Citations

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median overall survival of 15 months with standard-of-care treatment. GBM patients sometimes present with a cystic component, which can be identified through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7–22% of GBM patients and have reported mixed results regarding whether cystic GBM have a survival benefit compared to noncystic GBM. Using our large retrospective cohort of 493 first-diagnosis GBM patients, we aim to elucidate this link between cystic GBM and survival. Within this cohort, 88 patients had a significant cystic component at presentation as identified on MRI. Compared to noncystic GBM (n=405), cystic GBM patients had significantly better overall survival (15 vs 22 months median, log-rank, p=0.001) and were significantly younger at the time of presentation (t-test, p=0.002). However, within patients that received current standard-of-care treatment (n=184), cystic GBM (n=40) was not as beneficial for outcome (22 vs 25 months, log-rank, p=0.3). We also did not observe a significant survival benefit when comparing this standard-of-care cystic cohort to cystic GBM patients diagnosed before the standard was established (n=19, 25 vs 23 months, log-rank, p=0.3), but the analogous result for noncystic GBM patients gives a sizeable benefit, as expected (n=144, n=111, respectively, 22 vs 12 months, log-rank p < 0.0001). Together, these results on current standard-of-care may explain later studies that note no significant survival benefit for cystic GBM patients receiving current standard-of-care. We also report differences in the absolute and relative sizes of imaging abnormalities on MRI and in prognostic impact of cysts based on sex. We discuss current hypotheses for these observed differences, including the possibility that the presence of a cyst could be indicative of a less aggressive tumor.

Abstract Determining effective therapies for patients with recurrent glioblastoma remains difficult especially in small early phase clinical trials. Currently utilized estimators of treatment response rely on two-dimensional measurements of tumor progression (e.g. RANO, RECIST, MacDonald) that have often fallen short in reliably connecting patients who respond with positive survival outcomes. This has prompted consideration of advanced imaging and volumetric measurements by the RANO working group and others. Our proposed approach, Days Gained (DG), uses volumetric measurements to calculate a personalized response metric based on change in tumor growth characteristics pre/post-treatment. DG has shown promise for connecting imageable treatment response with clinically meaningful (statistically significant) survival benefit when applied in upfront and recurrent therapy settings, even in the context of coincident bevacizumab treatment. In this study, we seek to consider a new cohort of patients receiving bevacizumab in combination with other novel therapies to distinguish any subpopulation of patients with meaningful response. In this work, we identified a subset of 16 patients from bevacizumab clinical trials with data available for DG analysis requiring serial imaging (T1Gd and FLAIR) prior to and after the first cycle of therapy. Each trial evaluated bevacizumab alone versus bevacizumab plus either dasatinib or TRC105 in recurrent disease. Discrimination of time to progression (TTP) was evaluated at DG thresholds identified from our prior analysis of patients treated with bevacizumab. Using previously identified DG thresholds for clinically significant treatment benefit, in our cohort, DG measured by serial FLAIR imaging was significant in predicting longer TTP (120 DG, p=0.014), but T1Gd DG scores did not attain significance (p=0.630). Given the limited insights in connecting response metrics to accurately predicted outcomes, these data further support the use of DG as a burgeoning marker of treatment response (or lack of response) that may be useful for more routine integration into clinical trials.

Abstract INTRODUCTION Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median overall survival (OS) of 15months. Despite advancements in treatments, prognosis is dismal and the prognostic significance of tumor location is not entirely understood. METHODOLOGY: In our study, we investigated sex-specific volumetric, tumor growth kinetics, and outcome differences among GBMs in various brain locations. Primary GBM patients with pretreatment magnetic resonance imaging (MRI) data (N=289, 173 males, 116 females) were selected from our brain tumor repository. Tumor abnormality was segmented on T1-weighted post-gadolinium contrast agent (T1Gd) MRIs. We utilized the Harvard-Oxford brain atlases to determine the location of GBMs. RESULTS Overall, our study found smaller tumors in the left hemisphere. This may be expected as left-hemispheric GBM symptoms could present earlier, leading to earlier diagnosis and treatment. However, when the cohort was split by sex, we found this observation significant for females only in the parietal lobe (p < 0.0001). Further, female GBMs demonstrated smaller necrotic volume in the left hemisphere (p = 0.030). Sex-specific differences in incidence were noted in the temporal and occipital lobes (2M:1F). Comparing tumor growth kinetics in different brain locations and hemispheres, females had significantly lower tumor proliferation rates in the left hemisphere (p = 0.009) and lower tumor proliferation rates in the left frontal lobe (p = 0.031). Controlling for treatment, patients with frontal lobe tumors had significantly longer OS compared to those with GBMs in the temporal lobe (p = 0.046, 312 days). Differences in growth velocities were noted between frontal and parietal lobe with frontal GBMs having lower velocities in comparison to parietal lobe GBMs. CONCLUSION Together, our results demonstrate that tumor growth and proliferation rates may vary based on location and sex. Additional research is needed to further explore the clinical significance of tumor location.

