ALBERT

Description: Purpose: Drug resistance is the greatest obstacle to the successful treatment of multiple myeloma (MM). We investigated whether the clinical XPO1 inhibitor selinexor (KPT-330), when combined with bortezomib or carfilzomib, could overcome proteasome inhibitor (PI) resistance in myeloma. Experimental Design: PI-resistant human MM cell lines 8226-B25 and U266-PSR were treated with the XPO1 inhibitors selinexor or KOS-2464 in combination with bortezomib or carfilzomib and assayed for apoptosis and viability. Mice challenged with PI-resistant human MM cells (U266-PSR) were treated with selinexor +/- bortezomib. CD138+/light-chain+ MM cells from PI-refractory MM patients were treated with selinexor +/- bortezomib or selinexor +/- carfilzomib and assayed for apoptosis. All experiments were compared to the standard of care, bortezomib therapy. IkBα-protein was assayed by Western blot and immunofluorescence microscopy and IkBα-NFkB-complex formation by proximity ligation assay. IkBα protein knockdown in human MM cells by siRNA was performed to determine the mechanism of selinexor inhibitor action. Further analysis of selinexor/bortezomib treatment on intra-cellular protein levels and intra-cellular localization was performed by lysine and N-terminal labeling with six-plex tandem mass tags (heavy isotope) and assayed by LC-MS/MS discovery proteomics. Results: Selinexor in combination with bortezomib or carfilzomib decreased viability and induced apoptosis in PI-resistant MM cells. Resistant MM cell lines were up to 10-fold resistant to single agent bortezomib or carfilzomib when compared to parental cells. The combination of the XPO1 inhibitors selinexor or KOS-2464 sensitized drug resistant cells to bortezomib (P 〈 0.02) and carfilzomib (P 〈 0.005) when compared to single agents. Selinexor and bortezomib inhibited PI-resistant MM tumor growth and increased survival with minimal toxicity in NOD/SCID-g mice. Bone marrow mononuclear cells isolated and treated with selinexor or KOS-2464 and bortezomib or carfilzomib from newly diagnosed (n=8), relapsed (n=5), and bortezomib (n=8) and carfilzomib (n=6) refractory MM patient samples were all sensitized by selinexor and KOS-2464 to bortezomib (P 〈 0.043) and carfilzomib (P 〈 0.044) as shown by increased apoptosis. Normal, non-myeloma CD138/light-chain double-negative patient cells were not sensitized to apoptosis by XPO1 inhibitors. Immunofluorescence microscopy of IkBα in 8226-B25 PI-resistant cells showed an increase in IkBα after treatment with selinexor/bortezomib as compared with vehicle control or single agent bortezomib or selinexor. Nuclear IκBα was also increased by selinexor treatment. IkBα protein expression was increased by bortezomib (70%) and selinexor (50%) versus control. The selinexor/bortezomib combination increased IkBα protein (212%) as compared to vehicle control or single agent bortezomib or selinexor. Similar results were found in drug-naïve 8226 and U226 cells, as well as PI-resistant 8226-B25 and U225-PSR cells. The increase in nuclear IkBα after selinexor treatment was confirmed by ImageStream flow cytometry. Selinexor/bortezomib therapy significantly increased IkBα-NFkB-complexes in PI-resistant MM cells. Selinexor in combination with bortezomib increased proximity co-localization of NFkB and IkBα without affecting XPO1 protein expression after 4 hours of drug treatment. Analysis of the number of NFkB-IkBα foci/binding showed that selinexor/bortezomib increased the number of foci in the nucleus versus untreated control or single agent selinexor or bortezomib (P ≤ 0.00077). IkBα knockdown reduced selinexor-induced cytotoxicity in both IM-9 (9.5-fold) and 8226 (12.3 to 25.4-fold) human MM cells. Intracellular protein analysis by heavy isotope labeling and LC-MS/MS showed changes in several signaling pathways including p53, MAPK, VEGF and angiopoietin, IL-1, HMGB1/TLR and APRIL and BAFF as well as those related to NFkB signaling. Conclusion: Selinexor, when used in combination with bortezomib or carfilzomib has the potential to overcome PI drug resistance in MM. Disclosures Kashyap: Pharma: Employment. Landesman:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership.

