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Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing cell death in cancer cells. SEL 80 mg and dexamethasone (dex) 20 mg, both twice weekly (BIW), received accelerated approval from the FDA for patients (pts) with relapsed refractory multiple myeloma (RRMM). SEL continues to be evaluated in earlier lines of therapy with once weekly administration and in combination regimens. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard BIW BOR/dex (Vd) in the phase III BOSTON study. The combination of lenalidomide (LEN) and dex (Rd) is an approved regimen in RRMM and newly diagnosed MM (NDMM) with an ORR of 70-76% in RRMM but a low complete response rate. SEL showed synergistic antitumor activity with LEN in a MM xenograft model. Therefore, we hypothesized that the all oral combination of weekly SEL with standard Rd (i.e., SRd) could improve the efficacy compared with Rd in pts with RRMM and NDMM with acceptable toxicity profile. Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose, the recommended phase 2 dose (RP2D), efficacy and safety of SRd in pts with RRMM or NDMM. For RRMM, SEL was dose escalated in two regimens QW (starting at SEL 80 mg) or BIW (starting at 60 mg), LEN 25 mg PO daily and DEX 20 mg BIW or 40 mg QW. Results: As of June 1, 2020, 24 pts (13 male, 11 female) with RRMM were enrolled. The median age was 67 years (range, 49-84) and the median number of prior lines of therapy was 1.5 (range, 1 - 8). In the 60 mg BIW dosing, 4 pts experienced dose limiting toxicities (DLTs) out of 5 pts dosed (2 thrombocytopenia, 1 anorexia, 1 >25% missed dose due to unrelated QT interval prolongation). In the 80 mg QW dosing, 2 pts experienced DLTs out of 6 pts (both grade 4 thrombocytopenia). In the 60 mg QW dosing, no DLTs were observed. Based on these data, the RP2D of SRd was determined to be: SEL 60 mg QW, LEN 25 mg QD and DEX 40 mg QW. Common treatment related adverse events (TRAEs) (All Grades, ≥3) were thrombocytopenia (71%, 63%), neutropenia (63%, 63%), nausea (58%, 4%), fatigue (54%, 17%), decreased appetite (50%, 8%), and weight loss (42%, 8%). Amongst the 20 pts with RRMM where efficacy was evaluable, previously treated/documented refractory rates were: bortezomib (100%, 45%), LEN (40%, 25%), daratumumab (20%, 20%), and pomalidomide (20%, 20%). Amongst the LEN naïve pts (n=12), the ORR was 92% including 1 stringent complete response [sCR], 4 very good partial responses [VGPR] and 6 partial responses [PR, 2 unconfirmed]). PFS in LEN naïve pts has not been reached with a median follow-up period of 7.8 months. In the pts with prior LEN treatment (n=8), the ORR was 13%. Based on the high levels of activity of SRd in LEN naïve pts, 8 pts (4 males and 4 females) with NDMM were enrolled at the RP2D. The median age was 74 (range: 51-86) years. No DLTs were observed in 5 DLT evaluable pts. Common TRAEs (All Grades, ≥3) were thrombocytopenia (63%, 38%), neutropenia (75%, 75%), fatigue (63%, 50%), nausea (50%, 0%), weight loss (63%, 0%), and decreased appetite (13%, 13%). All 7 efficacy evaluable pts achieved a response, an ORR of 100%, including 1 CR, 4 VGPR, and 2 PR. With a median follow-up of 10.2 months, median PFS has not been reached. Out of these 7 pts, three pts withdrew consent to transit to successful autologous stem cell collection and transplantation. Conclusions: The all oral combination of SRd with once weekly SEL 60 mg, LEN 25 mg QD and DEX 40 mg QW was established as the RP2D for pts with RRMM or NDMM. The safety profile was similar in both settings. All TRAEs were manageable with adequate supportive care and/or dose modification. The all oral combination of SRd has demonstrated ORR of 92% in pts with LEN naïve RRMM and ORR of 100% in pts with NDMM, warranting further investigation of SRd with or without additional anti-MM agents for the treatment of pts with NDMM. Disclosures White: Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; MediCom Myeloma CME: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria. Bahlis:Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Lentzsch:Celularity: Consultancy; Sorrento: Consultancy; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Chen:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Lipe:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Tuchman:Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding; Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Celgene: Honoraria; Sanofi: Research Funding; Amgen: Honoraria; Janssen: Honoraria. Sebag:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria; Takeda: Honoraria. Callander:Cellectar: Research Funding; University of Wisconsin: Current Employment. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Zhou:Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & 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. Schiller:Ariad: Research Funding; Actinium: Research Funding; Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Kaiser Permanente: Consultancy; Trovagene: Research Funding; Tolero: Research Funding; Sangamo: Research Funding; Samus: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; Astellas Pharma: Honoraria, Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Abbvie: Research Funding; Constellation: Research Funding; Ono Pharma: Consultancy; Novartis: Consultancy, Research Funding; Stemline: Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Forma: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding.

Aims: To evaluate AMG 701, a BiTE® molecule binding BCMA on MM cells and CD3 on T cells, in RR MM (Amgen, NCT03287908); primary objective was to evaluate safety and tolerability and estimate a biologically active dose; secondary objectives were to characterize pharmacokinetics (PK), anti-myeloma activity per IMWG criteria, and response duration. Methods: Patients with MM RR or intolerant to ≥3 lines [proteasome inhibitor (PI), IMiD, anti-CD38 Ab as available] received AMG 701 IV infusions weekly in 4-week cycles until disease progression (PD). A 0.8-mg step dose was added prior to target doses ≥1.2 mg to prevent severe cytokine release syndrome (CRS). Target dose was achieved by day 8 or sooner with earlier escalation. Exclusion criteria included: solely extramedullary disease; prior allogeneic stem cell transplant (SCT) in the past 6 months; prior autologous SCT in the past 90 days; CNS involvement; prior anti-BCMA therapy. The first 3 cohorts (dose 5-45 μg) had 1 patient each, the next cohorts (0.14-1.2 mg) had 3-4 patients each, and subsequent cohorts (1.6-12 mg) were to have 3-10 patients each. Minimal residual disease (MRD) was measured by next-generation sequencing (NGS, ≤10-5 per IMWG) or flow cytometry (≤3×10-5). Results: As of July 2, 2020, 75 patients received AMG 701. Patients had a median age of 63 years, a median time since diagnosis of 5.9 years, and a median (range) of 6 (1-25) prior lines of therapy; 27% of patients had extramedullary disease, 83% prior SCT, and 93% prior anti-CD38 Ab; 68% were triple refractory to a PI, an IMiD, and an anti-CD38 Ab. Median (Q1, Q3) treatment duration was 6.1 (3.1, 15.3) weeks and median follow-up on treatment was 1.7 (1.0, 3.7) months. Patients discontinued drug for PD (n=47), AEs (adverse events, n=4, 3 CRS, 1 CMV / PCP pneumonia), withdrew consent (4), other therapy (1), investigator discretion (1), and CNS disease (1); 17 patients remain on AMG 701. The most common hematological AEs were anemia (43%), neutropenia (23%), and thrombocytopenia (20%). The most common non-hematological AEs were CRS (61%), diarrhea (31%), fatigue (25%), and fever (25%). CRS was mostly grade 1 (n=19) or 2 (n=21) per Lee Blood 2014 criteria. All grade 3 CRS (n=5, 7%) were assessed as dose-limiting toxicities (DLTs); all were reversible with corticosteroids and tocilizumab, with median duration of 2 days. CRS grade 3 drivers included transient LFT increases in 3 patients and hypoxia in 2 patients. Other DLTs were 1 case each of transient grade 3 atrial fibrillation, transient grade 3 acidosis, and grade 4 thrombocytopenia. Serious AEs (n=29, 39%) included infections (13), CRS (7), and asymptomatic pancreatic enzyme rise (2, no imaging changes, 1 treatment related). There were 4 deaths from AEs, none related to AMG 701 (2 cases of sepsis, 1 of retroperitoneal bleeding, and 1 of subdural hematoma). Reversible treatment-related neurotoxicity was seen in 6 patients, with median duration of 1 day, all grade 1-2, and associated with CRS in 4 patients. The response rate was 36% (16/45) at doses of 3-12 mg; at ≤1.6 mg (n=27), there was 1 response at 0.8 mg in a patient with low baseline soluble BCMA (sBCMA). With earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs), with 4/5 responders being triple refractory and 1 DLT of grade 3 CRS in this group. Across the study, responses included 4 stringent CRs (3 MRD-negative, 1 not yet tested), 1 MRD-negative CR, 6 VGPRs, and 6 PRs (Table). Median (Q1, Q3) time to response was 1.0 (1.0, 1.9) month, time to best response was 2.8 (1.0, 3.7) months, and response duration was 3.8 (1.9, 7.4) months, with maximum duration of 23 months; responses were ongoing at last assessment in 14/17 patients (Figure). MRD was tested in 4 patients (3 sCR, 1 CR) and all were negative (3 by NGS, 1 by flow); MRD negativity was ongoing at last observations up to 20 months later. AMG 701 exhibited a favorable PK profile in its target patient population of RR MM, with AMG 701 exposures increasing in a dose-related manner. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures; at higher doses, encouraging preliminary responses were seen even at the higher end of baseline sBCMA values. Summary: In this FIH study with ongoing dose escalation, AMG 701, an anti-BCMA BiTE® molecule, demonstrated a manageable safety profile, encouraging activity, and a favorable PK profile in patients with heavily pre-treated RR MM, supporting further evaluation of AMG 701. Disclosures Harrison: Janssen: Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; Haemalogix: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria. Minnema:Amgen: Honoraria; Servier: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding; Janssen Cilag: Honoraria. Lee:Celgene: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding. Spencer:AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria; Takeda: Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria; Pharmamar: Research Funding. Kapoor:Cellectar: Consultancy; Amgen: Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Madduri:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria. Larsen:Janssen Oncology: 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. Ailawadhi:Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Amgen: Research Funding; Takeda: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding. Kaufman:Amgen: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Raab:Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Iida:AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Davies:Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lesley:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Upreti:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Yang:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Sharma:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Minella:Amgen Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Beam Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lentzsch:Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Magenta: Current equity holder in private company; Sanofi: Research Funding; Karyopharm: Research Funding; Celularity: Consultancy; Sorrento: Consultancy. OffLabel Disclosure: AMG 701, a half-life extended BiTE® (bispecific T-cell engager) molecule is an investigational agent for multiple myeloma.

Background: Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd) in the phase III BOSTON study. Pomalidomide (POM) plus dex (Pd) achieved an ORR of 31% and PFS of 4 months in patients (pts) with disease refractory to BOR and lenalidomide (LEN). We hypothesize that the all oral Pd combination with the addition of QW SEL (SPd) would demonstrate improved activity and acceptable tolerability as compared with Pd. Methods: STOMP is a multicenter, open-label, phase 1b/2, dose escalation study with an expansion phase. Pts with RRMM who received ≥ 2 prior therapies including LEN and a proteasome inhibitor (in separate or the same regimens) were eligible for enrollment. Oral SEL was evaluated in 2 different dosing schedules in 28 days cycle: QW 60, 80 or 100 mg or twice weekly (BIW) 60 or 80 mg, with escalating doses of POM 2, 3 or 4 mg (days 1-21), and dex 20 mg BIW or 40 mg QW. The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, ORR and PFS of the combination of SPd in pts with RRMM. Results: As of June 1 2020, 52 pts (28 male and 24 female) were enrolled. The median age was 64 (range: 43-85) years. Pts received a median of 3 (range: 1-10) prior therapies including 44 (84.6%) with autologous stem cell transplantation. During the escalation phase, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (All Grades, Grades ≥3) neutropenia (62%, 56%), anemia (60%, 37%), and thrombocytopenia (56%, 35%). Common non-hematologic TRAE included nausea (62%, 2%), fatigue (56%, 12%), decreased appetite (48%, 2%), weight loss (42%, 0%), diarrhea (35%, 0%), vomiting (23%, 2%). Rates of ≥ Grade 3 hematological TRAEs were lower in QW vs BIW schedules of SEL: thrombocytopenia (29% vs 44%) and anemia (32% vs 44%). Based on all of the safety data, the RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), and DEX 40 mg QW. Out of 52 pts, 47 were evaluable for response. Previously treated / refractory rates were as follows (N=47 pts evaluable for efficacy): LEN (100% / 96%), BOR (94%, 45%), carfilzomib (38%, 34%), POM (30%, 30%), daratumumab (21%, 21%). Among POM naïve pts (N=33), all pts (100%) received prior LEN and 31 pts (94%) had MM documented LEN refractory. Among pts who were POM naive (N=33), the ORR was 58% (1 CR, 5 very good partial responses and 13 partial responses) and the median PFS and OS were 12.3 and 19.0 months, respectively. Amongst pts who received POM previously (N=14), the ORR was 36% (1 VGPR and 4 PR), and the median PFS and OS were 8.8 and 8.0 months, respectively. Conclusions: The RP2D is SEL 60 mg QW, POM 4 mg QD and dex 40 mg QW. The ORR was 58% in pts in LEN treated or refractory and POM naïve MM compared to previously published data of 31% ORR with Pd in a similar population. The median PFS on SPd of 12.3 months in POM naïve pts is longer than that historically observed with Pd (~4 months). All TRAEs were expected and manageable with appropriate supportive care (eg, G-CSF) and/or dose modifications. The all oral SPd combination appears to confer relatively high ORR with good durability and promising PFS in pts with heavily pretreated MM. Disclosures Chen: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. Tuchman:Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding. Lipe:Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Baljevic:Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; MediCom Myeloma CME: Honoraria; NCCN Hematologic Malignancies Congress: Honoraria. Kotb:Celgene: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Amgen: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. LeBlanc:Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schiller:Kite Pharma: Research Funding; Ariad: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; DeltaFly: Research Funding; MedImmune: Research Funding; Stemline: Speakers Bureau; Actinium: Research Funding; Abbvie: Research Funding; Jazz Pharmaceuticals: Research Funding; Forma: Research Funding; Novartis: Consultancy, Research Funding; Cyclacel: Research Funding; AstraZeneca: Consultancy; Mateon: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Gamida: Research Funding; FujiFilm: Research Funding; Geron: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Constellation: Research Funding; Genentech-Roche: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Deciphera: Research Funding. Lentzsch:Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sorrento: Consultancy; Celularity: Consultancy; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Wang:Karyopharm: Current Employment; Curis: Ended employment in the past 24 months. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & 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. White:Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins that cause cell cycle arrest and apoptosis in cancer cells. The combination of SEL with dexamethasone (dex), each administered twice weekly (BIW), received accelerated approval from the FDA in relapsed refractory multiple myeloma (RRMM). Subsequent evaluations of combination regimens have utilized once weekly (QW) SEL. The addition of oral SEL 100 mg QW to bortezomib also QW with dex (SVd) showed superior PFS and ORR with reduced peripheral neuropathy compared with standard BIW bortezomib plus dex (Dimopoulos et al. JCO 2020). SEL sensitized the activity of carfilzomib (CAR) in PI-resistant MM cell lines in vitro and ex vivo in PI-refractory MM cells derived from bone marrow aspirates of patients (pts) with RRMM. SEL and CAR also showed synergistic anti-tumor activity in a NOD-SCID mice xenograft model in vivo. Furthermore, a phase I trial in RRMM pts demonstrated that the combination of SEL and CAR both administered BIW with DEX showed high overall response rates (ORR) in pts with MM refractory to CAR. Carfilzomib QW was recently approved and we hypothesized that the addition of SEL QW to CAR QW plus dex (SKd) would be synergistic and convenient with an acceptable adverse event (AE) profile. Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the ORR according to the International Myeloma Working Group (IMWG) criteria. The starting SEL dose was 100 mg QW with 20/56 mg/m2 QW CAR (20 mg/m2 only on C1D1 and 56 mg/m2 thereafter, dosed Day 1, 8, and 15, 28 days cycle) with 40 mg QW DEX (Table 1). Eligible pts had MM progressing on study entry that was not refractory to CAR, were ≥ 18 years old, with Eastern Cooperative Oncology Group (ECOG) score of 0-2, WBC ≥ 1,500/mm3,Hb ≥ 8.0 g/dL, and platelet count ≥ 75,000/mm3. Results: The MTD was 20/56 mg/m2 CAR + 80 mg SEL + 40 mg DEX, all given QW. As of May 1, 2020, a total of 24 pts enrolled, of which 17 received the MTD. Median age was 70.5 (range, 50-76) years, 62.5% male, median number of prior therapies 3 (range, 1-8). Median years from initial diagnosis 5.0 (range, 2.7-11.3) years. Prior therapies in the 24 pts included bortezomib 24 pts (100%), lenalidomide 23 pts (95.8%), pomalidomide 15 pts (62.5%), daratumumab 14 pts (58.3%) and 19 (79.2%) stem cell transplantation. Common hematopoietic treatment-related AEs (TRAEs) were thrombocytopenia (70.8% all grades, 54.2% grades 3/4) and anemia (54.2%, 20.8%). Common non-hematological TRAEs were nausea (66.7%, 0%), fatigue (54.2%, 8.3%), anorexia (45.8%, 4.2%), weight loss (37.5%, 0%), and dysgeusia (37.5%, 0%). All TRAEs were expected and manageable with appropriate supportive care (eg, TPO receptor agonists for thrombocytopenia) and/or dose modifications; long term cumulative toxicities have not been observed. ORR was 75.0% including 4 CR (16.7%), 7 VGPR (29.2%) and 7 PR (29.2%). There was 1 MR yielding a clinical benefit rate of 79.2%. Amongst the 14 pts previously treated with daratumumab, 8 pts (57.1%) achieved ≥PR, 9 pts (64.3%) achieved ≥MR. Median time to the first response (≥PR) was 28 days (range, 27-98 days). Median progression free survival has not been reached with a median follow-up of 4.4 months. Conclusions: Weekly SKd (20/56 mg/m2 CAR + 80 mg SEL QW + 40 mg DEX QW) is active with an ORR of 75.0% and deep responses (CR 16.7%, VGPR 29.2%) in pts who had a median of 3 prior lines of therapy including bortezomib and lenalidomide. The ORR of 57.1% in patients previously treated with daratumumab warrants further investigation of this once weekly regimen in 1st or 2nd relapse including among patients with prior daratumumab. Disclosures Lipe: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Tuchman:Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding; Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Lentzsch:Sanofi: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Celularity: Consultancy; Sorrento: Consultancy; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Exelixis: Research Funding; MediCom Myeloma CME: Honoraria. Rossi:BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. White:Sanofi: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Chen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Research Funding. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Schiller:MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding.

Introduction Multiple myeloma (MM) bone disease remains one of the most devastating complications of this incurable cancer, causing bone fractures, pain, mobility issues and neurological deficits. MM cells produce osteoclast-activating factors that induce osteoclast activation, thereby leading to excessive bone resorption and lytic bone lesions1. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor that is highly secreted by MM cells. MMP-13 induces osteoclast fusion and bone-resorption via a mechanism independent of its proteolytic activity2. We recently reported that MMP-13 binds to checkpoint inhibitor programmed death-1 homolog (PD-1H/VISTA), a surface receptor that is expressed in osteoclasts at high levels3. Binding of MMP-13 to PD-1H/VISTA induces osteoclast fusion and bone resorption activity whereas knockdown or knockout of PD-1H/VISTA largely block MMP-13 mediated effects on osteoclasts3. However, the function of PD-1H inMM bone disease in vitro or in vivo has not been previously defined. Methods and Results To confirm the role of PD-1H in MMP-13 induced bone disease in MM, we first conducted MM-osteoclast trans-well co-culture assay using murine MM cell line, 5TGM1 cells, and bone marrow mononuclear cells from Pd-1h-/- or wild type (WT) mice. 5TGM1 control cells or MMP-13 knockdown 5TGM1 cells were seeded in the upper wells of the transwell plates; while WT or Pd-1h-/- bone marrow mononuclear cells were seeded in the lower wells and cultured for osteoclast differentiation assessed by TRAP staining. Results show that 5TGM1 induced differentiation of WT osteoclasts with significantly increased osteoclast size and nuclei number/osteoclast. Consistent with our previous results2, MMP-13 knockdown blocked the 5TGM1 MM cells-induced activation of WT osteoclasts. In contrast, neither 5TGM1 MM cells nor MMP-13 knockdown cells had significant effects on Pd-1h-/- osteoclasts. Hence, knockout of Pd-1h abrogated MMP-13 mediated MM induction of osteoclasts, indicating that MMP-13/PD-1H interactions are critically involved in MM-induced osteoclast activation. The in vivo role of PD-1H in MM bone disease was investigated using the intratibial 5TGM1 Rag2-/- MM bone disease mice model2. For this purpose, Pd-1h-/-Rag2-/- mice were generated by crossbreeding C57BL/6 Pd-1h-/- with C57BL/6 Rag2-/- mice. 3x105 firefly luciferase expressing 5TGM1 cells (5TGM1-luc) were intratibially injected into age and sex-paired Rag2-/- or Pd-1h-/-Rag2-/- mice (N=5). Tumor progression was monitored by weekly bioluminescence imaging (BLI). 3 weeks after tumor inoculation, tibiae were harvested for quantitative micro-CT, followed by histological analysis. Histological staining showed that intratibial injection of 5TGM1-luc MM cells induced extensive lytic lesions and trabecular bone loss in Rag2-/- mice. In contrast, in Pd-1h-/-Rag2-/- mice,the bone structure was maintained with markedly less bone loss. Morphological analyses of trabecular bone across proximal tibiae further indicated that in Rag2-/- mice, 5TGM1 induced significant changes in bone microarchitecture, with decreased bone volume fraction (bone volume/tissue volume), connective density, trabecular bone numbers, and trabecular bone thickness, as well as increased trabecular bone spacing (Table 1). In contrast, in Pd-1h-/-Rag2-/- mice, 5TGM1 failed to induce significant loss of trabecular bone, confirming the critical role of PD-1H in MM induced bone disease in vivo. Conclusions Taken together, our study, for the first time, reveal that checkpoint inhibitor PD-1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13-induced osteoclast fusion, activation and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/-mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD-1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment. References 1. Marino S, Petrusca DN, Roodman GD. Br J Pharmacol. 2019;10.1111/bph.14889. 2. Fu J, Li S, Feng R, et al. J Clin Invest. 2016;126(5):1759-1772. 3. Fu J, Li S, Yang C, et al. Blood. 2019; 134 (Supplement_1): 3072. Disclosures Lentzsch: Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Celularity: Consultancy, Other; Magenta: Current equity holder in private company; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months.

Advanced AL amyloidosis has a very poor prognosis with a high risk of early mortality due to persistent organ dysfunction caused by insoluble amyloid fibril deposits. To improve patient outcomes, t...

AL Amyloidosis (AL) is a plasma cell disease marked by production and deposition of toxic free light chains in organs including the heart, kidney and nervous system. While treatment is generally borrowed from multiple myeloma (MM), patients typically have difficulty tolerating many of these drugs, namely the immunomodulatory drugs (IMiDs), due to high cardiac and hematologic toxicities. Recently daratumumab has been shown to be active in (AL), however for patients who become refractory to daratumumab, options remain bleak. Given the relative prevalence of t(11;14) in patients with AL, and subsequent overexpression of BCL-2, we report two cases of deep and durable responses to treatment with venetoclax in combination with a proteasome inhibitor. Recently the FDA has put a hold on studying venetoclax in MM given the results of the BELLINI trial (NCT02755597) examining the efficacy of venetoclax in MM. Preliminary results indicate an increased rate of death in the venetoclax arm when compared to placebo, largely due to infection. We hope that with proper infectious prophylaxis we can abrogate the perceived increased rate of death and the hold on venetoclax can be lifted. Given the high quality and durable responses seen in these cases we believe venetoclax warrants further study in AL.

Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.

Transcription factors (TFs) are convergence points of signaling cascades that coordinate cell differentiation, proliferation, survival, and migration; and are commonly deregulated in solid and hematologic malignancies, including multiple myeloma (MM). Several recent studies indicate that the inhibition of TFs may lead to selective tumor cell death with little or no consequences for normal cells due to redundancy in signaling pathways. Nuclear hormone receptor (NHR)- TFs belong to the most common therapies in oncology today. In contrast, non-NHR-TFs have been considered 'un- druggable' until most recently.This review article summarizes advances of our knowledge on the complex composition of non-NHR-TFs and their binding to cognate DNA sequences that are propelling the development of novel strategies in MM.Protein-protein and protein-DNA- binding inhibitors, proteolysis- targeting chimeric molecules, and chromatin remodeling/epigenetic reader inhibitors are among the most promising novel compounds with a potentially high therapeutic index; they are likely to once more advance MM treatment strategies and improve patient outcome in the near future.

Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

8038 Background: Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins (TSPs), is associated with poor prognosis in MM, and contributes to proteasome inhibitor (PI) and immunomodulatory drug (IMiD) resistance. Selinexor (SEL) is a novel, oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing the nuclear retention and activation of TSPs. SEL in combination with low dose dexamethasone (dex) ± bortezomib (BOR) is FDA approved for previously treated MM. The synergy of SEL with the PI BOR has been confirmed in the phase 3 BOSTON study in MM patients (pts) with 1-3 prior therapies; once weekly (QW) SEL, QW BOR, and dex (XVd) significantly increased progression-free survival (PFS), time to next therapy, and overall response rate (ORR) as compared to standard twice weekly BOR/dex (Vd), despite XVd using 40% less BOR and 25% less dex than standard Vd. We hypothesized that the addition of QW SEL to the PI carfilzomib (CAR)-dex (XKd) would be an active and tolerable regimen in pts with heavily pretreated MM. Methods: In the XKd arm of the multi-arm Phase 1b/2 STOMP study, SEL at 80 or 100 mg QW was evaluated in combination with CAR at 56 or 70 mg/m2 QW plus dex at 40 mg QW in pts with heavily pretreated MM not refractory to CAR. Study objectives were to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) and assess the safety and activity of the XKd regimen. Results: As of 4Jan2021, 27 pts were enrolled: 18 (67%) were male, median age 71 years (range 50-76), and median of 4 (range 1-8) prior lines of therapy. All 27 pts were previously treated with BOR, 26 (96%) lenalidomide (LEN), 19 (70%) pomalidomide (POM), 18 (67%) daratumumab (dara). The majority (67%) of pts were triple-class pretreated (PI, IMiD, and anti-CD38 mAb), and 44% had triple-class refractory MM. Nine pts (33%) had MM quad-refractory to BOR, LEN, POM, and dara. Common hematologic treatment-related adverse events (TRAEs) (total, grade ≥3) included thrombocytopenia (74%, 56%), anemia (59%, 19%), and neutropenia (30%, 7%). Non-hematologic TRAEs included nausea (67%, 4%), fatigue (52%, 7%), and anorexia (52%, 4%). RP2D was identified as SEL 80 mg QW, CAR 56 mg/m2 QW, and dex 40 mg QW. As of 3Feb2021, ORR was 78% (21/27) with 5 pts reaching CR (19%), 8 VGPR (30%), and 8 PR (30%). Median PFS was 23.7 months. Among 18 pts pretreated with dara, ORR was 67% and median PFS 23.7 months. In 9 pts whose MM was refractory to BOR, LEN, POM, and dara, ORR was 67% with 4 VGPR (44%). Conclusions: In pts with heavily pretreated MM, weekly XKd is highly active with an ORR of 78% and deep responses (≥VGPR 48%) with an overall PFS of 23 months. All AEs including grade 3/4 thrombocytopenia can be managed with appropriate supportive care and dose modifications. These data support further investigation of XKd in pts with previously treated MM including those previously treated with dara.

8018 Background: Exportin 1 (XPO1) mediates the nuclear export and functional inactivation of tumor suppressor proteins (TSPs), is associated with poor prognosis in MM, and contributes to proteasome inhibitor (PI) and immunomodulatory drug (IMiD) resistance. Selinexor (SEL) is a novel, oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, forcing the nuclear retention and activation of TSPs. SEL is approved with low-dose dexamethasone (dex) ± bortezomib (BOR) for patients (pts) with previously treated MM. In the Phase 3 BOSTON study, once weekly (QW) SEL, QW BOR, and dex (XVd) significantly increased progression-free survival (PFS) and overall response rate (ORR) with marked reduction of peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd), despite XVd utilizing 40% less BOR and 25% less dex than Vd. Pomalidomide (POM) plus dex (Pd) has an ORR of 31% and median PFS (mPFS) of 4 months in MM pts refractory to BOR and lenalidomide (LEN). We hypothesized that the addition of once weekly SEL to Pd (XPd) would be an active, all-oral combination with an acceptable safety profile in pts with LEN refractory and BOR treated MM. Methods: In the SPd arm of the multi-arm Phase 1b/2 STOMP study, SEL was evaluated at 60, 80, or 100 mg QW or 60 or 80 mg twice weekly in combination with Pd. Study objectives were to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D), and assess the safety and activity of the SPd regimen including in pts receiving the RP2D. Results: As of 4 Jan 2021, 65 pts (33 male) were enrolled with median age of 64 years (range 37-85 years) and median of 3 (range 1-10) prior lines of therapy. Previously treated/refractory rates were LEN 100%/85%, BOR 92%/49%, carfilzomib 43%/37%, POM 31%/29%, and daratumumab (dara) 26%/26%. RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), dex 40 mg QW. Common hematologic, treatment-related adverse events (TRAEs) included (all grades, grades ≥3) neutropenia (63%, 55%), anemia (58%, 32%), and thrombocytopenia (54%, 31%). Non-hematologic TRAEs included nausea (62%, 2%), fatigue (55%, 11%), and decreased appetite (45%, 2%). Among POM naïve or nonrefractory MM pts (N = 44), ORR was 57% (1 sCR, 1 CR, 8 VGPR, 15 PR); mPFS was 12.2 months. In pts treated with RP2D (N = 20), ORR was 65% (1 sCR, 5 VGPR, 7 PR); mPFS was not reached with a median follow-up time of 3.9 months. In POM-refractory pts and those with prior dara, ORR was 44% (7/16) and 60% (9/15), respectively. Conclusions: SEL, once weekly, can be safely combined with Pd in pts with heavily pretreated MM. No new safety signals were identified. The all-oral combination of XPd is highly active with an ORR of 65% at RP2D (compared to expected ORR ≤30% for Pd) and produces durable responses with a mPFS of 12.2 months overall. These data support a planned Phase 3 study with an all-oral combination of XPd vs Pd in pts who have been previously treated with LEN, a PI, and an anti-CD38 mAb. Clinical trial information: NCT02343042.

8027 Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS ( RASmut) occur in up to 50% of MM and portend poor survival and high recurrence rates. MM cells with RASmut are susceptible to inhibition of germinal center kinase (GCK), resulting in IKAROS degradation independent of cereblon (CRBN). Selinexor is a selective inhibitor of nuclear export (SINE) compound that can induce IKAROS degradation through CRBN-independent pathways to overcome immunomodulatory drug resistance. We explored the benefit of selinexor treatment for pts with RASmut MM. Methods: In the randomized BOSTON study, pts with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study pts with penta-treated, triple class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 pts from BOSTON and STORM, respectively. Pts were considered RASmut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61. Results: There were 54 pts (45%) with RASmut in BOSTON (XVd = 26, Vd = 28), and 17 (33%) in STORM. In BOSTON, pts with RASmut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med] = 12.9 vs 6.7 months [mo], hazard ratio [HR] = 0.48 [95% CI 0.24-0.97], p = 0.039). For pts treated with Vd, those with RASmut had significantly shorter overall survival (OS) compared to RASwild-type (WT) (med = 16.8 mo vs not reached [NR], HR = 2.87 [95% CI 1.03-7.99], p = 0.035). PFS was not significantly different (med = 6.74 vs 9.82 mo, HR = 1.64 [95% CI 0.88-3.07], p = 0.122). Amongst pts on XVd, there was no difference in survival between RASmut and RASWT pts (PFS: med = 12.8 vs 12.9 mo, HR = 1.08 [95% CI 0.52-2.26], p = 0.83; OS: med = NR vs NR, HR = 0.94 [95% CI 0.36-2.45], p = 0.91). In STORM, pts with RASmut had shorter OS compared to RASwt pts (med = 6.1 vs NR, HR = 2.05 [95% CI 1.22-5.19], p = 0.010). Preliminary studies to explore the mechanisms of action related to RASmut MM sensitivity to XVd demonstrated that selinexor treatment in vitro leads to downregulation of GCK. Conclusions: Despite typically having the worst outcomes, pts with RASmut MM had a similar benefit from XVd as RASWT MM, showing that the XVd combination can overcome RASmut. Mechanistically, selinexor induced down regulation of GCK and enhanced killing of RASmut MM cells. With a manageable safety profile, the XVd regimen could provide a viable treatment option to improve survival of pts with MM with RAS mutations. Clinical trial information: NCT03110562. [Table: see text]

Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS.

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty-eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P 1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P

Domino liver transplantation, in which the liver of a patient with transthyretin-mediated amyloidosis is transplanted into another patient, has been an established procedure performed at several centers across the world. The risk of developing systemic amyloidosis in transthyretin-mediated amyloidosis liver transplant recipients is a topic of ongoing investigation. We report a case of rapidly progressive transthyretin amyloidosis in a patient who received a liver from a donor with a rare Ser23Asn mutation. We advise exercising caution when considering domino liver transplantation in patients with this particular mutation.

Introduction: RAS oncogenes are the most frequently mutated gene family in human cancers. 50% of newly diagnosed multiple myeloma patients carry a RAS/MAPK pathway mutation, with a rising percentage in the relapsed situation1. Thus, targeting RAS mutations in multiple myeloma will increase therapeutic efficiency and potentially overcome drug-resistance. Unfortunately, RAS mutations have been considered "undruggable" due to a lack of traditional small molecule binding pockets on the proteins. Therefore, key component in the RAS/MAPK pathway may represent an alternative therapeutic target for MM. Germinal center kinase (GCK), also named mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), is an upstream activator in the MAPK pathway. Indeed, we recently discovered the critical role of GCK in RAS mutated (RASmut) MM cell survival and growth. GCK knockdown in RASmut MM cells induced MM cell growth inhibition both in vitro and in vivo. However, the detailed mechanism is yet to be defined. Methods and Results: Our previous data showed that GCK knockdown induces MM cell growth inhibition, associated with the blockage of MKK4/7-JNK phosphorylation and the downregulation of critical transcriptional factors (TFs) including IKZF1/3, BCL-6, and c-MYC proteins. To confirm that GCK knockdown downregulates IKZF1/3 etc at protein level but not mRNA level, we conducted real-time PCR on GCK knockdown MM cells and compared the expression of GCK and TFs to the empty vector (EV) infected MM cells. Results showed that shRNA induced GCK silencing only led to the significantly decreased GCK mRNA, however, did not affect IKZF1 and c-MYC expressions at mRNA level. Consistent with the effects of GCK knockdown, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 proteins, inhibited MM cell proliferation and induced cell apoptosis. IKZF1/3 are the key targets of the immunomodulatory drugs (IMiDs), which are the backbone of MM therapy. IMiDs bind to cereblon (CRBN) and induce IKZF1/3 protein degradation, which subsequently lead to MM cell growth inhibition. Importantly, our data showed that IMiDs-resistant RPMI-8226 MM cells have high expression of GCK. GCK knockdown and inhibition induced IKZF1 downregulation, triggered growth inhibition and cell apoptosis in RPMI-8226 cells, suggesting that GCK regulates IKZF1 degradation via a CRBN-independent mechanism. To confirm this hypothesis, we silenced CRBN in N-Rasmut H929 MM cells by shRNA lentiviral infection and examined the response to IMiDs and GCK inhibitor. CRBN knockdown was confirmed by western blotting. CRBN silencing in H929 cells resulted in lenalidomide (LEN) resistance, evidenced by the WTS proliferation assay. In contrast, CRBN silencing failed to rescue N-Rasmut H929 MM cells from TL4-12 induced proliferation inhibition and IKZF1 downregulation, confirming that GCK regulated IKZF1 and cell growth is independent of CRBN. Conclusion: Taken together, our data demonstrated that GCK inhibition induces cell growth inhibition and triggers apoptosis especially in RASmut MM cells. Importantly, GCK inhibitor downregulates IKZF1 via a CRBN-independent mechanism. Our findings thus provide a rationale for the clinical evaluation of targeting GCK in RASmut MM patients and further mechanistic insight into the role of GCK in MM tumorigenesis as well as drug resistance. GCK inhibitors may represent a novel therapy for the treatment of RASmut MM patients, especially those who are resistant to IMiDs as well as with refractory or relapsed MM. References Walker, B.A., et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol33, 3911-3920 (2015). Disclosures Marcireau: Sanofi: Current Employment. Lentzsch:Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Consultancy; Sorrento: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celularity: Consultancy; Magenta: Current equity holder in private company; Sanofi: Research Funding.

8530 Background: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with refractory MM. We hypothesize that once weekly (QW) SKd may be an active well tolerated regimen and evaluated this combination in a dose escalation/expansion study. Methods: STOMP is a phase 1b/2 study evaluating various doses and enrolled pts with carfilzomib naive relapsed MM. Oral selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (on days 1, 8 and 15 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), as well as explore the efficacy and safety of SKd. Results: As of January 2020, 18 pts were enrolled. Median age was 71 years (range: 50-76). Median number of prior regimens was 4 (range: 1-8). All pts (n = 18) were previously treated with bortezomib and lenalidomide, and 50% and 56% pts were refractory to bortezomib and lenalidomide respectively. Nine (50%) pts received prior pomalidomide treatment and 8 (44%) pts were refractory. Eleven (61%) pts received prior daratumumab treatment and 9 (50%) were refractory. The MTD was selinexor 80 mg QW, carfilzomib 56 mg/m2 QW and dexamethasone 40 mg QW. The ORR and CBR were 72% and 79% respectively with 4 complete responses, 7 very good partial responses, 2 partial responses, and 1 minimal response. Stable disease was observed in 3 pts. With a median follow-up period of 4.7 (1.8-16.3) months, median progression-free survival has not been reached. Common treatment-related adverse events (total, Grade ≥3) were thrombocytopenia (83.3%, 66.7%), nausea (66.7%, 0%), anemia (55.6%, 11.1%), fatigue (50%, 11.1%), anorexia (44%, 5.6%), weight loss (44%, 0%), and neutropenia (33.3%, 11.1%). Conclusions: Once weekly SKd demonstrated an encouraging ORR of 72% in pts with a median of 4 lines of prior therapy. The majority of responses are deep and predominantly CR and VGPR. The combination is well tolerated with no new safety signal, no Grade ≥3 nausea, vomiting, diarrhea, weight loss or anorexia. The side effects are a function of the dose and schedule and can be managed with dose modification and supportive care. Enrolment is ongoing and supports a phase 3 study of SKd. Clinical trial information: NCT02343042 .

8510 Background: Selinexor is a first-in-class oral Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates exportin 1 (XPO1). Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with relapsed/refractory MM (RRMM). Single agent daratumumab has demonstrated an ORR of 29% in MM reftactory to proteasome inhibitors (PIs)/immunomodulatory drug (IMiDs). We evaluated the safety, tolerability and preliminary efficacy of the combination of Sel-dex and daratumumab (SDd) in pts with MM refractory to PIs/IMiDs. Methods: This is a multicenter, open-label, phase 1b/2 dose escalation and expansion study. Pts were eligible if they had received ≥ 3 prior lines of therapy, including a PI and an IMiD, or whose MM was refractory to a PI and an IMiD. In the expansion phase, pts were required to be anti-CD38 monoclonal antibody-naïve. One dose level was tested at each schedule: selinexor once-weekly (QW at 100 mg) or twice-weekly (BIW at 60 mg) with dexamethasone 40 mg. Daratumumab 16 mg/kg IV was administered per label. Primary objective was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), and assess safety, tolerability and efficacy of SDd in pts with RRMM. Results: A total of 34 pts were enrolled; 3 in the 60 mg BIW and 31 in the 100 mg QW cohorts. Median age was 69 and median number of prior treatment regimens was 3 (range, 1–10). Out of 34 pts, 62% and 65% were refractory to bortezomib and lenalidomide respectively. Common treatment related adverse events (all grades, grades 3/4) included: thrombocytopenia (71%, 47%), fatigue (62%, 18%), nausea (71%, 9%), anemia (62%, 32%) and neutropenia (50%, 26%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: Grade 3 thrombocytopenia and Grade 2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort (n = 6), no DLTs occured. 32 patients were evaluable for efficacy. The ORR was 73% (11 VGPR, 11 PR) for 30 daratumumab-naïve pts. Median progression-free survival was 12.5 months in both groups. Conclusions: Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dexamethasone 40 mg, administered QW. In pts with PI and IMiD refractory MM, weekly SDd demonstrated promising activity with an ORR of 73% in daratumumab-naïve pts and a median PFS of 12.5 months. This supports further development of a novel non-PI, non-IMiD backbone in earlier lines of therapy. Clinical trial information: NCT02343042 .

In a 2008 paper, Dispenzieri and colleagues at the Mayo Clinic proposed a risk stratification system for patients with smoldering multiple myeloma (SMM) based on the presence of three risk factors: serum M-protein ≥3 g/dL, bone marrow plasma cell percentage ≥10%, and a free light chain (FLC) ratio (κ to λ) of either ≤0.125 or ≥8. The patient in this vignette has all three risk factors, classifying him as high-risk, with an associated median time to progression (TTP) of 1.9 years. This is significantly worse than a patient with intermediate-risk (median TTP 5.1 years) or low-risk (10 years) disease.

Whole Body Low Dose CT (WBLDCT) has important advantages as a first-line imaging modality for bone disease assessment in patients with plasma cell disorders and has been included in the 2014 International Myeloma Working Group (IMWG) criteria for multiple myeloma (MM) definition. Nevertheless, standardization guidelines for the optimal use of WBLDCT in MM patients are still lacking, preventing its more widespread use, both in daily practice and clinical trials. The aim of this report by the Bone Group of the IMWG is to provide practical recommendations for the acquisition, interpretation and reporting of WBLDCT in patients with multiple myeloma and other plasma cell disorders.

TO THE EDITOR: Advances in therapy for rare diseases are causes for celebration because they are uncommon events. Conversely, decisions to close large-scale clinical trials testing promising therapies for rare diseases can cause disappointment.[1][1] NEOD001, a monoclonal antibody (mAb) targeting

Background: Bisphosphonates reduce skeletal-related events (SREs) in patients with multiple myeloma (MM) and, in some studies, improved survival. Since 2011, bisphosphonate use has been recommended by NCCN for all patients with newly diagnosed MM receiving antineoplastic therapy independent of the presence of bone disease. This study investigated their use after these guidelines were established. Methods: We identified patients aged ≥65 years in the SEER-Medicare database with newly diagnosed MM between January 1, 2012, and December 31, 2013, who received antineoplastic therapy, had ≥6 months of follow-up, and did not receive prior bisphosphonates. Presence of SREs at diagnosis was identified, including pathologic fracture, spinal cord compression, radiation to bone, or surgery to bone. Use of bisphosphonates was defined as having ≥1 claim for an intravenous or oral bisphosphonate within 6 months after the start of antineoplastic therapy. We used multivariable modeling to compare users with nonusers, controlling for demographic and clinical covariates. We compared overall survival between users and nonusers using proportional hazards analysis. Results: Of 1,309 patients identified, 720 (55%) used a bisphosphonate. Factors associated with use included SRE at diagnosis (adjusted odds ratio [AOR], 2.60; 95% CI, 1.98-3.40), hypercalcemia (AOR, 1.74; 95% CI, 1.26-2.41), and use of proteasome inhibitor + immunomodulatory imide therapy (AOR, 1.70; 95% CI, 1.21-2.39). Chronic kidney disease (AOR, 0.48; 95% CI, 0.35-0.66) was associated with decreased use. Bisphosphonate use was associated with reduced mortality (hazard ratio, 0.70; 95% CI, 0.56-0.88). Conclusions: Although bisphosphonate use is recommended for all patients with newly diagnosed MM receiving antineoplastic therapy, 45% of patients in the United States did not receive this guideline-recommended care.

Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow-up is presented. After 19.4 (range: 0 to 27.7) months of median follow-up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P 12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow-up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse.

Patients with relapsed or refractory AL amyloidosis have limited treatment options. Bendamustine, a bifunctional alkylating agent has shown potential in treating multiple myeloma, chronic lymphocyt...

This phase 1/2 study was the first to evaluate the safety and efficacy of the cyclin-dependent kinase (CDK) 4/6-specific inhibitor palbociclib (PD-0332991) in sequential combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. The recommended phase 2 dose was palbociclib 100 mg orally once daily on days 1-12 of a 21-day cycle with bortezomib 1.0 mg/m2 (intravenous) and dexamethasone 20 mg (orally 30 min pre-bortezomib dosing) on days 8 and 11 (early G1 arrest) and days 15 and 18 (cell cycle resumed). Dose-limiting toxicities were primarily cytopenias; most other treatment-related adverse events were grade≤3. At a bortezomib dose lower than that in other combination therapy studies, antitumor activity was observed (phase 1). In phase 2, objective responses were achieved in 5 (20%) patients; 11 (44%) achieved stable disease. Biomarker and pharmacodynamic assessments demonstrated that palbociclib inhibited CDK4/6 and the cell cycle initially in most patients.

Cannabinoid receptor-2 (CB2) is expressed dominantly in the immune system, especially on plasma cells. Cannabinergic ligands with CB2 selectivity emerge as a class of promising agents to treat CB2-expressing malignancies without psychotropic concerns. In this study, we found that CB2 but not CB1 was highly expressed in human multiple myeloma (MM) and primary CD138+ cells. A novel inverse agonist of CB2, phenylacetylamide but not CB1 inverse agonist SR141716, inhibited the proliferation of human MM cells (IC50 : 0.62 ∼ 2.5 μM) mediated by apoptosis induction, but exhibited minor cytotoxic effects on human normal mononuclear cells. CB2 gene silencing or pharmacological antagonism markedly attenuated phenylacetylamide's anti-MM effects. Phenylacetylamide triggered the expression of C/EBP homologous protein at the early treatment stage, followed by death receptor-5 upregulation, caspase activation, and β-actin/tubulin degradation. Cell cycle related protein cdc25C and mitotic regulator Aurora A kinase were inactivated by phenylacetylamide treatment, leading to an increase in the ratio inactive/active cdc2 kinase. As a result, phosphorylation of CDK substrates was decreased, and the MM cell mitotic division was largely blocked by treatment. Importantly, phenylacetylamide could overcome the chemoresistance of MM cells against dexamethasone or melphalan. Thus, targeting CB2 may represent an attractive approach to treat cancers of immune origin.

Daratumumab plus pomalidomide/dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy, and who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary endpoint. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary endpoints. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD-negative at a threshold of 10-5. Among the 62 responders, median duration of response was not estimable (NE; 95% CI, 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at ClinicalTrials.gov (identification number: NCT01998971).

We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia. The mechanism of action is unknown. Here we found that IMiD compounds cause selective ubiquitination and degradation of the transcription factor IKZF1 in CD34

Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of end-organ damage. MM is an incurable malignancy previously associated with poor survival rates. However, over the past two decades, the introduction of novel treatment options has resulted in a dramatic improvement in response rates and overall survival (OS). The combination of a proteasome inhibitor and an immunomodulator (IMiD) is the preferred induction treatment for newly diagnosed transplant-eligible MM patients. After induction, high-dose therapy with autologous stem cell transplant (ASCT) is still the standard of care for these patients. In patients who are transplant ineligible, dose adjusted IMiDs or proteasome inhibitor-based combinations are the preferred treatment option. With the recent approval of novel drugs like carfilzomib, ixazomib, pomalidomide, panobinostat, and monoclonal antibodies (elotuzumab and daratumumab), as well as improved understanding of risk stratification, management of comorbidities and treatment side effects, clinicians can optimize anti-MM therapy, particularly in relapse/refractory MM patients. In this review, we outline the current therapeutic approach to the management of MM.

Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kδ inhibitors, inhibited casein kinase-1 ε (CK1ε). Targeting CK1ε using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kδ/CK1ε inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1ε should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.

For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P

Detection of lytic bone lesions is crucial in the workup for multiple myeloma and very often dictates the decision to start treatment. Conventional radiography, despite decades of use, is often insufficient for detection of bone disease in multiple myeloma. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Novel whole-body low-dose computed tomography (WBLDCT) protocols allow for collection of superior image detail of the skeleton at doses of radiation similar to those used for conventional planar radiography. Several studies have shown that WBLDCT has a superior detection rate for lytic bone lesions compared with whole-body X-ray (WBXR), potentially leading to restaging and changes in therapy. MRI and PET provide imaging data important for assessing disease activity and prognostication. Because of several advantages over WBXR, WBLDCT is already the standard imaging technique for use in patients with multiple myeloma in many European institutions. However, the radiographic skeletal survey or WBXR is still the initial study of choice used to screen for myeloma bone disease in many institutions. In this review, we aim to explore the changing landscape of imaging for myeloma bone disease through use of modern imaging techniques. Clin Cancer Res; 20(23); 5888–97. ©2014 AACR.

Introduction: The only cure for sickle cell disease (SCD) is allogeneic hematopoietic stem cell transplant (HSCT) although autologous HSCT of genetically engineered hematopoietic stem cells is promising. Lack of suitable matched related donors (MRD) is a major limitation driving interest in improving outcomes using unrelated donors. While excellent outcomes are achieved with non-myeloablative MRD HSCT in adults (Hsieh et al, 2009 and 2014), results from matched unrelated donor (MUD) HSCT have been limited by excessive graft versus host disease (GVHD) and treatment-related mortality (Shenoy et al, 2016). Here we present updated follow up of our institutional experience using MUD and mismatched unrelated donors (MMUD) in comparison to patients with MRD. Methods: Eligibility for HSCT included frequent pain crises requiring hospitalization and evidence of end-organ damage. Non-myeloablative conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) was used for MRD HSCT (n=7), whereas patients without an MRD were transplanted using MUD, MMUD or haploidentical grafts (n=6) on a previously reported institutional protocol after conditioning with alemtuzumab (54 mg/m2), fludarabine (180 mg/m2), and melphalan (140 mg/m2), using a CD34+ selected graft with CD3+ cell add back. MRD recipients received sirolimus as GVHD prophylaxis. Non-MRD recipients initially received tacrolimus as GVHD prophylaxis (n=1) but subsequently received sirolimus (n=5) due to the first patient developing posterior reversible encephalopathy syndrome (PRES). All grafts were G-CSF mobilized peripheral blood grafts and all patients underwent RBC exchange to achieve Hgb S Results: Median follow up is 21.7 months (range 4.7 - 63.4). Median age for MRD recipients was 28.7 (21.4 - 35.5) years and 22.8 (18.5 - 34.6) for non-MRD recipients. Of note, the MRD group included one patient with a renal allograft from the same donor and another with stage V renal disease awaiting a kidney transplant. All patients where homozygous for hemoglobin S except one who had hemoglobin Sβo -thalassemia in the MRD group, and another heterozygous for hemoglobin S and C in the non-MRD group. Patients in the MRD group received unmanipulated grafts with a median of 14 (6.2 - 16.9) x 10E6 CD34+ cells/kg. Non-MRD recipients received CD34 - selected grafts with a median of 7.8 (4.1 - 15.1) x 10E6 CD34+ cells/kg with 2.2 x 10E5 (0.1 - 2.5) CD3+ cells add back. No growth factors were used post-transplant. All patient engrafted with no cases of graft failure. Median time to engraftment was significantly longer for the MRD group at 25 (22 - 30) vs 19 (13 - 21) days, p=0.003. Two patients in the MRD group developed acute/late acute GVHD (2 grade II), and 3 patients in the non-MRD group (1 grade II, 2 grade III), 2 of which developed in while switching immune suppression due to PRES. All GVHD cases were steroid responsive and resolved. Three patients in the non-MRD group developed PRES and none in the MRD group. There were no cases of treatment related mortality and all patients are alive and free of SCD. As both groups received alemtuzumab, and the non-MRD group received a CD34-selected graft, we examined lymphocyte subset reconstitution at day 100 and 1 year post-HSCT. The most striking difference was in median CD8+ T cell counts at day +100 which were lower in the non-MRD group approaching significance [101 (43 - 2995) vs 6.5 (3 - 2233) cells/uL, p=0.055, for the MRD and non-MRD respectively]. CD8+ T-cell counts were not significantly different at 1 year [402 (184 - 1066) vs 774 (143 - 1002) cells/uL, p Conclusion: We demonstrate excellent outcomes with 100% survival and no graft rejection following matched and mismatched unrelated donor HSCT for adult patients with severe SCD. Larger cohorts are needed to confirm these results and further delineate the impact of T-cell subset reconstitution on early-post transplant complications. Disclosures Assal: Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Bhatia:BMS: Consultancy; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy. Reshef:Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding.

Background: Monoclonal gammopathy of renal significance (MGRS) is a monoclonal B cell disorder, not meeting the definition of lymphoma or myeloma, that produces monoclonal proteins which deposit in the kidneys. Permanent renal damage can occur either as a consequence of direct deposition of toxic proteins or by an induced inflammatory response. Due to the low burden of the plasma cell clone, patients do not otherwise qualify for potentially toxic anti-plasma cell treatments and treatment is generally based on consensus opinion. To date there are no clinical trials exploring treatment options. Isatuximab is a chimeric mouse/human IgG1k monoclonal antibody which targets CD38 on both malignant and normal plasma cells and exhibits it antitumor effects primarily by antibody-dependent cellular toxicity. Isatuximab has recently been shown to be an active drug in the treatment of multiple myeloma, with improvements seen in hematologic and renal markers, and has been shown to have manageable toxicity. Given the efficacy of isatuximab in multiple myeloma, we propose a trial evaluating isatuximab monotherapy to treat the small plasma cell clone in MGRS with the hopes of maximizing response and minimizing toxicity. Study Design and Methods: The primary objective of this study is to evaluate efficacy of isatuximab monotherapy in patients with MGRS in order to establish a standard of care treatment for patients with this disease. Adult patients with proteinuria of at least 1 gram in 24 hours and a histopathological diagnosis of MGRS on renal biopsy in the last 24 months will be eligible for the trial. Patients will be excluded if their estimated GFR is below 30 mL/min, they have multiple myeloma, high risk smoldering myeloma, other B cell neoplasm meeting criteria for treatment, concurrent diabetic nephropathy, or require dialysis. Patients will be screened for B cell disorders with bone marrow biopsy and aspirate, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine protein electrophoresis (UPEP), free light chain (FLC) testing and screening PET/CT at time of enrollment. Enrolled patients will be administered isatuximab 20 mg/kg IV weekly for 4 weeks and then will receive the same dose every 2 weeks thereafter for a total of 6 months. Patients may be continued on treatment following completion of the 6 months at the discretion of the provider. To reduce the risk of infusion related reactions, patients will receive premedications with corticosteroids, diphenhydramine, H2 blockade and acetaminophen at least 60 minutes prior to infusion. Patients will have repeat SPEP + IFE, 24-hour UPEP + IFE and FLC testing every 4 weeks. There will be an optional repeat kidney biopsy 9-12 months following treatment initiation to assess pathologic response in the kidneys. Statistical Methods: The study will be comprised of 20 patients being treated with isatuximab over a span of 24-30 months. Ten patients will be initiated on the therapy for a period of 6 months. Interim analysis will be done after these patients have completed all the treatment cycles. If 4 out of 10 patients show response in form of improved/stable renal function, the study will proceed to include next 10 patients. If >50% of the first group of 10 patients show doubling of creatinine while on therapy, that would be considered as an indication to discontinue the therapy and the study due to drug toxicity. Endpoints: The primary endpoint will be efficacy as measured by renal response and hematologic response. Renal response will be measured by assessing the amount of proteinuria in a 24 hour urine sample. A sustained reduction in proteinuria by 30% from the patient's baseline amount of proteinuria with stable renal function (serum eGFR within 20% of baseline) will be considered a positive renal response. Hematologic response will be quantified per the 2016 International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. An important secondary endpoint will be safety and will be analyzed from all patients who receive any study drug. Adverse events will be characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Other endpoints include time to dialysis and rate of minimal residual disease (MRD) negativity. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our trial will be evaluating the efficacy of targeting CD38 on plasma cells with isatuximab in patients with monoclonal gammopathy of renal significance (MGRS). We will evaluate the effects of this drug on 24 hour proteinuria and hematologic response.

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Matrix metalloproteinases (MMPs) have been initially recognized for their role in degradation of extracellular matrix (ECM) and collagen remodeling. However, MMPs have been shown to play a crucial role in inflammation, tumor cell invasion, adaptive and innate immunity. Acute and chronic Graft versus Host Disease (GVHD) are characterized by distinctive histopathological features involving tissue infiltration with donor cells, tissue damage and remodeling. We therefore hypothesized that GVHD-associated organ damage may involve MMPs. We have now identified a novel immunomodulatory function for MMP-13 (alternatively called collagenase-3)and have uncovered a previously unknown role of MMP-13 in regulating GVHD.To address the function of MMP-13 in GVHD we first assesed the effect of MMP-13 on alloresponses in vitro. Using fully Major Histocompatibility Complex (MHC)-mismatched standard mixed lymphocyte reaction we demonstated that antigen presentig cells (APC) from B6.MMP-13-/-(H2b) mice led to signifcantly enhanced antigen-driven activation and proliferation of Carboxyfluorescein succinimidyl ester (CFSE)-labeled Balb/c responder splenocytes. Thus, MMP-13 deficiency in either splenocytes or bone marrow-derived dendritic cells used as stimulators resulted in enhanced proliferation, activation and IFN-gproduction in the allo-reactive lymphocyte responders. Similarly, exogenous MMP13 reduced proliferation of responder T cells as determined tested by CFSEdilution (CFSEloof CD4+T cells from 62.3% decreased to 40.6%, CFSEloof CD8+T cells from 74.1% down to 47.9%). We next assessed the impact of MMP-13 in vivousing fully MHC-mismatched rodent acute GVHD models. To study the role of host-derived MMP-13 we induced GVHD in B6.MMP-13-/-or B6.WT recipient mice following lethal TBI (1075 rad) using splenic T cells from Balb/cdonors. We observed signifcantly accelerated GVHD-related mortality (Median Survival Time 7 vs. 47 days post-transplant, p Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Proclara: Consultancy; BMS: Consultancy.

Introduction Multiple myeloma (MM) bone disease is characterized by the development of osteolytic bone lesions due to the over-activation of osteoclast and inhibition of osteoblast cells. MM cells secret pro-osteoclastogenic factors which lead to osteoclast (OCL) activation. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor which is highly secreted by MM cells. MMP-13 induces osteoclast fusion and bone-resorption by triggering the ERK1/2-dependent up-regulation of the cell fusogen, DC-STAMP. This process operates independently of the MMP-13 proteolytic activity. The fact that MMP-13 regulates OCL signaling via a proteolytic independent mechanism suggests that MMP-13 functions as a paracrine message protein mediating the crosstalk between MM cells and OCL. However, the mechanism is yet to be identified. Methods and Results To screen for MMP-13 cellular binding proteins/receptors, we performed a MMP-13 pull-down assay wherein recombinant MMP-13-His6 was incubated with mouse mononuclear bone marrow cells (BMCs) lysates and Ni-NTA magnetic beads were used to pull-down MMP-13- associated proteins. Following mass spectral analysis, programmed death-1 homolog (PD-1H) was identified as a major MMP-13-binding protein. PD-1H, also known as V-domain Ig suppressor of T cell activation (VISTA), is a critical negative checkpoint regulator expressed on myeloid cells and involved in immune responses. Binding of MMP-13 and PD-1H was confirmed by co-expressing both proteins in HEK293 cells and subsequent co-immunoprecipitation assay. Further, following PD-1H expression in HEK293 cells, an MMP-13-GFP fusion fluorescence protein docked to the cell surface where mutagenesis studies demonstrated that the PD-1H extracellular domain (ECD) mediates the specific binding interaction. Western blot and immunohistochemistry revealed that PD-1H was highly expressed in mononuclear BMCs, pre-OCL and mature OCL. ShRNA-mediated knockdown of PD-1H in mouse mononuclear BMCs blocked the ability of MMP-13 to induce osteoclast fusion and activation. These results were further confirmed by using BMCs from Pd-1h-/- mice and WT littermates for in vitro osteoclast differentiation. While MMP-13 induced WT OCL fusion and activation, these effects were completely blocked in Pd-1h-/-OCLs in tandem with a loss in MMP-13 induced ERK1/2 phosphorylation, NFATc1 and DC-STAMP upregulation. Conclusions Taken together, our study, for the first time, revealed that checkpoint inhibitor PD-1H is highly expressed in pre- and mature osteoclast. More importantly, we identified PD-1H as the critical receptor for MMP-13 in OCL, thereby mediating MMP-13-induced OCL fusion, activation and bone resorption. Hence, MMP-13 as a novel PD-1H ligand might not only induce bone disease, but also play a potential role in the regulation of T-cell activity in MM. As such, targeting MMP-13 and PD-1H interactions may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment. Disclosures Lentzsch: Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background: Carfilzomib and Bendamustine are currently FDA approved for therapy of relapsed refractory multiple myeloma (MM). Bendamustine, in addition to interference with DNA replication, it can induce inhibition of mitotic checkpoints, inefficient DNA repair, and initiation of a p53-dependent DNA-damaging stress response leading to apoptosis of tumor cells (1). It has previously shown significant activity in relapsed myeloma (2). Carfilzomib is a second generation, irreversible proteasome inhibitor has demonstrated promising activity in first line therapy (3,4). we hypothesized that combining them will yield an effective induction regimen in the newly diagnosed MM. Study design: Inclusion criteria included newly diagnosed MM with measurable disease, age ≥18, ECOG PS 0-2, adequate renal (creatinine clearance >30 mL/min), cardiac and hepatic function. Carfilzomib was given IV on days 1, 2, 8, 9, 15, 16. All patients received 20 mg/m2 on days 1 and 2 of cycle 1, after which their dose was escalated to one of the following levels: 27, 36, 45, or 56 mg/m2. Bendamustine IVPB on days 1, 2, at 70 (dose levels 1 and 2) or 90 mg/m2 (dose levels 3-5). Dexamethasone 20 mg PO or IV D 1, 2, 8, 9, 15, 16, 22, 23. Each cycle of therapy was 28 days, and a total of 8 cycles was given. Stem cell harvest was done after 4 cycles and eligible patients proceeded to ASCT after 8 cycles. Maintenance was recommended - either carfilzomib (36mg/m2 D 1,2, 15, 16 of a 28-day cycle for 2 years, or investigator's choice. Primary objective was to determine the recommended phase 2 dose (RP2D) and additional objectives assessed efficacy and safety. Results: Between February 2014 and May 2018, 20 patients with newly diagnosed MM pts were accrued onto study (5 pts in phase I and 15 in phase II). Median age was 65 (range 48-74), and 14 (70%) patients were male. 7 (35%) were of Hispanic ethnicity. 3 patients (15%) were R-ISS stage 3, and 1 (5%) had high-risk cytogenetics. We did not observe any DLTs with our study treatment and established the RP2D as: carfilzomib 56 mg/m2, bendamustine 90 mg/m2 and dexamethasone 20 mg on the dosing schedule given above. The most common and severe toxicities were hematologic. Grade 3/4 hematologic toxicities were lymphocytopenia in 90% of patients, neutropenia 40%, anemia 20% and thrombocytopenia 20%. Notable non-hematologic toxicities were grade 3/4 infection in 20% of patients (typically upper respiratory and pneumonia), grade 1/2 acute kidney injury in 45% of patients, and grade 1/2 diarrhea in 40% of patients. No treatment emergent hypertension or heart failure were noted. 1 patient died while on study, from septic shock due to pneumonia 7 weeks after completion of induction. The regimen was highly effective, with an ORR of 100%. Best responses were: 2 (11%) PR, 5 VGPR (26%), and 12 CR (63%) (Figure 2). Among the CRs, 4 were MRD-positive, 5 were MRD-negative, and 3 did not have MRD testing. With a median follow-up of 28 months (range 11-71), 2 patients have progressed - 1 with del(17p) at 19 months after diagnosis, and the other with standard cytogenetic risk disease at 56 months. 2 patients have died - the patient with del(17p) from refractory myeloma at 37 months after diagnosis, and the other from septic shock as discussed above. Median PFS was 56 months, and median OS has not been reached. Conclusion: Carfilzomib, Bendamustine and Dexamethasone is safe and highly effective for newly diagnosed transplant eligible MM and should be further explored in a larger prospective trial for this patient population. References: 1. Leoni LM, Hartley JA. Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. Seminars in hematology 2011;48 Suppl 1:S12-23. 2. Lentzsch S, O'Sullivan A, Kennedy RC, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood 2012;119:4608-13. 3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. The Lancet Oncology 2017;18:1327-37. 4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801-9. Disclosures Bhutani: Sanofi: Membership on an entity's Board of Directors or advisory committees. Assal:Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Lentzsch:Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. OffLabel Disclosure: Carfilzomib, Bendamustine and Dexamethasone for newly diagnosed multiple myeloma.

Background: MGRS is a group of heterogeneous disorders characterized by renal dysfunction related to monoclonal immunoglobulin deposition where the underlying plasma cell or B cell clone does not cause tumor complications or meets current hematological criteria for specific therapy (1). The diagnosis of these disorders is established by renal biopsy demonstrating glomerular or tubulointerstitial monoclonal protein deposition. The glomerular disorders include proliferative glomerulonephritis with monoclonal Ig deposition (PGNMID), paraprotein associated C3 glomerulopathy, immunotactoid glomerulopathy, and paraprotein associated fibrillary glomerulonephritis and Type 1 cryoglobulinemic glomerulonephritis. The tubulointerstitial disorders include fanconi syndrome and proximal light chain tubulopathy (2). Given the pathogenesis of the disorders, therapies targeting the underlying plasma cell and/or B cell clone have been used in the past but standard therapy has not been established. Given the rarity of MGRS as defined above, we report our single center experience for therapy of such disorders. Methods: We retrospectively reviewed the charts of patients treated for MGRS at Columbia University Medical Center and collected information on the renal pathologic diagnosis, presence or absence of monoclonal gammopathy and therapy and response. The diagnosis of MGUS and MGRS was based on standard criteria (3). For the assessment of renal response, we used criteria for renal organ response for AL amyloidosis (4). Results: A total of 8 patients were treated at our center for MGRS between 3/2015 and 1/2019. The type of MGRS diagnosis was PGNMID in 5 patients, C3 glomerulopathy in 1 patient, immunotactoid GN in 1 patient and MGUS associated dense deposit disease (DDD) in 1 patient. Monoclonal Ig deposit was IgG kappa type in 3, IgG Lambda in 2, IgM lambda in 1 patient and only Complement deposits C3 glomerulopathy and DDD. All pts had proteinuria at diagnosis with median proteinuria 4g/24hr (range 2.8-11.7g/24hr). Impaired renal function was present 5/8 pts with median serum creatinine 1.4mg/dl (range 1-4.6). None of the patients with PGNMID (N=5) had a concurrent monoclonal gammopathy by standard testing but the rest 3 patients had MGUS with positive SPEP and bone marrow involvement by a clonal plasma cells. First line treatment regimens included use of Bortezomib based regimen (Bortezomib, cyclophosphamide, dexamethasone) in 3 patients, Rituximab based regimens (Rituximab, Prednisone and Rituximab, cyclophosphamide, prednisone) in 4 patients and Daratumumab in one patient. Second line Daratumumab based therapy was used in 2 patients who did not respond to the first line therapy and lead to response in one patient. Improvement in proteinuria was seen in 6/8 patients with >30% decrease in proteinuria (range 50-90% reduction). The median time to response was 2 months (range 1-4 months). Improvement in eGFR was seen in 1/8 patients but majority of patients continuing to have stable eGFR and 1/8 patient progressed to ESRD. The responses were durable and after a median follow-up of 11.8 months only one patient had recurrent disease. Conclusion: Currently there is no standard of care therapy for treatment of patients diagnosed with MGRS disorders. Clone directed therapies including Bortezomib, Daratumumab and Rituximab based regimens aimed at suppressing the production of the involved immunoglobulin are effective for treatment of these disorders both in the presence and absence of a concurrent MGUS. These therapies should be explored further in a larger prospective multi-center trial for MGRS disorders. References: 1. Frank Bridoux, Nelson Leung, Colin A. Hutchison et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney International (2015) 87, 698-711. 2. Nelson Leung, Frank Bridoux, Colin A Hutchison et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood.2012;120(22):4292-4295. 3. Leung N, Bridoux F, Batuman V, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019 Jan;15(1):45-59. 4. Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-2332. Disclosures Bhutani: Sanofi: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. OffLabel Disclosure: Bortezomib, Cyclophosphamide, Dexamethasone, Rituximab, Daratumumab. For treatment of Monoclonal Gammopathy of renal significance.

Introduction: Next-generation sequencing revealed frequent mutations of the RAS/mitogen-activated protein kinase (MAPK) pathway, with mutations in NRAS, KRAS or BRAF in up to 50% of newly diagnosed MM patients1. The majority of the NRAS, KRAS and BRAF mutations occur in hotspots causing constitutive activation of the corresponding pathways2. Given the upstream activator role of Germinal Center Kinase (GCK) in the MAPK pathway, GCK might be an attractive therapeutic target in MM. Indeed, we recently discovered the critical role of GCK, also named mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), in MM cell survival and growth. Methods and Results: Our data show that GCK is higher expressed in RAS mutated MM cells compared to the wild type (WT) RAS MM cells. Silencing of GCK in RASmut MM cells (MM.1S and RPMI-8226) by using an inducible Tet-on-shGCK significantly decreased MM cell proliferation and induced cell death (Figure 1). In contrast, knockdown of GCK in RASwt MM cell lines (LP1 and U266) induced only modest inhibition of proliferation. The higher sensitivity to GCK knockdown in RASmut cells suggests that targeting GCK is especially effective in multiple myeloma which harbors RAS mutations. To exclude a potential off-target effect associated with GCK knockdown that led to the inhibition of MM proliferation, we set up an shGCK-resistant GCK allele (GCKshRNA-RES) by introducing mismatch mutations on the shRNA targeted sequences without changing the encoded amino acids. In the shGCK rescue experiment using GCKshRNA-RES we showed that all shRNA induced phenotypes (lack of growth, apoptosis and downstream effectors decrease) were corrected by the GCK resistant allele expression, ruling out the off-target hypothesis. Moreover, we expanded the in vivo studies of GCK knockdown on MM tumor progression. To monitor the tumor progression, we transduced MM.1S cells with firefly luciferase and established an inducible GCK knockdown system. Luciferase-expressing GCK inducible knockdown MM cells or non-targeting control shRNA (shCNTL) transduced MM cells were s.c. injected into SCID/Beige mice and the tumor progression was monitored by bioluminescence imaging. Doxycycline (for induction of shRNA) or vehicle treatment were started after the tumor was established on day 16 to induce shGCK and subsequently silence GCK expression. In contrast to the vehicle-treated MM.1S-Tet-on-shGCK or doxycycline-treated MM.1S-Tet-on-shCNTL tumors, doxycycline-treated animals bearing MM.1S-Tet-on-shGCK xenografts showed a significant inhibition (P Lysine 45 is critical for GCK kinase activity. Point mutation of K45A will completely abolish its kinase activity. We introduced K45A mutation into GCKshRNA-RES (GCKshRNA-RESK45A→ shGCK resistant and kinase dead GCK). Tet-on-shGCK with GCKshRNA-RES or GCKshRNA-RESK45A were co-transduced in MM.1S cells. As expected, the GCK knockdown effects were rescued by GCKshRNA-RES but not by the kinase-dead mutant GCKshRNA-RESK45A. In contrast to GCKshRNA-RES, GCKshRNA-RESK45A failed to stimulate MM cell proliferation, to suppress MM cells apoptosis and to restore the downstream effectors expression. Our findings demonstrated that GCK kinase activity is required for its function in myeloma cell physiology. Conclusion: Taken together, our findings provide a rationale for the clinical evaluation of targeting GCK in MM patients and the role of GCK in MM tumorigenesis as well as drug resistance. The subsequent development of small molecules inhibiting this pathway, such as GCK kinase inhibitors, will address the unmet need of developing targeted treatments for RASmut myeloma and potentially for other RASmut malignancies. References 1. Walker, B.A., et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol33, 3911-3920 (2015). 2. Xu, J., et al. Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis6, e337 (2017). Disclosures Marcireau: Sanofi: Employment. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Bayer: Consultancy.

Introduction: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (MM). The recommended phase 2 dose (RP2D) of twice-weekly combination of selinexor, carfilzomib, and dexamethasone (SKd) was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg (NCT02199665). The ORR of this regimen in patients with MM refractory to carfilzomib in last line of therapy (n=13) was 62% and clinical benefit response was 77% (Jakubowiak et al. Br J Haematol 2019). This is consistent with data from the combination of selinexor, bortezomib and dexamethasone where a 43% ORR was observed in bortezomib refractory disease. We conducted the STOMP study to assess the safety and preliminary efficacy of SKd combination using once weekly (QW) dosing in patients with relapsed/refractory MM. Methods: STOMP is a multicenter, open-label study. Patients with relapsed/refractory MM that was not refractory to carfilzomib, and who may have had prior proteasome inhibitor exposure were enrolled. Oral Selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (excluding day 22 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose, RP2D and evaluate the efficacy and safety of SKd in patients with relapsed/refractory MM. Results: As of July 01 2019, 12 patients were enrolled in the study. Of these, 5 were male and 7 were female. The median age was 70 years (range: 50-76 years). The median number of prior treatments was 4 (range: 2 - 8). Nine of 12 patients received prior autologous stem cell transplantation. All 12 patients were carfilzomib naïve. Nine of 12 patients had MM refractory to bortezomib; 11 patients had MM refractory to lenalidomide and/or pomalidomide including 5 patients with MM refractory to both; and 7 patients with MM refractory to daratumumab. Four dose limiting toxicities (DLTs) were observed across 3 dose cohorts (Table 1). Common treatment related adverse events (Grade 1/2 , Grade ≥3) included anemia (42%, 17%), thrombocytopenia (17%, 58%), leukopenia (17%, 17%), nausea (67%, 0%), decreased appetite (33%, 0%), insomnia (33%, 0%), hyperglycemia (25%, 17%), fatigue (25%, 8%), vomiting (25%, 8%), and pneumonia (0%, 17%). The ORR was 75% including 3 complete responses, 5 very good partial responses and 1 partial response. Two patients had stable disease and 1 patient had minimal response. As of July 01, 8 patients remain on treatment. Conclusions: The once weekly SKd combination demonstrated encouraging preliminary activity with an ORR of 75% including complete responses and very good partial responses. Most DLTs were thrombocytopenia and all the DLT events occurred in patients with baseline Grade 1/2 thrombocytopenia. This activity and manageable side effect profile with QW selinexor in combination with carfilzomib and dexamethasone is promising. Disclosures Gasparetto: Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Constellation Pharmaceutical: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Tuchman:Roche: Research Funding; Alnylam: Honoraria, Research Funding; Karyopharm: Honoraria; Prothena: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding. Bahlis:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chen:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Other: Internal Review Committee participant. Kotb:Takeda: Honoraria; Amgen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Karyopharm: Equity Ownership. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sebag:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Research Funding; J&J: Research Funding; Sanofi: Honoraria; Takeda: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding.

Introduction: The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM) and associated with poor prognosis. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forces the nuclear retention and re-activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Pomalidomide/dexamethasone achieved an ORR of 31% and progression-free survival (PFS) rate of < 4 months in patients refractory to prior bortezomib and lenalidomide. We conducted the STOMP study to assess the efficacy and safety of the combination of selinexor, pomalidomide and dexamethasone (SPd) in patients with relapsed/refractory multiple myeloma. Methods: STOMP is a multicenter, open-label, phase 1/2b, dose escalation study with an expansion phase. Patients with relapsed/refractory multiple myeloma who received prior therapies including lenalidomide and a proteasome inhibitor were eligible for enrollment. Oral selinexor was evaluated in 2 different dosing schedules: once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with escalating doses of pomalidomide 2, 3 or 4 mg PO (days 1-21), and low dose dexamethasone 20 mg BIW or 40 mg QW. The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of the combination of SPd in patients with relapsed/refractory multiple myeloma. Results: As of July 01 2019, 48 patients (26 male and 22 female) were enrolled. The median age was 64 years (range:43-83 years). Patients received a median of 4 (range: 2-13) prior treatment regimens. Forty patients (83%) received prior autologous stem cell transplantation (one patient received prior autologous and allogenic stem cell transplantation). The phase 1 dose escalation enrollment is now complete. Across all cohorts, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (Grades 1/2, Grades ≥3): neutropenia (8%, 54%), thrombocytopenia (21%, 33%), anemia (17%, 29%) and leukopenia (13%, 15%). Common non-hematologic TRAE included: nausea (56%, 0%), fatigue (40%, 10%), decreased appetite (46%, 0%), weight decreased (33%, 0%), diarrhea (27%, 0%), vomiting (21%, 2%). Lower rates of ≥ Grade 3 thrombocytopenia (27% vs 44%) and anemia (20% vs 44%) were observed in QW dosing vs BIW dosing. Out of 48 patients, 44 were evaluable for response (27 patients lenalidomide refractory/pom naive, 4 patients lenalidomide treated/pom naïve, 13 patients refractory to pomalidomide and lenalidomide, and 19 patients refractory to lenalidomide and bortezomib). Among patients who were pomalidomide naive (N=31), the ORR was 58% (7 very good partial responses and 11 partial responses) and the median PFS was 12.2 months. Among patients refractory to lenalidomide/pomalidomide (N=13) the ORR was 31% (4 partial responses) and the median PFS was 4.2 months. Conclusions: The all oral SPd combination is durable and active with an ORR of 58% in patients with disease that is lenalidomide refractory and pomalidomide naïve compared to previously published data of 31% ORR for pomalidomide/dexamethasone in a similar patient population. The median PFS on SPd of 12.2 months in pomalidomide naïve patients is longer than that observed with pomalidomide/dexamethasone ( Disclosures Chen: Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Bahlis:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Honoraria; Alnylam: Honoraria, Research Funding; Sanofi: Research Funding; Prothena: Research Funding; Roche: Research Funding; Amgen: Research Funding; Merck: Research Funding. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Karyopharm: Other: Internal Review Committee participant; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kotb:Celgene: Honoraria; Karyopharm: Equity Ownership; Merck: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Bensinger:Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant; Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Takeda: Honoraria; J&J: Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Astellas: Research Funding; Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. White:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

e19518 Background: Most patients with multiple myeloma (MM) have detectable monoclonal protein. While guidelines do not specify the frequency of lab testing for response evaluation, most MM clinical trials perform monthly assessment. We examined the use of 4 serologic tests – protein electrophoresis (SPEP), immunofixation (IFE), quantitative immunoglobulins (QIG), and free light chain (FLC) in newly-diagnosed MM patients. Methods: We identified patients age ≥65 with MM (ICD-O 34000) in the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 2000-2013. Patients were required to have bone marrow biopsy within 6 months of diagnosis, and taken chemotherapy approved for MM. Use of a test was defined as having ≥1 instance of its CPT code within 12 months of diagnosis. Patients with > 12 instances were defined as overusers. Multiple instances of a test on the same date were counted once. Multivariable logistic regression models using covariates including: age and year at MM diagnosis, race, marital status, Charlson comorbidity, chemotherapy use, number of hospitalizations and oncology office visits within 12 months of diagnosis, were developed to examine associations with overuse. Results: Among 6,214 identified patients, users were: SPEP 5,532 (89%), IFE 4,745 (76%), QIG 5,524 (89%), and FLC 3,864 (62%). The median (interquartile range) times each test was used in the first year following diagnosis were: SPEP 6 (3-10), IFE 3 (2-7), QIG 6 (3-10), FLC 5 (2-9). The numbers of overusers were: SPEP 721 (13%), IFE 265 (6%), QIG 498 (9%), FLC 350 (9%). 231 (4%) patients were overusers of 2 tests. Factors associated with overuse common to all 4 tests were: younger age at diagnosis (eg, SPEP: odds ratio (OR) 2.0 for aged 65-74 vs ≥85; P < .001), more oncology office visits (eg, QIG: OR 2.2 for > 15 vs 0-6; P < .001), and use of combination chemotherapy (eg, SPEP: OR 2.2 for proteasome inhibitor + immunomodulatory drug (IMID) vs those on IMID ; P < .001). Conclusions: In our Medicare population, patients on average underwent response evaluation much less often than monthly, but we also found overuse. Further investigation of the use of these tests is warranted given their central importance to MM care and their cumulative financial cost.