Abstract Background AFM13 is a bispecific, tetravalent NK cell-engaging antibody construct binding to CD30 on CD30+ tumor cells and CD16A on NK cells. By engaging CD16A-positive NK cells, AFM13 leads to NK cell-mediated killing of CD30-positive lymphoma cells (Reusch et al., 2014) making it an attractive agent to target classical Hodgkin lymphoma (HL). Pembrolizumab is a PD-1 blocking antibody which has shown high single-agent response rates in patients (pts) with relapsed/refractory HL (RRHL; Armand et al., 2016, Chen et al., 2017). AFM13 has shown clinical activity in RRHL as a single agent in a preceding Phase 1 study (Rothe et al., 2015). Preclinical in vivo data of the combination of AFM13 with PD-1 blockade showed synergistic activity and the potential for induction of cross-talk between innate and adaptive immunity (Zhao et al., 2016). We hypothesize that the combination of the two agents could improve outcomes in pts with RRHL. Methods This Phase 1b study is evaluating the safety and tolerability of the combination of AFM13 with pembrolizumab (Keytruda) as salvage therapy after failure of standard therapies including brentuximab vedotin (BV) in HL (NCT02665650). Pts receive escalating doses of AFM13 in combination with pembrolizumab at a dose of 200 mg flat administered every 3 weeks following a classical 3+3 design, followed by enrollment into an extension cohort at the maximum tolerated dose (MTD)/maximum administered dose (MAD). Response assessment is performed every 12 weeks by PET/CT according to the Lugano Classification (Cheson et al., 2014). The main objectives of the study is to ascertain the MTD/MAD along with the preliminary efficacy of the combination. Results As of June 29, 2018, 30 pts have been enrolled into the study. The median age is 34 years (range, 18-73), with a median of 4 (range 3-7) prior lines of therapy. All pts had relapsed or refractory disease (43% relapsed, 57% refractory) and had failed standard treatments including BV and 43% of pts (13/30) had BV as their latest therapy. Thirty seven percent (11/30) had undergone prior autologous stem cell transplantation. All 30 pts have completed the 6-week dose-limiting toxicity (DLT) observation period. Twelve pts were enrolled into the dose escalation cohorts (Cohorts 1 (n=3), 2 (n=3), and 3 (n=6)) and 18 into the Extension Cohort, with a total of 24 patients treated at the MAD (dose level 3). One DLT was observed in Cohort 3 (missing ≥25% of AFM13 during the DLT period) and another observed in the Extension Cohort (G4 infusion-related reaction; IRR). The most common related adverse events (AEs) were IRRs (80%), rash (30%), pyrexia (23%), nausea (23%), diarrhea (20%), fatigue (17%), headache (17%), increased aspartate aminotransferase (13%), and increased alanine aminotransferase (10%). Treatment related G3/4 AEs included IRRs (13%), elevated AST (3%), gastritis (3%), hypotension (3%), nausea (3%), neutropenia (3%), and vomiting (3%). The majority of IRRs were manageable with standard of care measures and did not lead to treatment discontinuations. Included in the efficacy analysis were the best response from 29 evaluable pts who had at least one post-baseline disease assessment as of the data cutoff on June 29, 2018. The overall response rate (ORR) and complete response (CR) rate for evaluable pts treated at the dose and schedule chosen for expansion (n=23; Cohort 3 and Extension Cohort) were 87% and 35% by the investigator-confirmed assessment, respectively. Independent assessment resulted in an ORR of 87% and CR rate of 39% for these pts. Updated data for all 30 patients will be presented at the meeting. Conclusions The combination of AFM13 and pembrolizumab is a well-tolerated salvage therapy in pts with RRHL. IRRs were the most frequently observed adverse events; however, most of these events were of mild or moderate severity and manageable. Both the ORR and CR rate compare favorably to monotherapy pembrolizumab in a similar RRHL population (Chen et al., 2017). The combination of AFM13 and pembrolizumab could be a potential new therapeutic option for HL patients. Disclosures Bartlett: Immune Design: Research Funding; Affimed: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Millennium: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech Inc.: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Domingo-Domenech:Affimed: Research Funding. Forero-Torres:Affimed: Research Funding. Garcia-Sanz:Affimed: Research Funding. Devata:Affimed: Research Funding. Rodriguez Izquierdo:Affimed: Research Funding. Lossos:Affimed: Research Funding. Reeder:Affimed: Research Funding. Sher:Affimed: Research Funding. Choe-Juliak:Affimed: Employment. Prier:Affimed: Research Funding. Schwarz:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Takeda: Research Funding.

Abstract Background Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are mainly diagnosed based on morphological changes in the bone marrow. The diagnosis can be challenging in patients (pts) with pancytopenia with minimal dysplasia, and is subject to inter-observer variability. Somatic mutations can be identified in either disease but no genes, in isolation or in combination, are specific for disease phenotype. We developed a geno-clinical model that uses mutational data, peripheral blood values, and clinical variables to predict an MDS vs. CMML diagnosis in pts who presented with cytopenias, in the absence of bone marrow biopsy results. Method We combined genomic and clinical data from 1897 pts treated at our institution (593) and the Munich Leukemia Laboratory (1304). Pts were diagnosed with MDS or CMML according to 2008 WHO criteria. Diagnosis of MDS and CMML was confirmed by independent hematopathologists that were not associated with the study. A genomic panel of 40 genes commonly mutated in myeloid malignancies was included. The initial cohort was randomly (computer generated) divided into learner (80%) and validation (20%) cohorts. Multiple machine learning algorithms were applied to predict the phenotype. Feature extraction algorithms were used to extract genomic/clinical variables that impacted the algorithm decision and to visualize the impact of each variable on phenotype. Prediction performance was evaluated according to the area under the curve of the receiver operator characteristic (ROC-AUC) and confusion/accuracy matrices. Results Of 1897 pts included, 1368 pts had MDS and 529 had CMML. The median age for the entire cohort was 72 years (range, 11-102); 37% were female. The median white blood cell count (WBC) was 5.1x109/L (range, 0.60-176), absolute monocyte count (AMC) 0.19 x109/L (range, 0-96), absolute lymphocyte count (ALC) 0.77x109/L (range, 0-62), absolute neutrophil count (ANC) 2.44x109/L (range, 0-170), hemoglobin (Hgb) 10.2 (range, 3.9-19.6), and platelet (Plt) count 111x103/mL (range 2-1491). The most commonly mutated genes in all pts were: TET2 (33%), ASXL1 (26%), SF3B1 (21%), SRSF2 (16%), RUNX1 (12%), DNMT3A (10%), CBL (7%), U2AF1 (7%), STAG2 (6%), EZH2 (6%), ZRSR2 (6%), NRAS (6%). In CMML, they were: TET2 (51%), ASXL1 (43%), SRSF2 (25%), RUNX1 (18%), CBL (16%), KRAS (12%), NRAS (11%), EZH2 (9%), JAK2 (6%), U2AF1 (5%), SF3B1 (4%), and DNMT3A (3%). In MDS, they were: TET2 (27%), SF3B1 (24%), ASXL1 (21%), SRSF2 (13%), DNMT3A (12%), RUNX1 (10%), STAG2 (8%), U2AF1 (8%), ZRSR2 (7%), TP53 (7%), BCOR (5%), and EZH2 (5%).The median total number of mutations/sample was 2 (range 0-27) for all pts, 2 (range 0-8) for CMML, and 2 (range 0-27) for MDS. A set of 83 genomic/clinical variables were evaluated and several feature extraction algorithms were used to identify the least number of variables that have the most significant impact on the algorithm's decision. These variables included: AMC, ALC, TET2, ANC, ASXL1, SF3B1, Hgb, number of mutations/sample, AEC, age, Plt, splenomegaly, RUNX1, NRAS, CBL, U2AF1, STAG2, DNMT3A, TP53, EZH2, SRSF2, and ZRSR2, Figure 1. When applying the model to the validation cohort, the ROC-AUC was .98 with an accuracy of 94%, with other statistical values as follows: specificities CMML 93%, MDS 96%; sensitivities CMML 96%, MDS 93%; positive predictive values CMML 84%, MDS 98%; negative predictive values CMML 98%, MDS 84%. Individual pt data can also be entered into the model, with a probability of whether the diagnosis is MDS vs. CMML provided along with the impact of each variable on the decision, as shown in Figure 1. When the analysis was restricted to mutations only, the accuracy of the model dropped dramatically (77%, ROC-AUC .85). Conclusions We propose a novel approach using interpretable, individualized modeling to predict MDS vs. CMML phenotypes based on genomic and clinical data without the need for bone marrow biopsy data. This approach can aid clinicians and hematopathologists when encountering pts with cytopenias and a diagnosis suspicious for MDS vs. CMML. The model also provides feature attributions that allow for quantitative understanding of the complex interplay among genotype, clinical variables, and phenotype. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Walter:MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gerds:CTI Biopharma: Consultancy; Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy. Sallman:Celgene: Research Funding, Speakers Bureau. Komrokji:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Nazha:MEI: Consultancy.