Description: Purpose Human multiple myeloma (MM) remains an incurable disease despite relatively effective treatments, including proteasome inhibitors, immunomodulator-based therapies, and high-dose chemotherapy with autologous stem cell rescue. New agents are needed to further improve treatment outcomes. In previous studies, we have shown that inhibitors of the nuclear export receptor XPO1, in combination with bortezomib, carfilzomib, doxorubicin, or melphalan, synergistically induced apoptosis in MM cells in vitro, in vivo and ex vivo without affecting non-myeloma cells. In early clinical trials, the oral, brain penetrating XPO1 inhibitor selinexor showed clear anti-myeloma activity however adverse events have been recorded, including nausea and anorexia. Our purpose was to investigate the use of oral KPT-8602, a novel small-molecule inhibitor of XPO1 with minimal brain penetration, which has been shown to have reduced toxicities in rodents and primates while maintaining potent anti-tumor effects. Experimental Procedures To test the efficacy of KPT-8602, we treated human MM cell lines (both parental and drug-resistant) with KPT-8602 ± currently used MM drugs, including bortezomib, carfilzomib, dexamethasone, doxorubicin, lenalidomide, melphalan, topotecan, and VP-16. Human MM cell lines assayed included RPMI-8226 (8226), NCI-H929 (H929), U266, and MM1.S, PI-resistant 8226-B25 and U266-PSR, doxorubicin-resistant 8226-Dox6 and 8226-Dox40, and melphalan-resistant 8226-LR5 and U266-LR6 cell lines. MM cells (2-4x106 cells/mL) were treated for 24 hours with KPT-8602 (300 nM), followed by treatment with one of the listed anti-MM agents for an additional 24 hours. MM cells were then assayed for cell viability (CellTiter-Blue, Promega). In addition, cells were treated with KPT-8602 ± anti-MM agents concurrently for 20 hours and assayed for apoptosis by flow cytometry. In vivo testing was done in NOD/SCID-g mice by intradermal injection of U266 MM cells. Treatment started 2 weeks after tumor challenge with KPT-8602 (10 mg/kg) ± melphalan (1 or 3 mg/kg) 2X/week (Tuesday, Friday) or with KPT-8602 alone 5X weekly (10 mg/kg) (Monday-Friday). A parallel experiment was run using the clinical XPO1 inhibitor KPT-330 (selinexor). Ex vivo testing was performed on MM cells from newly diagnosed/relapsed patient bone marrow aspirates with KPT-8602 ± bortezomib, carfilzomib, dexamethasone, doxorubicin, lenalidomide, melphalan, topotecan, or VP16. CD138+/light-chain+ cells were assayed for apoptosis by flow cytometry. Results Viability assay showed that KPT-8602 had low IC50values (~140 nM) as a single agent and functioned synergistically with bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16. (CI values 〈 1.0). This synergistic effect was less pronounced in myeloma cells when KPT-8602 was used in combination with dexamethasone or lenalidomide. KPT-8602 ± bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 combination therapy also induced apoptosis in all MM cell lines tested, including drug-resistant cell lines, as shown by caspase 3 cleavage and flow cytometric analyses. NOD/SCID-gamma mouse tumor growth was reduced and survival increased in KPT-8602/melphalan-treated mice when compared to single-agent controls. In addition, mice treated with KPT-8602 5X weekly had significantly reduced tumor growth and increased survival when compared to 2X weekly drug administration. No toxicity was observed in KPT-8602-treated mice as determined by weight loss in both the 2X and 5X groups. In patient bone marrow biopsies, the combination of KPT-8602 ± bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 was more effective than single agents at inducing apoptosis in CD138+/LC+ MM cells in both newly diagnosed and relapsed/refractory patient samples. Conclusions We found that the novel XPO1 inhibitor KPT-8602 sensitizes MM cells to bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 as shown by apoptosis in parental and drug-resistant cell lines and by cell viability assays. Sensitization was found to be synergistic. In addition, KPT-8602 was effective in treatment of human MM tumors in mice as a single agent or in combination with melphalan and was effective when combined with several MM drugs in MM cell lines and MM patient bone marrow aspirates. KPT-8602 may be a potential candidate for future clinical trials. Disclosures Shacham: Karyopharm: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics, Inc.: Employment, Patents & Royalties.

Description: Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for 〉5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for 〉4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: 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; 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. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Description: 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 (Sd) or in with protesome inhibitors (PIs) or immunomodulatory drugs (IMiDs), has shown anti-MM activity in patients (pts) with relapsed or refractory MM. Daratumumab (Dara), an anti-CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short PFS and an ORR of ~21% in quad-refractory MM. Selinexor in combiniation with dara have shown preclinical synergistic killing of MM cells. Methods - Pts were eligible if they had received ≥ 3 prior lines of anti-myeloma therapy, including a PI and an IMiD. Selinexor was dose-escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg). Dara was 16 mg/kg IV (recommended schedule) and dexamethasone (dex) was 40 mg QW or 20 mg BIW. The objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability and preliminary efficacy of the combination of this SDd combination in pts with PI/IMiD refractory MM Results - As of Jul 20th2018, 25 pts (11 males / 14 females) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 22 pts in the 100 mg QW cohorts. Pts have a median age of 68 years and a median of 3 (range, 2 - 10) prior treatment regimens. Common SDd treatment related adverse events included (all grades, grades 3/4): thrombocytopenia (58%, 42%), leukopenia (54%, 38%), anemia (46%, 29%), nausea (50%, 0%) and fatigue (46%, 8%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: G3 thrombocytopenia and G2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort, 6 pts enrolled, 5 evaluable, with no DLTs. This cohort was expanded and enrollment is ongoing. A total of 21 pts were evaluable for response. In 19 dara-naïve pts, the ORR was 74% (5 VGPR, 9 PR, 2 MR, 2 SD, 1 PD), including 3 unconfirmed PRs, 1 unconfirmed MR. In the 2 pts with dara refractory MM, there was one PD and one SD. The longest duration of therapy is 13 months. Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dex 40 mg, administered QW. Conclusions - Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex. The preliminary ORR of 74% with SDd in patients with PI/IMiD refractory MM who are dara naïve is promising and compares favorably to 21% ORR of Dara and Sd in quad refractory myeloma. This once weekly regimen is well tolerated with no major organ toxicities to date. Data from the full phase 1 dose expansion will be presented. Disclosures Gasparetto: Takeda: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Chen:Amgen: Honoraria. Shah:Karyopharm Therapeutics: Employment. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin: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. Lipe:Celgene: Consultancy.

Description: Introduction: Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired-resistance in MM. Materials and Methods: PI-resistant myeloma cell lines, RPMI8226-B25 and U226 PSR, and their respective parental cell lines RPMI8226 and U266, were treated both in vitro with selinexor/bortezomib or selinexor/carfilzomib and assayed for apoptosis. In vivo studies using U266 and U266PSR tumors were performed in NOD/SCID-gamma (NSG) mice. Mice were treated with selinexor/bortezomib and single agents. Bone marrow biopsies from refractory myeloma patients were treated ex vivo with selinexor/bortezomib or selinexor/carfilzomib and assayed for apoptosis. Mechanistic studies included NFkB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry and proximity-ligation assay. IkBα knockdown and NFkB transcriptional activity were measured in selinexor/bortezomib treated MM cells. Results: We found that selinexor restored sensitivity of PI-resistant RPMI8226-B25 and U266PSR MM cells to bortezomib (P = 0.00055) and carfilzomib (P = 0.0017). Bortezomib, when combined with selinexor reduced U266 MM tumor growth versus single-agent bortezomib (P = 0.022) in NSG mice. NSG mice challenged with PI-resistant U266PSR MM tumors also had reduced tumor growth with selinexor/bortezomib as compared to single agent bortezomib (P = 0.0006). Combining bortezomib and selinexor improved survival in mice with U266 MM tumors (P = 0.0072) and PI-resistant U266PSR when compared to single-agent bortezomib (P = 0.0072). Myeloma cells from PI-refractory MM patients (n=14) were sensitized by selinexor to bortezomib (P = 0.002) and carfilzomib (P = 0.001) without affecting non-myeloma cells. Immunofluorescence microscopy of PI-resistant human MM cell lines found a greater than 212% increase in IkBα when compared to untreated cells (confirmed by Western blot). A similar increase in IkBα immunofluorescence was found in newly diagnosed, relapsed and refractory patient MM cells. ImageStream analyses of MM cells showed an increase in total and nuclear IkBα from selinexor/bortezomib exposure. Proximity-ligation assays showed that IkBα-NFkB-complexes were increased 12-fold in bortezomib/selinexor treated MM cells. IkBα knockdown abrogated selinexor/bortezomib induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFkB transcriptional activity in addition to a reduction of NFkB induced IAP-1, IAP-2, BCL-2, cyclin D2 and c-myc protein expression.. Conclusions: Selinexor, when used with bortezomib or carfilzomib has the potential to overcome proteasome-inhibitor drug-resistance in MM. Sensitization may be due to inactivation of the NFkB pathway by IkBα. Selinexor, an orally active selective inhibitor of XPO1-mediated nuclear export (SINE), is currently undergoing phase I/II studies in a variety of indications, including a combination with carfilzomib, in both relapsed and refractory MM patients (NCT02199665). The results presented in this study support combinatorial clinical trials in relapsed and refractory MM that utilize PI therapies. Disclosures Kashyap: Karyopharm Therapeutics: Employment, Equity Ownership. Shain:Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Signal Genetics: Research Funding; Novartis: Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Landesman:Karyopharm Therapeutics Inc: Employment, Other: stockholder.

Description: Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

Description: Introduction:Multiple myeloma (MM) is an incurable cancer of plasma cells. It accounts for approximately 10% of all hematologic malignancies. In the US, it is estimated that there will be approximately 30,330 new cases and 12,650 deaths in 2016. In the past decade, responses/survivals have been significantly increased by newer therapies. However, almost all of the patients will eventually die from multi-drug resistant disease. Materials and Methods:Weused XPO1 inhibitors (XPO1i) selinexor (300nM) or KPT-8602 (300nM) +/- melphalan (15 μM) to treat human MM parental RPMI8226 and U266 cells, and melphalan resistant LR5 and LR6 cell lines for 20 hours and then assayed for apoptosis and viability by flow cytometry. DNA damage was assayed by the comet assay and phospho-H2AX protein expression in H929 human myeloma cells. p53, NFkB, IKKα, FANCF, and FANCL were assayed by Western blot in H929 MM cells. We also treated cells from patients with newly diagnosed or relapsed/refractory MM with the XPO1i (300nM)/ melphalan (10μM) combination and assayed for apoptosis. In addition, selinexor/melphalan treated NOD/SCID-gamma mice with U226 MM tumors were assayed for tumor growth, survival, and toxicity. Results:Cell viability of all tested MM cell lines was decreased synergistically and apoptosis increased by XPO1i/melphalan treatment (selinexor/melphalan, P = 2.2x10E-6 to 0.0032, KPT-8602/ melphalan, P = 1.2X10E-7 to 0.0031). Comet assays showed that the XPO1i/ melphalan drug combination increased DNA damage more than single agent melphalan or XPO1i alone. Phospho-H2AX expression also was increased (selinexor/ melphalan, P = 0.005 and KPT-8602/melphalan, P = 0.001). Western blot analysis showed that XPO1i treatment can increase p53 and decrease NFkB, IKKα, FANCF, and FANCL in MM cells. Apoptosis assays showed that both melphalan-resistant and parental MM cell lines were sensitized to melphalan by XPO1i. In addition, CD138+/light chain+ MM cells from newly diagnosed and relapsed/refractory MM patients were sensitized (20-fold and 5 to10-fold respectively) by XPO1i to melphalan. XPO1i/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect when compared to single-agent melphalan (selinexor, P = 0.0024 and KPT-8602, P = 0.0030) in NOD/SCID-gamma mice challenged with U266 MM tumors. XPO1i/ melphalan treated mice had increased survival and no significant toxicity. Conclusions:XPO1i's can improve the response of human MM cell lines and patient MM cells to melphalan both in vitro and ex vivo. The mechanism of this synergy reversing melphalan resistance may be due to increased nuclear p53, in combination with decreased NFkB and IKKα, and decreased DNA repair proteins FANCL and FANCF of the Fanconi Anemia/BRCA pathway. Our preliminary data suggest that the synergistic cell kill may be because XPO1i's increase melphalan-induced DNA damage and block the repair of the DNA damage. Thus using combination therapies of XPO1i, especially the clinical compounds selinexor and KPT-8602 +/- melphalan may have potential to improve the treatment outcomes of MM. Based on these promising pre-clinical data, we designed a phase 1/2 clinical trial evaluating the combination of selinexor and high-dose melphalan as a conditioning regimen for autologous hematopoietic cell transplantation in patients with multiple myeloma (NCT02780609). Disclosures Shain: Novartis: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Signal Genetics: Research Funding; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baloglu:Karyopharm Therapeutics Inc: Employment, Other: stockholder. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding.