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The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10−5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd.

PURPOSE Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

BACKGROUND Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment.

Proteasome inhibitors are the backbone of AL amyloidosis treatment – bortezomib being most widely used. Carfilzomib is a proteasome inhibitor licenced to treat multiple myeloma; autonomic and peripheral neuropathy are uncommon toxicities with carfilzomib. There is limited data on the use of carfilzomib in AL amyloidosis. Here, we report the results of a phase Ib dose-escalation study of Carfilzomib-Thalidomide-Dexamethasone (KTD) in relapsed/refractory AL amyloidosis. The trial registered 11 patients from 6 UK centres from September 2017 to January 2019; 10 patients received at least one dose of trial treatment. 80 adverse events were reported from 10 patients in the 1st three cycles. One patient experienced dose-limiting toxicity (acute kidney injury) at a dose of 45 mg/m2, and another patient had a SAR (fever). Five patients experienced an AE ≥ grade 3. There were no haematologic, infectious, or cardiac AE ≥ grade 3. The overall haematological response rate (ORR) at the end of three cycles of treatment was 60%. Carfilzomib 45 mg/m2 weekly can be safely given with thalidomide and dexamethasone. The efficacy and tolerability profile appears comparable to other agents in relapsed AL amyloidosis. These data provide a framework for further studies of carfilzomib combinations in AL amyloidosis.

IntroductionMultiple myeloma is a malignancy of plasma cells with around 6000 new cases per year in the UK. Cyclophosphamide plus prednisolone is considered a standard of care for disease and symptom control in the advanced relapsed or refractory myeloma setting within the UK NHS. The selective nuclear export inhibitor, selinexor, has been relatively well tolerated in previous clinical trials and offers promise when used in combination with a wide range of other anti-cancer treatments. Here, we investigate if the addition of selinexor can improve responses to cyclophosphamide plus prednisolone without adding prohibitive toxicity.Methods and analysisMUKtwelve is a UK-based, randomised, controlled, open, parallel group, multicentre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with relapsed or refractory multiple myeloma. A calibration arm will receive cyclophosphamide and prednisolone alone (CP). Participants who experience disease progression on the CP arm may, if eligible, receive SCP.The MUKtwelvetrial results will be the first to assess clinical efficacy of selinexor with low-dose CP in relapsed/refractory multiple myeloma. It is widely accepted that the relapsing-remitting nature of the disease is accompanied by cellular changes that often result in the requirement for novel agents and drug combinations to regain disease control. Patients also often experience cumulative toxicities throughout their treatments, limiting the treatment intensity that can be given at relapse. Thus, there is a need for novel effective combination therapies with acceptable toxicity profiles.Ethics and disseminationEthics approval is obtained. Results will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN15028850.

As a part of a growing information society, nowadays the issue of security is more crucial than ever. In order to achieve high level of security, the potential of accurately recognize subjects based on their unique measurable physiological or behavioral characteristics has been receiving an increased concern by the research and development community. As biometrics has advanced, iris has been considered a preferred trait because unique pattern texture, lifetime stability, and regular shape contribute to good segmentation and recognition performance. The incredible uniqueness of iris patterns as well as the ability to capture iris images non-invasively has motivated us to develop automated system for iris recognition based on 2-D iris images. The 2DPCA (two-dimensional Principal Component Analysis) and GA (Genetic Algorithm) have been used as feature extraction and feature selection techniques for reducing the dimensionality of iris features without the loss of relevant Information. The Back Propagation Neural Network (BPNN) is implemented using Levenberg–Marquardt’s learning rule for iris recognition. The experimental results illustrated that the 2DPCA-GA achieved a high classification accuracy of 96.40 %.

This report details the case of a woman in her 50s who presented with symptoms of congestive heart failure and raised inflammatory biochemical markers. Her investigations included an echocardiogram, which revealed a large pericardial effusion and a subsequent CT-thorax/abdomen/pelvis showing extensive retroperitoneal, pericardial and periaortic inflammation and soft-tissue infiltration. Genetic analysis of histopathological samples detected a V600E or V600Ec missense variant within codon 600 of the BRAF genewith BRAF variants, confirming the diagnosis of Erdheim-Chester disease (ECD).The patient’s clinical management involved several treatments and interventions with input from a variety of clinical specialties. This included the cardiology team for pericardiocentesis, the cardiac surgical team for pericardiectomy due to recurrent pericardial effusions and finally the haematology team for further specialist treatment with pegylated interferon and consideration of BRAF inhibitor therapy. The patient became stable following treatment with significant improvement in her heart failure symptoms. She remains under regular joint cardiology and haematology team follow-up. The case highlighted the importance of using a multidisciplinary approach to best manage the multisystem involvement of ECD.

To judge the ability of convolutional neural networks (CNNs) to effectively and efficiently transfer image representations learned on the ImageNet dataset to the task of recognizing COVID-19 in this work, we propose and analyze four approaches. For this purpose, we use VGG16, ResNetV2, InceptionResNetV2, DenseNet121, and MobileNetV2 CNN models pre-trained on ImageNet dataset to extract features from X-ray images of COVID and Non-COVID patients. Simulations study performed by us reveal that these pre-trained models have a different level of ability to transfer image representation. We find that in the approaches that we have proposed, if we use either ResNetV2 or DenseNet121 to extract features, then the performance of these approaches to detect COVID-19 is better. One of the important findings of our study is that the use of principal component analysis for feature selection improves efficiency. The approach using the fusion of features outperforms all the other approaches, and with this approach, we could achieve an accuracy of 0.94 for a three-class classification problem. This work will not only be useful for COVID-19 detection but also for any domain with small datasets.

Introduction: The BOSTON study is a Phase 3 trial comparing the novel triplet regimen of once weekly oral selinexor with once weekly bortezomib and dexamethasone (SVd) versus standard twice weekly Vd in patients with multiple myeloma (MM) after 1-3 prior therapies. The SVd regimen conferred a 47% increase in median progression-free survival (PFS) and time to next therapy (TTNT), higher overall response rates (ORR) and deeper responses compared to Vd. Furthermore, this is the first trial of a bortezomib-based triplet therapy (i.e., SVd) that showed lower rates of overall and Grade ≥2 peripheral neuropathy (PN) compared with doublet Vd while conferring a longer PFS, and the regimen requires ~35% fewer clinic visits than standard twice weekly Vd. This abstract reports analyses of the patient reported outcomes (PROs) in BOSTON to evaluate patterns in therapy-induced PN symptoms, pain and function. Methods: PROs were assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-CIPN20 questionnaires. The QLQ-CIPN20 assesses patients' experience of symptoms and functional limitations related to chemotherapy induced PN (CIPN) and has 3 subscales: sensory, motor, and autonomic. The QLQ-C30 includes several functional and symptom scales and focuses on physical functioning, role functioning, and pain subscales as pre-specified domains of interest. Mixed effects repeated measures models were fit to the longitudinal data to estimate differences over time. Meaningful change thresholds derived using anchor- and distribution-based methods or estimated from the literature were used to identify patients who had experienced a meaningful worsening of symptoms or deterioration in functioning. Time to definitive deterioration was defined as the time from randomization to the first occurrence of meaningful deterioration that was not followed by subsequent improvement. Cox proportional hazard models compared the hazard rates between arms adjusted for baseline questionnaire score, randomization stratification factors (prior PI therapy, number of prior anti-MM regimens, R-ISS stage at MM) and prior bortezomib exposure. Results: A total of 402 patients were enrolled in the trial; 388 completed a baseline QLQ-CIPN20 assessment and are included in these analyses. Based on the mixed model repeated measures analysis (Table 1), a benefit was demonstrated for SVd in change from baseline to Day 106 for sensory (-5.3 points difference, p=0.0006) and pain (-6.6, p=0.007) scores. Patients in the SVd arm had a greater increase in autonomic symptom scores (+5.0, p=0.022). The number of patients with definitive deterioration in QLQ-CIPN20 sensory symptoms was greater in the Vd arm (86 patients, 45.7%) compared to 52 (27.7%) patients in the SVd arm (Table 2). The median time to deterioration was 20.7 months (95% confidence interval [CI]: 15.4, not estimable [NE]) in the SVd arm compared to 12.5 months (95% CI: 7.8, 19.9) in the Vd arm. The adjusted hazard ratio (HR) comparing time to deterioration in sensory scores between SVd and Vd arms was 0.53 (95% CI: 0.38, 0.75; p = 0.0004). Worsening of motor symptoms also trended in favor of SVd with a HR = 0.72 (p=0.052). Roughly half of the patients in each treatment arm experienced worsening autonomic symptoms (54.6% and 48.4%, SVd and Vd respectively) with no significant difference between arms (HR=1.14, p=0.37). While not statistically significant, fewer SVd patients had definitive deteriorations in pain and physical function compared to Vd patients, with similar or extended time to deterioration (Table 2). Conclusions: In the setting of a significant increase in PFS and TTNT, patients with MM after at least one prior therapy who received weekly SVd reported lower sensory symptom and pain scores but higher autonomic symptom scores. Further, patients treated with twice weekly Vd experienced a more rapid rate of sensory symptom worsening and a trend to more rapid worsening of motor symptoms, compared to patients treated with SVd. The improved pain scores in patients treated with SVd may be related to superior disease control. The reduction in PN-related pain and sensory symptoms observed with SVd in the setting of increased PFS and TTNT supports a potentially improved patient experience and decreased health care burden and long term morbidity. Disclosures Leleu: Janssen: Honoraria; BMS-celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Oncopeptide: Honoraria; AbbVie: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria. Beaumont:Clinical Outcomes Solutions: Current Employment; Karyopharm Therapeutics: Consultancy. Yu:Clinical Outcomes Solutions: Current Employment; Karyopharm Therapeutics: Consultancy. Hudgens:Clinical Outcomes Solutions: Current Employment; Sierra Oncology: Consultancy; Karyopharm Therapeutics: Consultancy. Auner:Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Quach:Sanofi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria. Delimpasi:Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; GENESIS: Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Hajek:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chai:Karyopharm Therapeutics Inc: Current Employment. Ma:Karyopharm: Current Employment, Current equity holder in private company. Tang:Karyopharm Therapeutics: Current Employment. Leong:AbbVie: Ended employment in the past 24 months; Karyopharm Therapeutics: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Introduction Selinexor is a first-in-class, oral, potent selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, leading to cancer cell apoptosis. Selinexor has demonstrated antimyeloma activity in triple class refractory multiple myeloma (MM) [Chari et al. NEJM 2019]. Selinexor synergizes with proteasome inhibitors (PIs) in PI-sensitive and -resistant cell lines and produces high response rates in patients with PI refractory and non-refractory MM (Bahlis et al. Blood 2018). In the phase 3 BOSTON study, the combination of once weekly (QW) selinexor, QW bortezomib, and dexamethasone (SVd) in patients who had received 1-3 prior therapies led to a significantly longer (47%) median progression-free survival (PFS) of 13.93 vs 9.46 months, with a hazard ratio of 0.70 (P=0.0075) compared to standard twice weekly bortezomib and dexamethasone (Vd). In addition, SVd regimen produced higher response rates and deeper responses (ORR: 76.4% vs 62.3% and ≥CR 16.9% vs 10.2%) compared with Vd. The benefit with SVd was observed across all efficacy endpoints and was associated with lower incidence and severity of bortezomib-induced peripheral neuropathy. Here we analyzed the effect of prior PI therapy (bortezomib, carfilzomib, ixazomib) on the efficacy and safety of SVd compared with Vd. Methods BOSTON is an open-label, randomized phase 3 study in patients with MM comparing SVd (QW oral selinexor 100 mg, QW subcutaneous bortezomib 1.3 mg/m2, and BIW oral dexamethasone 20 mg), versus Vd (BIW bortezomib 1.3 mg/m2 and QIW dexamethasone 20 mg). Patients previously treated with a PI must have had at least a partial response (PR) to the PI and 6 months since the last PI regimen. The study primary end point was PFS. Here we report subgroup analysis of treatment outcomes based on prior PI treatment. Results Subgroups consisted of PI naïve patients (n=95; 24%) and patients with prior PI treatment (n=307; 76%). Both the subgroups and study arms were comparable for baseline patient demographic and disease characteristics. However, those with prior PI treatment more frequently had a previous stem cell transplant (38% vs 24%) or 3 lines of prior anti MM therapy (21% vs 13%). Median PFS was improved with SVd compared with Vd in both the PI naïve group (PFS not reached (NR) vs 9.7 months; HR 0.2585 [95% CI, 0.1116-0.5988]; P=0.0003) and in the PI treated group (11.7 vs 9.4 months; HR 0.7839 [95% CI, 0.5791-1.0612]; P=0.06). Other efficacy endpoints are shown in the table. Peripheral neuropathy ≥grade 2 (a secondary study endpoint) was less frequent in the SVd compared with the Vd arm (PI naïve: 25.5%, Vd 43.8%, P=0.0302; PI treated: SVd 19.6%, Vd 31.4%, P=0.0092). Adverse events of ≥grade 3 occurred in 71% of patients in the PI naïve group (SVd 77%, Vd 65%) and 74% of patients in the PI treated group (SVd 88%, Vd 60%). Thrombocytopenia was more frequent in patients in the SVd arms (PI naïve: SVd 32%, Vd 13%; PI treated: SVd 42%, Vd 19%) as was anemia (PI naïve: SVd 15%, Vd 6%; PI treated: SVd 16%, Vd 12%), and fatigue (PI naïve: SVd 15%, Vd 2%; PI treated: SVd 13%, Vd 1%). Conclusions The once-weekly SVd combination was associated with significant clinical benefit and reduced peripheral neuropathy as compared with standard twice-weekly Vd in patients with MM and 1-3 prior therapies, regardless of prior therapy with a PI. However, the benefits of SVd over Vd were more pronounced in patients who had never been treated with a PI (PFS HR 0.26), suggesting that selinexor could be an optimal partner for combining with weekly bortezomib as the first PI-containing MM regimen. Figure 1 Disclosures Mateos: Roche: Honoraria; Seattle Genetics: Honoraria; EDO Mundipharma: Honoraria; Adaptive Biotechnologies: Honoraria; GlaxoSmithKline: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Auner:Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Leleu:AbbVie: Honoraria; GSK: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria. Hajek:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Kryachok:Janssen, Bayer, Karyopharm, MSD, Acerta, AvbbVie, Debiopharm: Research Funding; Takeda, Janssen: Consultancy; Takeda, MSD, AbbVie, Ro: Other: Travel, accommodations, expenses; Takeda, Janssen, Novartis, Roche, MSD, Bayer: Consultancy, Research Funding. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Moreau:Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Honoraria. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Anderson:Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Bahlis:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy: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. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Introduction Selinexor is a first-in-class, oral, potent selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, leading to cancer cell apoptosis. Selinexor has demonstrated antimyeloma activity in triple class refractory multiple myeloma (MM) [Chari et al. NEJM 2019]. Selinexor synergizes with proteasome inhibitors (PIs) in PI-sensitive and -resistant cell lines and produces high response rates in patients with PI refractory and non-refractory MM. (Bahlis et al. Blood 2018). In the phase 3 BOSTON study, the combination of once weekly (QW) selinexor, QW bortezomib and dexamethasone (SVd) in patients who had received 1-3 prior therapies led to a significantly (47%) longer median progression-free survival (PFS) of 13.93 versus 9.46 months (HR 0.70; P=0.0075) compared to standard twice weekly bortezomib and dexamethasone (Vd). In addition, SVd regimen produced higher response rates and deeper responses (ORR: 76.4% vs 62.3% and ≥CR 16.9% vs 10.2%) compared with Vd. The benefit with SVd was observed across all efficacy endpoints and was associated with lower incidence and severity of bortezomib-induced peripheral neuropathy. Here we present subgroup analyses according to number of prior lines of therapy and prior treatment with lenalidomide (LEN). Methods BOSTON is an open-label, randomized phase 3 study in patients with MM comparing SVd (QW selinexor 100 mg, QW subcutaneous bortezomib 1.3 mg/m2, and 20 mg twice weekly [BIW] dexamethasone), versus Vd (1.3 mg/m2 bortezomib BIW and dexamethasone 20 mg 4 x weekly [QIW]). Patients previously treated with a PI must have had at least a partial response (PR) to the PI and 6 months since the last PI regimen. The study primary end point was PFS. Results Of the 402 patients in the BOSTON study, 198 (49%) had 1 prior line versus 204 (51%) with 2-3 prior lines. In addition, 154 (38%) comprised the LEN treated subgroup, versus 248 (62%) in the LEN naïve subgroup. Of note, 41% patients received prior thalidomide, which is consistent with most of the BOSTON study patients being treated in the EU. Baseline demographic and disease characteristics were well balanced between treatment arms across subgroups. A very good partial response (VGPR) or better to most recent prior line anti-MM therapy was more frequent in patients with 1 prior line of therapy (63% vs 41%) versus those with 2-3 prior lines of therapy. Patients with prior LEN therapy were more likely to have had 2-3 prior therapies (72.1%) compared with LEN naive patients (37.5%). As shown in the table, SVd was associated with longer PFS compared with Vd in all subgroups. Overall response rates (ORR) and times-to-next-treatment (TTNT) were statistically greater with SVd compared with Vd in all subgroups. Rates of very good partial response or better (VGPR) were statistically greater for SVd vs Vd in the LEN-naïve group and 1 prior treatment group. Grade ≥2 peripheral neuropathy (a key secondary endpoint prespecified in the study) occurred less frequently across all SVd subgroups compared with Vd: LEN treated (21% SVd, 37% Vd, P=0.0166); LEN-naïve (21% SVd, 33% Vd, P=0.0252), 1 prior line (21% SVd, 33% Vd, P=0.0501); 2-3 prior lines (21% SVd, 36% Vd, P=0.0107). Adverse events of ≥grade 3 were more commonly reported in the SVd treatment arm than in the Vd arm, LEN treated (83% SVd, 57% Vd), LEN-naïve (76% SVd, 55% Vd), 1 prior line (77% SVd, 56% Vd), 2-3 prior lines (81% SVd, 56% Vd), and were mostly managed with dose modification and/or supportive treatment. Pneumonia occurred at comparable rates between treatment arms. There were no differences between subgroups in grade 3 adverse events. Conclusions In the BOSTON study, once-weekly SVd significantly improved PFS, ORR, TTNT and reduced rates of ≥grade 2 peripheral neuropathy compared with Vd regardless of number of prior treatments or whether patients were previously treated with LEN. Adverse events were managed with dose modification and treatment-related discontinuation rates did not differ between the 2 regimens for any subgroup. The PFS of 16.6 months with SVd after 1 prior therapy, and the HR of 0.63 in patients with prior LEN treatment support the use of once-weekly SVd for the second line treatment of MM following a LEN-containing regimen. Table Disclosures Mateos: Takeda: Honoraria; Abbvie: Honoraria; GlaxoSmithKline: Honoraria; EDO Mundipharma: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Jagannath:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria. Delimpasi:GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Kryachok:Takeda, Janssen, Novartis, Roche, MSD, Bayer: Consultancy, Research Funding; Janssen, Bayer, Karyopharm, MSD, Acerta, AvbbVie, Debiopharm: Research Funding; Takeda, MSD, AbbVie, Ro: Other: Travel, accommodations, expenses; Takeda, Janssen: Consultancy. Gavriatopoulou:Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Auner:Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Leleu:BMS-celgene: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria. Sinha:Dr Reddys Lab, Intas Pharmaceuticals, Karyopharm Therapeutics: Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Quach:Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Moreau:Novartis: Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Levy:Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Anderson:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Bahlis:Genentech: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Chai:Karyopharm Therapeutics Inc: Current Employment. Arazy: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. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272

The proteasome inhibitors, carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these proteasome inhibitors in combination with cyclophosphamide and dexamethasone (KCd vs. VCd) in second-line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomized patients (2:1) to KCd (n=201) or VCd (n=99); responding patients on carfilzomib were randomized to maintenance carfilzomib (n=69) or no further treatment (n=72). Primary endpoints were: (i) very good partial response (non-inferiority, odds ratio [OR] 0.8) at 24 weeks, and (ii) progression-free survival. More participants achieved a very good partial response or better with carfilzomib than with bortezomib (40.2% vs. 31.9%, OR=1.48, 90% confidence interval [CI]: 0.95, 2.31; non-inferior), with a trend for particular benefit in patients with adverse-risk disease. KCd was associated with higher overall response (partial response or better, 84.0% vs. 68.1%, OR=2.72, 90% CI: 1.62, 4.55, P=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, P

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562.

Developments in management and treatment of myeloma have extended survival rates in the myeloma population (Kumar et al, 2008) resulting in older patients living with the effects of myeloma and treatments and also the concurrent problems of ageing. The myeloma multidisciplinary team (MDT) in Leicester UK introduced frailty assessment for newly diagnosed patients over 65 years using QIP methodology as a Clinical Nurse Specialist (CNS) led initiative. The aim being to improve MDT decision making and documentation about treatment attenuation and furthermore to proactively identify frailty to enable enhanced support for frailer patients. This was aimed to be the initial development of an older person’s pathway of care. The International Myeloma Working Group (IMWG) frailty score (Palumbo et al 2015) and Clinical Frailty Score (Rockwood et al, 2005) were used as assessment tools, the latter being widely used throughout UK healthcare settings. Following initial audit and project planning, stakeholder engagement was undertaken using questionnaires, experience surveys and presentations. Interventions were planned using the Plan-Do-Study-Act (PDSA) method. Data was collected via audit of a number of team documentation sources and via patient feedback questionnaires. The aim of the project was surpassed and in both PDSA 2 and 3, 100% of newly diagnosed patients were frailty assessed, results being discussed in MDT, documented and communicated to primary care. The quality of information about patient frailty and function assisted MDT decision-making processes and improved over the QIP. This enabled clear rationales for MDT decisions to be documented in relation to individualised patient treatment options. There were no extra demands on CNS time, in fact consultation time decreased. Patient experience was maintained. The MDT recognised during the project that frailty scores need to be used with caution taking into consideration myeloma burden and presenting complications to avoid the risk of under-treatment (American Society of Haematology, 2019). Frailty scoring is now embedded into practice and assessment.

[Background]: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., [Patients and Methods]: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., [Results]: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., [Conclusion]: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., This study was sponsored by Janssen Research & Development, LLC.

NA

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (

Background In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. Methods The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. Results Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. Conclusions Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. Trial registration ClinicalTrials.gov identifier NCT02195479, registered September 21, 2014

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1–3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n=70; Vd, n=71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n=125; Vd, n=136). Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p=0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p= 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p=0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p=0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.

Summary Background Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma. Methods This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib–dexamethasone (isatuximab group) or carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. Findings Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. Interpretation The addition of isatuximab to carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. Funding Sanofi. Video Abstract Video abstractYouTube link: https://youtu.be/5kXtQQlzRh4

Summary Background Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. Methods This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov , NCT03110562 . The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. Findings Of 457 patients screened for eligibility, 402 were randomly allocated—195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group—and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2–19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4–19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73–not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11–10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53–0·93], p=0·0075). The most frequent grade 3–4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32–0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. Interpretation A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. Funding Karyopharm Therapeutics.

Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.

Background: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. Methods: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. Findings: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34–0·51]; p

Background: Successful vaccination against SARS-CoV2 is highly effective in preventing serious COVID-19 illness and is particularly recommended for at risk populations including patients with multiple myeloma (MM). However, there is uncertainty to which extent modern intensified therapies targeting plasma cell features might attenuate vaccination responses; some early vaccination recommendations for MM have proposed extended treatment breaks of several weeks to maximise vaccination success. Such an approach can be challenging in UHiR MM and pPCL, where maintaining treatment intensity is hallmark for preventing rapid relapse of the aggressive tumor. To address this uncertainty, we measured post-vaccination serological responses in patients treated uniformly with intensified Dara-VR consolidation and Dara-R maintenance post-ASCT for UHiR NDMM or pPCL in the UK OPTIMUM/MUKnine trial (NCT03188172). Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM or pPCL were recruited to OPTIMUM and received intensified post-ASCT consolidation with Dara-VR(d) for 18 cycles followed by maintenance with Dara-R until progression. In an exploratory analysis, centrally stored serum samples available for patients with a completed and documented vaccination history of two doses of an anti-SARS-CoV2 vaccine were analyzed for serological vaccine responses Total IgG/IgA/IgM Anti-SARS-CoV-2 spike glycoprotein was measured by ELISA (MK654; The Binding Site). As per UK national guidance and local availability, patients received two vaccine doses 12 weeks apart of either tozinameran (Pfizer/Biontech) or vaxzevria (AstraZeneca); serum taken at least 3 weeks after patients received their second dose was analyzed. Results were correlated with baseline characteristics and annotated with treatment and response data. Patient with available matched serological and vaccination status data at time of data cut-off (09 JUL 2021) were included. Collection of vaccination status data is ongoing and updated results comprising additional patients enrolled in OPTIMUM, as well as antigen levels, will be presented. Data will also comprise longitudinal antibody level measurements for patient with available sequential material. Results: Serological vaccine response data was available for 40 OPTIMUM patients with documented completed double vaccination status. Median patient age was 58.5 years (range 39-70) and clinical and molecular tumor features were similar to the overall trial safety population. All patients had received their second dose before June 2021. Of the 40 patients, 42.5% had received tozinameran and 57.5% vaxzevria. Baseline characteristics of the two groups were comparable. At time of second vaccine dose, 55% of patients were receiving Dara-VR consolidation treatment and 45% Dara-R maintenance. There was no recommendation to pause trial treatment for purposes of vaccination and no extended times off treatment for this reason were reported. Overall, 72.5% of patients had a positive vaccine antibody level as per manufacturer cut-point for high specificity evidence of antigen exposure (infection or vaccine). The response rate was nominally higher for vaxzevria (91.3%) than for tozinameran (47.1%), a dysbalance that will be further investigated with ongoing extension of the cohort. Of note, 90% of patients analyzed had reached a complete response (CR) of their MM prior to being vaccinated, and the majority of patients not in CR had a positive vaccine response. Response rates were nominally slightly higher in patients in receipt of Dara-R maintenance at time of second dose with 77.8% compared to Dara-VR consolidation with 68.2%. Conclusions: These results show a high serological response rate to COVID-19 vaccination in UHiR MM patients receiving intensified post-ASCT consolidation and maintenance therapy in remission. Findings suggest that continuation of intensified post-ASCT therapy for patients with aggressive tumors and a high risk of relapse are compatible with serological responses to commonly used COVID-19 vaccines. Disclosures Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy. Hall: BMS/Celgene: Research Funding; Janssen: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Pratt: Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Cook: Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Amgen: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy.

Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a 'digital comparator arm' trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the 'MyXI prior'. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior. Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life. Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare ( Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. Figure 1 Figure 1. Disclosures Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.

Introduction: Treatment of multiple myeloma (MM) has greatly improved over the last two decades. However, most pts will relapse and develop refractory disease. Most anti-cancer regimens require dose modifications (interruption, reduction, or discontinuation) during the treatment course in order to optimize the therapeutic window; appropriate modifications improve tolerability while maintaining anti-cancer activity. Selinexor, an oral selective inhibitor of XPO1-mediated nuclear export (SINE) compound, enforces the nuclear retention and functional activation of tumor suppressor proteins within the nucleus and prevents the translation of oncoproteins. The combination of once weekly (QW) selinexor, QW bortezomib, and dexamethasone (XVd) is FDA approved for previously treated MM. Compared to standard twice weekly (BIW) bortezomib plus dexamethasone (Vd) and using 40% less bortezomib and 25% less dexamethasone, XVd demonstrated significantly prolonged median progression-free survival (PFS) and time-to-next-treatment (TTNT), increased the overall response rate (ORR), reduced rates of peripheral neuropathy, and showed a trend towards improved overall survival (OS) in the Phase 3 randomized BOSTON study (NCT03110562). The recommended starting dose of selinexor in XVd is 100mg QW, but the median dose administered in BOSTON was 80 mg QW. Here, we analyzed the efficacy outcomes and adverse events (AEs) in pts whose dose was reduced compared to those where it was not. Methods: The BOSTON study consisted of two arms: pts treated with selinexor QW (100mg), bortezomib QW (1.3mg/m 2) and dexamethasone BIW (20 mg) (XVd; n=195 in the intention-to-treat [ITT] population) compared to standard BIW Vd. Results: Of the XVd pts in the BOSTON study, 126 had a dose reduction of selinexor and 69 did not. The median age was 66.0 in both groups (range: with reduction, 47-87; without, 40-84) and the median number of prior therapies was 1.0 (range, 1-3) for both groups (Table 1). The median time to dose reduction in these pts was 68 days (range, 8-561 days). The median duration of study treatment for these pts was 34.5 weeks (range, 3-120 weeks) compared to 20.0 weeks (range, 1-118) in pts with no dose reduction. In the group with dose reduction, the median dose of selinexor received per week was 71.3 mg (range, 29.7, 101.4) compared to 100 mg (range, 33.3, 136.7) in pts with no reduction. Pts who dose reduced had a median PFS of 16.6 months compared to 9.2 months in pts who did not (one-sided p value, The most common adverse events (AEs; dose reduction and without dose reduction) of any grade were thrombocytopenia (69.8% and 42.0%), nausea (55.6% and 40.6%), and fatigue (49.2% and 29.0%). The rate of treatment discontinuation in the dose reduced group was 24.6% and 14.5% without dose reductions. In the dose reduced group, there were 6 (4.8%) deaths and 6 (8.7%) in the group with no dose reduction. As pts with a dose reduction stayed on therapy for a prolonged period of time, to best understand the impact of dose reduction on the AE, we present the duration-adjusted incidence rates of AEs of clinical interest. The duration-adjusted incidence rates of AE were considerably lower after dose reduction of selinexor compared to the rates on or before dose reduction: thrombocytopenia (62.5% vs 47.6%), nausea (31.6% vs 7.3%), fatigue (28.1% vs 9.9%), decreased appetite (21.5% vs 6.4%), anemia (17.9% vs 10.3%), and diarrhea (12.9% vs 5.2) (Table 3). Conclusions: While all pts on XVd initiated therapy at 100mg selinexor QW, and it was associated with very low rates of progressive disease (1 in 195 pts), appropriate dose reductions of selinexor were associated with a longer PFS, DOR, and TTNT, and significantly reduced AE with improved tolerability, highlighting dose reductions as an important tool to personalize and optimize the therapeutic window for pts with RRMM. Figure 1 Figure 1. Disclosures Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Badros: Janssen: Research Funding; GlaxoSmithKline: Research Funding; J&J: Research Funding; BMS: Research Funding. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Moreau: Celgene BMS: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Gavriatopoulou: Takeda: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Garg: University Hospital Leicester: Current Employment; Amgen Janssen Novartis Sanofi Takeda: Honoraria; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses. Gironella Mesa: BMS, Janssen: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Radinoff: Janssen, Pfizer, Novartis, Servier etc.: Consultancy, Honoraria; Amgen, Bayer, Takeda, etc.: Research Funding; the Bulgarian Minister of Health: Membership on an entity's Board of Directors or advisory committees. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, 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, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bila: Takeda, AMGEN, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. 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. Richardson: GlaxoSmithKline: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

Introduction: Patients with multiple myeloma (MM) have a high rate of relapse resulting in a need for multiple lines of therapy. In contrast to MM with standard risk cytogenetics (SR-Cyto), high-risk cytogenetics (HR-Cyto) in MM such as del(17p), t(4;14), t(14;16), and gain(1q) (≥3 copies), can result in shorter progression-free survival (PFS) and overall survival (OS) with less durable responses. Treatment regimens that can overcome the negative effect of HR-Cyto abnormalities are required to address this area of unmet medical need. Exportin 1 (XPO1), is overexpressed in many hematologic and solid tumor malignancies including MM, and exports tumor suppressor proteins from the nucleus to the cytoplasm, leading to their inactivation. Elevated levels of XPO1 are correlated with more aggressive MM and resistance to therapy and confers a poor prognosis. The potent oral XPO1 inhibitor, selinexor, has been approved as a triplet combination with bortezomib and dexamethasone for previously-treated MM. In the Phase 3 BOSTON study, treatment with XVd in patients with previously treated MM significantly prolonged median PFS and improved the overall response rate (ORR), with a trend towards a prolonged OS amongst all patients as well as those with HR cytogenetics. Methods: We performed post hoc analyses on patients with previously-treated MM from the XVd arm of the Phase 1b/2 study STOMP (NCT02343042) and the Phase 3 BOSTON (NCT03110562) study to determine the effects of cytogenetic abnormalities on outcomes. The HR-Cyto group included patients with at least one of the following cytogenetic abnormalities at initial diagnosis or screening: del(17p), t(4;14), t(14;16), or gain(1q) (≥3 copies). Efficacy was based on independent review committee. Results: A total of 106 patients with HR-Cyto were identified, including del(17p) (n=25), t(4;14) (n=25), t(14;16) (n=10), and gain(1q) (n=80). There were 131 patients classified as SR-Cyto including those with unknown cytogenetics. Baseline demographics were similar between groups with median age of 66 years old (range 40-87). Patients with HR-Cyto had a median PFS of 12.9 months and patients with SR-Cyto had a median PFS of 16.6 months; PFS on the BOSTON Vd control arm were 8.6 and 9.5 months with HR- and SR-Cyto, respectively. Of the individual abnormalities, a PFS of 13.2 and 13.9 months was observed in the t(4;14) and gain1q subgroups, respectively. Of the HR-Cyto subgroups with more than 10 patients, a similar median OS was observed in comparison to SR-Cyto and ranged from 20.4 months to not reached. The response of XVd treatment was maintained across HR-Cyto risk subgroups, with an ORR of 76.4% overall and the following values for subgroups: del(17p) (72.0%), t(4;14) (88.0%), and gain1q (73.8%). The ORR of the SR group was 69.5%. Of all patients that received XVd, there were 6 CRs (5.7%) and 32 VGPRs (30.2%) in the HR group and 9 CRs (6.9%) and 29 VGPRs (22.1%) in the SR group. The ORRs on the BOSTON Vd control arm were 57.7% and 64.7% for HR- and SR-Cyto, respectively. The rates of the most common treatment emergent adverse events (TEAEs) of any grade were similar across risk groups (HR- vs SR-Cyto): thrombocytopenia (65.1% vs. 54.2%), nausea (53.8% vs. 53.4%), fatigue (47.2% vs. 45.0%) decreased appetite (37.7% vs. 42.0%) and anemia (34.6% vs 40.5%). Rates of AEs of any grade peripheral neuropathy (PN) were 35.8% overall, 40.0% in del(17p), t(4;14) (40.0%), t(14;16) (30.0%), gain(1q) (38.8%), and 23.7% in the SR group. The rates of PN in the HR and SR groups of the XVd arm of the BOSTON and STOMP studies were 37.1% and 29.6% and 11.1% and 15.2%, respectively. The corresponding rates for Vd alone in the BOSTON study were 48.6% and 47.0%. Conclusions: Patients with MM with HR-Cyto treated with XVd demonstrated a comparable ORR and PFS, with a manageable safety profile compared to patients with SR-Cyto, supporting the use of XVd in patients with any cytogenetic profile. These results are consistent with the distinct and broad mechanism of action associated with XPO1 inhibition and the use of the agent in earlier lines of therapy. Further assessment of selinexor in combination with other therapies in patients with MM across the entire cytogenetic spectrum is warranted. Figure 1 Figure 1. Disclosures Bahlis: Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Richard: Karyopharm, Janssen: Honoraria. White: Amgen, Antengene, BMS/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: Consultancy, Honoraria. Chen: Gilead: Research Funding; BMS, Janssen, Abbvie, Novartis, Gilead, AstraZeneca: Consultancy. Delimpasi: Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Celgene: Consultancy; Karyopharm: Research Funding. Sebag: Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Gavriatopoulou: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria. Lentzsch: Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; Janssen: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kriachok: Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau; Takeda, Roche, Abbivie, Janssen, MSD: Consultancy. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Garg: Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria; University Hospital Leicester: Current Employment. Quach: Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, 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, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jagannath: Karyopharm Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos: Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: 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; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Bluebird bio: Honoraria; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. 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. Richardson: Secura Bio: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.