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

Abstract Background Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has been validated as both relapse and upfront therapies for multiple myeloma. To optimize pre transplant response, we combined carfilzomib with the widely accessible backbone of cyclophosphamide-thalidomide-dexamethasone (CTD). We previously reported results of the Phase I component of the trial (in which no MTD was reached); we now report results for the MTD and fully accrued expansion cohorts at the MTD of the CYCLONE trial NCT01057225. Methods Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with carfilzomib IV Days 1,2,8,9,15,16 (see Table below for dosing per cohort) along with cyclophosphamide 300 mg/m2 PO Days 1,8,15, thalidomide 100 mg PO Days 1-28 and dexamethasone 40 mg PO Days 1,8,15,22. The initial phase I/ II regimen is shown below – as no DLTs were observed, we increased dosing of carfilzomib to 36 and then 45mg/m2 and have now nearly fully accrued to the Phase II dose level +1 (27mg/m2) and expansion MTD (36mg/m2). Treatment was for 4 cycles with planned SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results A total of 54 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II (CFZ 27mg/m2), and 27 at CFZ 36-45mg/m2. Median age was 63 (range 27-77) and 52% were male. ISS Stage was advanced (II-III) in 57% The overall partial response rate or better following 4 cycles of CYCLONE at dose level 0 or greater is 91%: CR 18%, VGPR 58%, PR 16%, MR 2%, SD 4%. One patient withdrew from the trial after cycle 1. At dose level 2, 3/7 patients experienced dose-limiting toxicity in cycle 1 including: grade 3 alanine aminotransferase increase (possibly related); grade 3 infusion reaction (probably related); and grade 4 heart failure with grade 3 dyspnea, atrial fibrillation, and fatigue (all possibly related). No dose-limiting toxicity was observed in 6 patients at dose level 1 and thus DL1 was deemed the MTD. Across dose levels, adverse events are fully evaluable in 48 patients. AEs of grade 3 or higher at least possibly related to CYCLONE occurred in 26 (54%) – 35% non hematological and 33% hematological. Most commonly reported non hematological toxicities (all grades) included fatigue (63%), constipation (46%), elevated creatinine (27%), hyperglycemia (27%), lethargy (25%) peripheral sensory neuropathy (25% - all grade 1), and somnolence (21%); however, grade 3/4 toxicities occurring in >5% were uncommon: hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%). Three cases of pneumonia required hospitalization. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included lymphopenia (23%) and neutropenia (17%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. 90% completed at least 4 cycles. With median follow-up of 16 months (range 0-64), 1-year PFS was 90% and 1-year OS was 98%. Conclusion The 4 drug CYCLONE regimen is highly efficacious with an overall response rate after only 4 cycles of 91% (76% ≥VGPR) at the dosing level of carfilzomib IV 20/27-36 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. CYCLONE is a combination that results in rapid and deep responses with minimal neuropathy prior to stem cell transplant. Comparative studies of this regimen with longer duration of therapy (as induction or consolidation) at the defined MTD should be considered. Disclosures: Mikhael: Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Reeder:Millenium: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Costa:Otsuka: Research Funding. Stewart:Celgene: Honoraria; Millenium: Honoraria, Research Funding; Onyx: Research Funding.

Abstract Introduction - With over 12,000 deaths from MM anticipated in 2016, nearly all patients (pts) with multiple myeloma (MM) will become "quad refractory" to IMIDs (lenalidomide and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), and eventually "penta refractory" to anti-CD38 Abs (daratumumab and isatuximab), defining high unmet need populations. Selinexor, an oral selective XPO1 inhibitor, induces nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and inhibition of translation of several oncoprotein mRNAs such as c-myc and cyclin D. Selinexor showed potent induction of apoptosis of MM cells independent of p53 signaling. In phase 1 clinical studies, selinexor with low dose dexamethasone (Sd) demonstrated potent anti MM activity in pts with MM. Methods - This phase II clinical trial evaluated Sd in pts with MM refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide ("quad"), with a subset also refractory to an anti-CD38 Ab ("penta"). Inclusion required CrCL≥20 mL/min, ANC≥1000/µL, platelets ≥50K/µL (≥30K if plasma cells were ≥50% of marrow cellularity). Pts were treated twice weekly (BIW) with oral selinexor 80 mg for 6 or 8 doses per 28 day cycle and dexamethasone (dex) 20 mg BIW. All pts received 5-HT3 antagonists. The primary objective was to determine the overall response rate (ORR) per IMWG criteria and duration of response (DOR), both adjudicated by an independent review committee (IRC). Secondary endpoints include progression free survival (PFS) and overall survival (OS). FISH analyses and gene expression profiling were performed on bone marrow aspirates. Results - 79 pts were enrolled: 48 quad (24 M/24 F, median age 62 yrs) and 31 penta (13 M / 18 F, median age 68 yrs). Both groups had a median of 7 prior treatment regimens including multiple dex-containing regimens. Baseline laboratory abnormalities included grade (Gr)≥3 anemia in 13% and Gr≥3 thrombocytopenia in 8%. Most penta pts received 8 doses / cycle (65%); most quad pts received 6 doses / cycle (83%). Common treatment-related adverse events (TRAEs) hematological: thrombocytopenia (72%, Gr 3/4 58%), anemia (48%, Gr 3 25%) and neutropenia (29%, Gr≥3 21%). TRAEs non-hematological: nausea (72%, Gr 3 6%), fatigue (62%, Gr 3 14%) anorexia (49%, Gr 3 3%), vomiting (43%, Gr3 4%), asymptomatic hyponatremia (42%. Gr 3 20%), diarrhea (42%, Gr 3 5%) and weight loss (33%, Gr 3 1%). There was one case of febrile neutropenia (1%) and one case of clinically significant bleeding related to thrombocytopenia (1%). Seventy pts have discontinued therapy: PD (73%), AEs (17%), physician/pt preference (1%) and 6 deaths (one case related to selinexor, intracranial bleed in pt with Gr4 thrombocytopenia). Nine pts remain on study. Efficacy was evaluated in 78 pts (1 pt did not have measurable disease). The IRC-determined ORR (≥PR) for all pts was 21%, including 5% VGPR. ORR was 21% for quad pts and 20% for penta pts. Clinical benefit rates (≥MR) were 32% (all), 29% (quad), and 37% (penta). Median OS was 9.3 months (mo) for all pts, >11 mo (median not reached) for responders (≥PR), and 5.7 mo for non-responders. Median DOR in responding pts was 5 mo, and median PFS in all pts was 2.1 mo. Baseline cytogenetics were assessed in 41 pts. The ORR in 18 pts with high-risk FISH abnormalities was 33% (Table 1). Notably, 3 of the 13 pts with a 17p abnormality responded (ORR 23%). Transcriptomic profiling revealed differentially expressed genes (DEGs) between responders and non-responders in both whole blood RNA and CD138+ bone marrow cells. Pathways enriched in responders included IL-6, IL-8 and IGF-1 pathways. Conclusions - Oral Sd is active in heavily pretreated pts with refractory MM, including those with MM refractory to anti-CD38 Ab and those with high-risk cytogenetic abnormalities. Response was associated with longer survival. The main toxicities of Sd are thrombocytopenia, nausea, anorexia, and fatigue. AEs were manageable with supportive care and dose interruptions/reductions. To our knowledge, this is the first report of anti-tumor activity in the penta-refractory MM population. This population of MM pts has exhausted all currently available treatment options and has an extremely poor prognosis and therefore requires new therapies. Expansion of this trial in this high unmet medical need, penta refractory population is planned. Table 1 Activity of Sd in Patients with High Risk MM Cytogenetics Table 1. Activity of Sd in Patients with High Risk MM Cytogenetics Disclosures Vogl: Constellation: Research Funding; Karyopharm: Consultancy; Acetylon: Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding. Jagannath:Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene: Consultancy. Baz:Bristol-Myers Squibb: Research Funding; Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Signal Genetics: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Merck: Research Funding. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Richter:Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Vij:Karyopharm: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Schiller:Incyte Corporation: Research Funding. Costa:Sanofi: Honoraria, Research Funding. Chari:Array Biopharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding. Siegel:Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Merck: Honoraria. Fonseca:Janssen: Consultancy; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Novartis: Consultancy; Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Bayer: Consultancy; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Saint-Martin:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment.