg (median 60 mg) are better tolerated than doses 〉 65 mg, based upon decreased weight loss, incidence of high grade AEs, and greater numbers of days on study. Based on this superior risk-benefit, a flat dose of 60 mg selinexor, twice weekly, is the RP2D for patients with hematological cancers. Similar results have been observed for solid tumors. Disclosures Chen: Celgene: Consultancy, Honoraria, Research Funding. Jacoby:Novo Nordisk: Consultancy; Sunesis: Research Funding. Stone:AROG: Consultancy; Celator: Consultancy; Novartis: Research Funding; Pfizer: Consultancy; Juno: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Agios: Consultancy; Roche/Genetech: Consultancy; Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Merck: Consultancy. Baz:Sanofi: Research Funding; Celgene Corporation: Research Funding; Karyopharm: Research Funding; Millennium: Research Funding. Gabrail:Sanofi: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; BI: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Wang:Celgene: Research Funding. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Marshall:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Carlson:Karyopharm: Employment. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership. Kuruvilla:Gilead: Consultancy; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Lundbeck: Honoraria; Karyopharm: Honoraria.

Abstract: Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in & gt;5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.

Abstract: Exportin 1 (CRM1/XPO1) is the exclusive transporter of the majority of Tumor Suppressor Proteins (TSP) out of the nucleus, rendering these TSPs non-functional. Selinexor (KPT-330) is a potent, oral SINE XPO1 antagonist, forcing the nuclear retention and activation of 〉 10 TSPs resulting in NHL and CLL cell death in vitro, while sparing normal lymphocytes and other hematopoietic cells. Oral Selinexor has marked activity in murine models of NHL and CLL including R-CHOP resistant tumors. Dogs with spontaneous B- and T-cell lymphomas exposed to the related SINE Verdinexor demonstrate potent anti tumor effect and good tolerability. Methods Patients (pts) with advanced NHL or CLL relapsed/refractory to all available drug classes were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a Phase 1 trial in hematological malignancies (NCT01607892). Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were obtained. Response evaluation was performed every cycle. Results 18NHL/CLL pts with median age 66.5yrs; ECOG PS 0/1: 8/10; median number of prior regimens: 4.5 [range 2-11], received KPT-330 across 6 dose levels (3 to 30 mg/m2). Ten pts experienced drug-related grade 3/4 Adverse Events (AEs) including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), fatigue (n=1). The most common grade 1/2 toxicities were: anorexia (10/18pts; 56%), fatigue (9/18; 50%), diarrhea (6/18; 33%), vomiting (6/18; 33%), neutropenia (5/18; 28%), malaise (3/18; 17%), anemia (3/18; 17%) and weight loss (3/18; 17%). These adverse events were manageable with supportive care. 23mg/m2, one case of Grade 4 thrombocytopenia for 〉 5 days without bleeding was reported as a DLT for the cohort; this patient with refractory follicular NHL was continued on therapy at the same dose and schedule with intermittent platelet support with SD for 83 days on study.Dose escalation continues.There were no clinically significant cumulative toxicities or major organ dysfunction and pts have remained on therapy for ≥6 cycles. Maximum tolerated dose has not been reached; dosing at 35 mg/m2 twice weekly is ongoing.PK analysis at doses of 3-35 mg/m2demonstrated a dose proportional increase in Cmax and AUC with increasing dose. Elimination half-life was independent of dose and ranged from 4.7-7.0 hours. Significant increases (2-20x) in total leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction.Evaluation of lymph node biopsies from 2 pts confirms Selinexor-induced nuclear localization of multiple TSPs as well as apoptosis of tumor cells. Response was evaluable in 15pts; Selinexor treatment induced tumor shrinkage or disease stabilization in 80%(n=12) of pts with relapsed/refractory NHL/CLL who had progressive disease on study entry (Figure 1). 20% (n=3) of pts had clinical progression. One patient with ibrutinib-refractory CLL with Richter's transformation who progressed on chemotherapy achieved a rapid 60% reduction in lymph nodes in Cycle 1 and was referred for transplantation. A patient with DLBCL refractory to R-CHOP and bone marrow transplantation achieved a near CR (93% tumor shrinkage) and remains on study 〉 11 months. Conclusions Oral Selinexor is generally well tolerated, with favorable PK andPDn parameters. In this cohort of heavily pretreated, refractory/refractoryNHLand CLL with progressive disease on study entry, single agent oral Selinexor induced tumor shrinkage in the majority of pts. Disclosures: Kuruvilla: Seattle Genetics: Consultancy, Honoraria, Research Funding; Hoffman LaRoche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shah:Seattle Genetics, Inc.: Research Funding; NCCN: Membership on an entity’s Board of Directors or advisory committees; SWOG: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau. Garzon:Karyopharm: Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Speakers Bureau. Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Rashal:Karyopharm Therapeutics: Employment, Equity Ownership. Yau:NPM Pharma Inc: NPM Pharma hired Ozmosis Research as CRO for this trial Other. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. McCartney:Karyopharm Therapeutics: Employment, Equity Ownership. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therapeutics: Employment. Pond:Ozmosis Research: Consultancy. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Mirza:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Abstract: Background: The nuclear export protein, XPO1 is overexpressed in all types of malignant lymphoma. The SINE selinexor (KPT-330) is a slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over 10 tumor suppressor proteins (TSP) such as p53, IkB, FOXO and p21. In addition, selinexor inhibits the nuclear export and the translation of oncogenic mRNAs such as c-myc and Bcl-XL levels. Together these effects result in apoptosis of cancer cells in preclinical models of both T- and B- cell NHL. In DLBCL cell lines (n=10), selinexor induced potent cytotoxicity against both germinal center (GCB) and nonGCB including those with high MYC and/or BCL2/6 protein levels. Methods: Selinexor was administered orally for 4-10 doses in a 28-day cycle in this phase 1 study. Serial tumor biopsies were performed. Response evaluation was performed in cycle 1 and 2 and then every 2 cycles. All pts had heavily pretreated NHL with documented progressive disease (PD) on study entry. Results: 58 pts (34 males 24 females; median age 62 yrs; ECOG PS 0/1/2: 19/35/4; median prior regimens: 3) received selinexor across 13 dose levels (3 to 80 mg/m2). The recommended Phase 2 dose is 60 mg/m2 based on results across all Phase 1 studies. Grade 3/4 events ( 〉 5%) include thrombocytopenia (31%), neutropenia (22%), fatigue (10%), and anemia (7%). The most common Grade 1/2 AEs were: nausea (66%), anorexia (47%), fatigue (40%), and vomiting (40%) that were manageable with supportive care and were seen less frequently following cycle 1. Increases in XPO1 mRNA levels were observed at all doses and sustained for 4-48 hours, supporting twice weekly dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reductions, and apoptosis induction of cancer cells. Objective responses were observed in all classes of NHL studied (Table 1). An objective response rate (ORR) of 31% was observed across all NHL types. An ORR of 40% was observed in pts with rel/ref aggressive B-NHL (DLBCL, Follicular NHL grade 3b (FLgrd3b) and transformed NHL) at doses ³60 mg/m2 vs an ORR of 33% at 23-50 mg/m2 and 25% at ²20 mg/m2. Across all NHL types, time to best response was delayed, including 5 complete responses (CR) (4 in DLBCL and 1 T-NHL). Nine pts out of 34 have remained on therapy for 〉 6-23 months without clinically significant cumulative toxicities or major organ dysfunction. Conclusions: Selinexor treatment is generally well tolerated with supportive care and can be given over a prolonged period. Durable single agent activity in pts with heavily pretreated NHL has been observed. Phase 2 studies in DLBCL, Richter's transformation and T-NHL of single agent selinexor as well as in combination with other agents including CD20 antibodies are expected to begin in the near future. Abstract 396. Table 1 Cancer Type Selinexor Dose (mg/m2) N* ORR (%) CR (%) PR (%) SD (%) PD (%) WC/NE (%) Aggressive B-NHL (DLBCL, FLgrd3b, Transformed) ≤20 4 1 (25%) -- 1 (25%) 1 (25%) 2 (50%) -- 20 – 50 21 7 (33%) 4 (19%) 3 (14%) 5 (24%) 6 (29%) 3 (14%) ≥60* 10 4 (40%) -- 4 (40%) 4 (40%) -- 2 (20%) Follicular & Other Indolent NHL ≤30 4 -- -- -- 4 (100%) -- -- ≥35 4 2 (50%) -- 2 (50%) 1 (25%) -- 1 (25%) Mantle Cell Lymphoma ≤30 2 1 (50%) -- 1 (50%) 1 (50%) -- -- ≥35 2 -- -- -- -- 1 (50%) 1 (50%) T-Cell Lymphoma ≤30 4 -- -- -- 2 (50%) -- 2 (50%) ≥35 1 1 (100%) 1 (100%) -- -- -- -- Richter's Transformation ≤30 3 1 (33%) -- 1 (33%) 2 (67%) -- -- ≥35 3 1 (33%) -- 1 (33%) -- -- 2 (67%) TOTAL 58 18 (31%) 5 (9%) 13 (22%) 20 (34%) 9 (16%) 11 (19%) * First pt in this population was dosed on 23-July-2012 ORR=Objective Response Rate; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; WC=Withdrew Consent; NE=Non-Evaluable Disclosures Byrd: Pharmacyclics, Genentech: Research Funding. Porcu:Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Flinn:AstraZeneca: Research Funding. Kukreti:Celgene: Honoraria. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therpeutics: Employment. Shacham:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership. Carlson:Karyopharm Therapeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therpeutics: Employment, Equity Ownership.

Abstract: Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (dex) has demonstrated potent anti-cancer activity in patients with heavily pretreated MM. While the development of proteasome inhibitors (PIs) has transformed the treatment of MM, acquired resistance to PIs limit their efficacy. Preclinical studies have shown that selinexor, when combined with bortezomib, can restore sensitivity of bortezomib-resistant MM to this drug, inducing tumor growth inhibition and increasing survival in MM models in mice. In this clinical trial (NCT02343042), we investigated the safety, tolerability and efficacy of the combination of selinexor, bortezomib and low dose dex (SdB) in patients (pts) with refractory MM. Methods - This phase 1b/2 dose escalation study using a standard 3+3 design, was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for SdB. The study included pts with refractory MM, after ≥ 1 prior therapy. Pts with prior PI relapsed and/or refractory disease were included, provided the patient's MM was not refractory to bortezomib as last therapy. Selinexor was independently dosed escalated in once-weekly (QW, starting at 80 mg; N=7, 100 mg N=6 pts) or twice-weekly (BIW, starting at 60 mg; N=3, 80 mg N=6 pts) regimens. Bortezomib (1.3 mg/m2 sc) was administered either once-weekly or twice-weekly and dex was given orally 40 mg QW or 20 mg BIW. Results - As of July 25th, 2016, enrollment in the dose escalation cohorts has been completed with 22 pts (12 male /10 female). The median age is 65 years (range, 46 - 74), with a median of 4 (range, 1 - 12) prior treatment regimens. One dose limiting toxicity (Grade 4 thrombocytopenia without bleeding) in the 80 mg BIW cohort was observed but the MTD has not been reached. Common related grade 1/2 adverse events (AEs) include: fatigue 41%, nausea 41%, anorexia 36%, and weight loss 18%. Grade 3/4 AEs include: thrombocytopenia 41%, anemia 18%, and neutropenia 18%. One case of grade 1 peripheral neuropathy in the 80 mg BIW cohort was reported. All pts were evaluable for response. The ORR (≥partial response, PR) was 77% with ≥VGPR 27% (1 pt in CR and 5 pts in VGPR) and 11 PRs. There were 3 minor responses (14%), 1 stable disease, 1 progressive disease (5% each). Seven of the 12 pts with PI-refractory MM responded (ORR 58%). A summary of response by PI treatment history is shown in Table 1. Ten patients have remained on study 〉 4 months, including 7 patients still on trial (longest 〉 9 months). Based on tolerability and anti-MM activity, RP2D of SdB is selinexor 100 mg, bortezomib 1.3 mg/m2 and dex 40 mg, all given once weekly. At the RP2D, all six pts achieved ≥PR (ORR 100%). Conclusions - Selinexor in combination with bortezomib and dex is well tolerated and highly active in refractory MM. Toxicities are manageable and similar to selinexor or bortezomib monotherapy. Peripheral neuropathy is uncommon, consistent with the use of weekly bortezomib sc and the lack of neuropathy with selinexor. Overall, the SdB regimens induced an ORR of 77% with ≥VGPR of 27%. In patients with PI-refractory MM, the ORR was 58%, indicating that the addition of selinexor restores sensitivity to bortezomib. These results confirm the preclinical data supporting synergistic effects of selinexor when combined with PIs. This promising, once-weekly treatment regimen may provide deeper and more durable responses in pts with relapsed / refractory MM, including those with PI-refractory disease. Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Disclosures Bahlis: Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria. Sebag:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Sutherland:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Amgen: Honoraria; J+J: Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Kouroukis:Amgen: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Takeda: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Lentzsch:BMS: Consultancy; Celgene: Consultancy, Honoraria. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding.

Abstract: Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM. Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3 (or ≥75k if marrow plasma cells 〈 50%), and creatinine clearance ≥20 mL/min. The primary endpoint was ORR. Secondary endpoints: duration of response (DOR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Efficacy was assessed by an Independent Review Committee (IRC) based on IMWG criteria. OS was also compared to a cohort of pts with PI, IMiD, dara refractory MM from the Flatiron Health Analytic Database (FHAD), (ref: ASH 2018 abs ID: 116493),who met all the inclusion criteria for STORM. Results: As of 1-Jun-2018, 122 pts (71 M/ 51 F) were enrolled in 38 sites (US and EU). Pt characteristics were [medians (range)]: age 65 yrs (40-85); 7 (3 - 18) prior treatment regimens, 6.6 yrs ( 〈 1 - 23.4) from initial MM diagnosis.65 pts (53%) had high risk cytogenetics, 86 pts (70%) had prior dara in combination, 102 pts (84%) had prior stem cell transplantation, 2 pts had prior CAR-T therapy. All pts enrolled with progressive disease (PD), 72% of pts had increases (3% - 792%) in MM markers from screening to C1D1 (median 11 days). Frequently reported Sd treatment related adverse events (AEs) included (all grades, grades 3/4): thrombocytopenia (67%, 53%), nausea (67%, 10%), fatigue (68%, 21%), anorexia (50%, 2%), anemia (46%, 28%), and weight loss (46%, 0%). Eight pts remain on study and 114 pts discontinued treatment (most commonly for PD). There were 4 deaths on treatment: sepsis, respiratory failure, pulmonary embolism, and an unrelated, unspecified cardiac event. IRC determined ORR (≥PR) was 26.2%, with 6.5% ≥ very good partial response, including 2 stringent complete responses (sCRs; MRD negative at 1:10-6 and at 1:10-4sensitivity). Both pts who relapsed after CAR-T achieved PRs. The CBR (≥minimal response, [MR]) was 39.3%, and 79% of pts achieved ≥stable disease (SD). Responses typically occurred within the first month. Medians: DOR 4.4 months (mo) (range 〈 1 - 10 mo), PFS 3.7 mo, and OS 8.0 mo. Pts with ≥MR had significantly longer OS than pts with PD/NE (median not reached vs 1.9 mo, p= 〈 0.0001). Compared to the FHAD cohort, STORM cohort had longer OS (Figure 1, HR 0.41, p=0.0001). Conclusions: Results of the pivotal STORM Part 2 in penta (PI, IMiD, dara)-refractory MM demonstrated that oral selinexor plus low-dose dexamethasone (Sd) was highly active with an ORR of 26.2%. Importantly, responses were rapid and deep with 2 patients achieving sCRs (both MRD negative) in these heavily pre-treated penta-refractory MM pts (median 7 prior regimens, 53% high risk). AEs are a function of dose/schedule/disease severity and can be managed with dose modifications and supportive care. No major organ toxicity was observed and AEs were typically transient and reversible. Sd is an all-oral, first in class mechanism with novel MOA and represents a potential therapeutic option to the growing number of pts with penta-refractory MM who have exhausted approved therapies. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene and Janssen: Research Funding; Amgen, Celgene, Janssen and Takeda: Consultancy. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Mohty:Amgen: Consultancy, Honoraria; Molmed: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Bristol Myers: Consultancy, Research Funding. Sylvain:Gilead: Other: scientific advisor board. Costa:Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; BMS: Research Funding. Shah:Karyopharm Therapeutics: Employment. Picklesimer:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Li:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Novartis: Consultancy; Merck: Consultancy.

Abstract: Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IkB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl & gt;60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl & gt;60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl & lt;60 mL/min) compared to those with normal (CrCl ≥60 mL/min) renal function. No dose adjustments are required in patients with renal dysfunction and DLBCL who are treated with selinexor. Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & 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) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, 〈 20 mg DEX and 20 mgs DEX. Results: In MM.1s cells Sel-Dex showed synergy for nuclear retention of the DEX activated GR (Ser211-phosphorylated) and concomitant GR transcriptional activation. Sel-Dex showed highly synergistic cytotoxicity in MM.1s cells in vitro and in vivo, with a corresponding increase in apoptosis. Selinexor alone was potently cytotoxic in the DEX resistant MM cell lines MM.1R and ANBL6, but addition of DEX provided no additional effect. Twenty-eight pts with heavily pretreated refractory MM (16 M, 12 F; median age 62; ECOG PS 0/1: 7/21; median prior regimens: 6) received selinexor at 30 – 60 mg/m2 with either 0, 〈 20, or 20 mgs DEX. All pts have received a proteasome inhibitor and an Imid and the majority of the pts have received pomalidomide (68%) and/or carfilzomib (36%). The most common Grade 1/2 AEs for these three groups were: nausea (82%/86%/70%), fatigue (55%/86%/40%), anorexia (36%/71%/60%), and vomiting (36%/57%/10%). Of the 28 pts treated; 10 heavily pretreated refractory MM pts treated with a combination of selinexor (45 mg/m2 twice weekly) and DEX (20 mg with each selinexor dose) were found to have dramatically improved disease response (n=10, ORR 60%), with one stringent complete response (sCR, 10%), 5 partial responses (PR, 50%) and clinical benefit rate (CBR) rate of 80% (Figure 1). Treatment with ³30mg/m2 selinexor and 〈 20 mg DEX (n=7), resulted in ORR of 14% and CBR of 86%, while treatment with selinexor (30-60 mg/m2) without DEX (n=12) showed best response of stable disease (50%). Sel-Dex was also associated with an increase in time on study relative to selinexor alone, with 7 of out 10 pts in the 20 mg DEX combo group still on study (11-25 weeks). Five additional pts were treated with selinexor at a dose of 60 mg/m2 in combination with 20 mg DEX. Response evaluation is pending. Conclusions: Sel-Dex combination is markedly synergistic in preclinical models, which is supported by the preliminary clinical data presented. One potential mechanism underlying this synergy is the amplification of GR activity due the combined effects of selinexor-induced nuclear retention of activated GR coupled with DEX-mediated GR agonism. These results provide a promising basis for the continuing study of Sel-Dex for treatment of pts with refractory MM. Phase 2 studies of Sel-Dex in pts with MM refractory to both pomalidomide and carfilzomib are planned for early 2015. Disclosures Chen: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, 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, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.