ALBERT

Description: Introduction In a phase 1/2 study designed to assess KRd w/o ASCT, KRd provided a high rate of stringent complete response (sCR) (55%) in NDMM patients (pts) after a median of 24 cycles and 47.5 months (mo) of follow-up (f/u), with 4-year (yr) progression-free survival (PFS) and overall survival (OS) rates of 64% and 93%, respectively (Jakubowiak et al. Blood. 2012;120:1801-9; Jakubowiak et al, EHA 2016). To further improve response and outcomes, we designed a phase 2 study to assess KRd with ASCT. Methods The study enrolled ASCT-eligible pts with NDMM requiring tx per International Myeloma Working Group (IMWG) criteria with no age limitation. Pts received initial four 28-day cycles of KRd induction with CFZ IV 20/36 mg/m2 on Days (D) 1, 2, 8, 9, 15, 16 (20 mg/m2 given on D1, 2 in Cycle [C] 1 only); LEN PO D1-21 at 25 mg, DEX PO 40 mg/week followed by stem cell collection using G-CSF and plerixafor, melphalan 200 mg/m2 and ASCT, and KRd consolidations (C 5-8) using the same doses and schedule except LEN 15 mg in C5 with option to escalate to prior dose and DEX reduced to 20 mg weekly. After C8, pts received maintenance KRd for an additional 10 cycles using the same doses as in C8 except CFZ on D 1, 2, 15, 16 only. Single-agent LEN was recommended off-study after C18. The primary endpoint was rate of sCR at the end of C8, with minimal residual disease (MRD) among secondary endpoints. We estimated that an sCR rate of 50% or better for KRd plus ASCT would indicate superior outcome compared with a historical sCR rate of 30% for KRd w/o ASCT at this time point. Responses were assessed using current IMWG criteria. MRD was evaluated by 10-color multiparameter flow cytometry (MFC) with 10-4-10-5 sensitivity and by next generation sequencing (NGS) at landmark time-points: after KRd induction (after C4), ASCT, and KRd consolidation (after C8); at the end of KRd tx (after C18); and then yearly. NGS analysis was done using the immunoSEQ® MRDplatform with a threshold at 10-6 for MRD negativity. MRD-negative status required CR, as per current IMWG criteria. Results As of July 1, 2016, enrollment was completed (76 pts); 72 pts completed KRd induction, 71 ASCT, 66 KRd consolidation, and 44 KRd maintenance with 25 pts remaining on protocol tx. Median age was 59 y (range 40-76), ISS stage II/III 57%, high-risk cytogenetics 36% as per IMWG criteria. Efficacy and toxicity data were available for 73 pts. Based on January 1, 2016 cut-off date, response rates at the end of C8 were 96% VGPR, 73% CR, and 69% sCR. The rate of sCR has been improving during the post-transplant phase of the KRd tx, from 20% post-ASCT to 69% after 4 cycles of KRd consolidation (C8), and to 82% after 10 additional cycles of KRd maintenance (C18). MRD rates in pts evaluated to date were 82% by MFC (N=33) and 66% by NGS (N=29) at the end of C8, and 90% (N=20) and 71% (N=16), respectively, at the end of C18. MRD rates in a subset of high-risk pts evaluated for MRD were 90% by MFC (10 of 11 pts with high-risk) and 63% by NGS (6 of 8 pts) at the end of C8, and 100% (6 of 6 pts) by MFC and 80% (4 of 5) by NGS at the end of C18. After median f/u of 17.5 mo, 2-yr PFS was 97% and 2-yr OS 99% for all 76 pts. For NGS and/or MFC MRD-negative pts at the end of C8, 2-yr PFS/OS was 100% and for MRD-positive/unknown PFS was 93% and OS 98%. For high-risk disease pts (N=27), 2-yr PFS was 96%. KRd-related adverse events (AEs) were generally Grade (G) 1/2, and included (any G) for hematologic AEs thrombocytopenia (57%), lymphopenia (39%), anemia (39%), and neutropenia (28%) and for non-hematologic AEs fatigue (53%), peripheral neuropathy (39%), diarrhea (3%), and infection (34%). Most common G3/4 AEs were lymphopenia (28%), neutropenia (18%), and infections (8%). Two of 71 pts evaluated pre-transplant had asymptomatic decrease of ejection fraction (EF) 45-50%, with no baseline ECHO or MUGA, all remaining pts had normal pre-transplant EF. Updated results, including larger sample of MRD data, will be presented at the meeting, with nearly all patients completing 18 KRd cycles at the next data cut. Conclusions These results show that extended KRd tx with incorporated ASCT results in high rates of sCR and MRD-negative disease in both standard and high risk disease, which correspond to high rates of PFS and OS. These results compare favorably with data from the KRd w/o ASCT study, based on pre-specified improvement of sCR rate at the end of 8 cycles and beyond, and with historical studies in NDMM. These results will require validation in ongoing and planned randomized trials. Disclosures Vij: Janssen: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Reece:Merck: Research Funding; Otsuka: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Rosenbaum:Celgene: Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: 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.

Description: Background There are an increasing number of multiple myeloma (MM) patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and carfilzomib (CFZ), necessitating development of novel therapeutics. Pre-clinical evaluation of selinexor (SEL), an orally available Selective Inhibitor of Nuclear Export (SINE) compound, demonstrated synergistic myeloma cell death with CFZ and mechanistic rationale for overcoming resistance to CFZ (Rosebeck et al., 2016), providing support for this phase 1 trial. Aims The primary objectives were to assess the maximum tolerated dose (MTD) of a SEL, CFZ and dexamethasone (DEX) combination and to obtain preliminary efficacy data for this novel regimen in RRMM pts. Methods Pts with RRMM who progressed after at least two prior treatment regimens of myeloma therapy were eligible for enrollment. Dose escalation followed the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 SEL PO on days (D) 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ IV on D 1, 2, 8, 9, 15, 16, and DEX PO (20mg cycles 1-4/ 10mg cycles 5+) in 28-day cycles (C) in up to 5 dose levels. An expansion cohort has enrolled additional pts to a total of 12 CFZ-refractory pts treated at the recommended Phase 2 dose (RP2D). Dose Limiting Toxicities (DLTs) were evaluated through C2D1. Responses were assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2016, the study has completed dose escalation and enrolled a total of 18 pts; 5 at dose level 1 (30 mg/m2 SEL, 20/27 mg/m2 CFZ, 20/10 mg DEX), 3 at dose level 2a (30 mg/m2 SEL, 20/36 mg/m2 CFZ, 20/10 mg DEX), and a total of 10 (7 in dose escalation, 3 in cohort expansion) at dose level 2b (60mg flat dose SEL, 20/27 mg/m2 CFZ and 20/10 DEX). Pts age ranged between 55 to 74 years with a median of 63.5 years; and had a median of 4 prior treatment regimens (range 2-10). Sixteen pts were evaluable for response, all refractory to their last line of therapy. All 16 response evaluable pts were refractory to CFZ, of which 11 were refractory to CFZ combinations as their last line of therapy, including 8 to a KPd combination of CFZ, pomalidomide, and DEX. Fifteen pts were evaluable for DLT and 3 of 18 pts required replacement for DLT evaluation (1 had DEX reduced not due to DLT; 2 did not receive all scheduled C1 doses). In the dose escalation phase, there was one DLT of cardiac amyloidosis (CA) in a pt with history of prior congestive heart failure and CA at baseline. While the maximum tolerated dose (MTD) has not been reached, the RP2D was identified at dose level 2b based on tolerability. Grade 3/4 adverse events (AEs) included: thrombocytopenia (67%), neutropenia (33%), anemia (17%), fatigue (17%), and infections (11%). The most common all grade AEs included: gastrointestinal disorders (78%), thrombocytopenia (73%), fatigue (72%), anemia (47%), dyspnea (33%), and elevated liver and pancreatic enzymes (28%). There were 2 (11%) serious AEs, 1 upper respiratory infection and 1 lower gastrointestinal bleeding. All adverse events were manageable with concomitant medications. Response rates for all evaluable pts were 75% ≥MR (12 of 16), 63% ≥PR, and 25% ≥VGPR. Response rates in CFZ-refractory pts at last line of treatment were 73%, 64%, and 18% respectively. Responses occurred rapidly; after C1 with 75% ≥MR. As of the data cutoff date, 15 pts progressed (between 1 and 14 months on study) and 3 pts remained on treatment (1 - 4 months). Conclusions The combination of SEL, CFZ, and DEX demonstrates encouraging activity and safety in heavily pretreated, mostly CFZ-refractory myeloma. In addition, with 64% PR or better for pts progressing on CFZ, these results provide early clinical evidence that selinexor has the ability to overcome CFZ resistance, warranting further investigation of this regimen in RRMM. Disclosures Jakubowiak: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: 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; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenbaum:Celgene: Speakers Bureau. Chari:Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Zonder:Pharmacyclics: Other: DSMC membership; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria.

Description: Background There is an increasing number of multiple myeloma patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and Carfilzomib (CFZ), necessitating development of novel effective therapeutics. Pre-clinical evaluation of selinexor, a novel orally available selective inhibitor of nuclear export (SINE), in human myeloma cell lines (HMCL), primary plasma cells derived from myeloma patients, and HMCL tumor-bearing mice demonstrated synergistic myeloma cell death with CFZ (Rosebeck et al. ASH 2013) and the ability to overcome resistance to CFZ (Rosebeck et al. ASH 2014). Aims The primary objective is to assess the maximum tolerated dose (MTD) of selinexor and CFZ in combination with DEX in RRMM pts and to provide preliminary evaluation of efficacy of this novel triplet regimen. Methods Pts with RRMM, including CFZ-refractory pts, who have failed at least two prior treatment regimens of myeloma therapy, were eligible for enrollment. Dose escalation follows the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 selinexor PO on days 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ given IV on days 1, 2, 8, 9, 15, 16, and DEX PO 20/10mg (cycles 1-4/cycles 5+) in 28-day cycles. At least 12 and up to 48 pts are planned for evaluation. Dose Limiting Toxicities (DLT) are measured for the Cycle 1 as well as Day 1 of Cycle 2. Dose modifications are allowed to manage toxicities. Response was assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2015 the study has enrolled 8 pts, 5 pts were treated at dose level 1 (30 mg/m2 selinexor, 20/27 mg/m2 CFZ, 20/10 mg DEX) and 3 patients were treated at dose level 2a (30 mg/m2 selinexor, 20/36 mg/m2 CFZ, 20/10 mg DEX). Pts had median age of 65.5 (range 55-73) and a median of 5 prior treatment regimens (range 2-5). Six pts were refractory to CFZ combinations at their last line of therapy, including 4 to CFZ, pomalidomide (POM), and DEX. Of the 2 remaining pts, 1 was refractory to high dose CFZ with DEX in prior line of therapy and both were refractory to last line of therapy. Six pts were DLT-evaluable and two pts required replacement for DLT evaluation (1 pt had DEX reduced in cycle 1 not due to DLT; 1 pt did not receive all scheduled cycle 1 doses due to progressive disease). There have been no DLTs and MTD is not yet established. Adverse events (AEs) were reversible and managed with concomitant therapy. G3/4 hematologic AEs include thrombocytopenia (75%), neutropenia (50%), leukopenia (37.5%), lymphopenia (25%), and anemia (25%). The most common G3/4 non-hematologic AEs included fatigue (25%) and upper respiratory tract infection (25%). The most common G1/2 AEs are fatigue (75%), dyspnea (62.5%), nausea (62.5%), anemia (50%), leukopenia (50%), and thrombocytopenia (50%). Response rates for all enrolled pts are 87.5% ≥MR, 75% ≥PR, 12.5% ≥VGPR. Responses occurred rapidly; after 1 cycle: 75% ≥MR, 63% ≥PR, 12.5% VGPR. As of the cut off date, 4 pts have progressed (after 1, 2, 4, and 4 months) and 4 pts remain on treatment (10+, 1+, 1+, and 1+ months); 1 pt did not respond and died due to progression of disease. Conclusions Although still very early, the combination of selinexor, CFZ, and DEX demonstrates encouraging activity with 75% PR or better and no unexpected toxicities in highly refractory MM pts, including those previously refractory to CFZ. Responses in pts refractory to very active CFZ combinations in the last line of therapy suggest that this regimen has the ability to overcome CFZ resistance. Disclosures Jakubowiak: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: The combination of Carfilzomib and Selinexor is being used for the treatment of Multiple Myeloma. Rosenbaum:Celgene: Speakers Bureau. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Rashal:Karyopharm Therapeutics Inc: Employment. Youssoufian:Karyopharm Therapeutics Inc: Employment. Henry:Karyopharm: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership.