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Abstract To enable modularization for network-based prediction, we conducted a review of known methods conducting the various subtasks corresponding to the creation of a drug–target prediction framework and associated benchmarking to determine the highest-performing approaches. Accordingly, our contributions are as follows: (i) from a network perspective, we benchmarked the association-mining performance of 32 distinct subnetwork permutations, arranging based on a comprehensive heterogeneous biomedical network derived from 12 repositories; (ii) from a methodological perspective, we identified the best prediction strategy based on a review of combinations of the components with off-the-shelf classification, inference methods and graph embedding methods. Our benchmarking strategy consisted of two series of experiments, totaling six distinct tasks from the two perspectives, to determine the best prediction. We demonstrated that the proposed method outperformed the existing network-based methods as well as how combinatorial networks and methodologies can influence the prediction. In addition, we conducted disease-specific prediction tasks for 20 distinct diseases and showed the reliability of the strategy in predicting 75 novel drug–target associations as shown by a validation utilizing DrugBank 5.1.0. In particular, we revealed a connection of the network topology with the biological explanations for predicting the diseases, ‘Asthma’ ‘Hypertension’, and ‘Dementia’. The results of our benchmarking produced knowledge on a network-based prediction framework with the modularization of the feature selection and association prediction, which can be easily adapted and extended to other feature sources or machine learning algorithms as well as a performed baseline to comprehensively evaluate the utility of incorporating varying data sources.

With the launch of the National Cancer Institute’s Precision Medicine Initiative in 2015, there has been a shift to trial designs that tailor health care solutions to individual patients by using a screening platform and by moving away from the one-trial/one-biomarker-at-a-time approach. To make precision medicine a reality, it is critical to identify and validate potential biomarkers to help select patients who will truly benefit from a targeted therapy. In this article, we discuss five trial designs: enrichment, umbrella, basket, subgroup, and window of opportunity. For each trial design, we describe the design characteristics, use ongoing or completed trials as case studies, provide any recent advances to the trial design, and discuss advantages and disadvantages of each design.

AbstractIntroductionUlcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes.MethodsThis retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models.ResultsAmong 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy.DiscussionThis study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.

Abstract BACKGROUND There is a paucity of investigation on the impact of spondylolisthesis surgery on back pain-related sexual inactivity. OBJECTIVE To investigate predictors of improved sex life postoperatively by utilizing the prospective Quality Outcomes Database (QOD) registry. METHODS A total of 218 patients who underwent surgery for grade 1 degenerative lumbar spondylolisthesis were included who were sexually active. Sex life was assessed by Oswestry Disability Index item 8 at baseline and 24-mo follow-up. RESULTS Mean age was 58.0 ± 11.0 yr, and 108 (49.5%) patients were women. At baseline, 178 patients (81.7%) had sex life impairment. At 24 mo, 130 patients (73.0% of the 178 impaired) had an improved sex life. Those with improved sex lives noted higher satisfaction with surgery (84.5% vs 64.6% would undergo surgery again, P = .002). In multivariate analyses, lower body mass index (BMI) was associated with improved sex life (OR = 1.14; 95% CI [1.05-1.20]; P < .001). In the younger patients (age < 57 yr), lower BMI remained the sole significant predictor of improvement (OR = 1.12; 95% CI [1.03-1.23]; P = .01). In the older patients (age ≥ 57 yr)—in addition to lower BMI (OR = 1.12; 95% CI [1.02-1.27]; P = .02)—lower American Society of Anesthesiologists (ASA) grades (1 or 2) (OR = 3.7; 95% CI [1.2-12.0]; P = .02) and ≥4 yr of college education (OR = 3.9; 95% CI [1.2-15.1]; P = .03) were predictive of improvement. CONCLUSION Over 80% of patients who present for surgery for degenerative lumbar spondylolisthesis report a negative effect of the disease on sex life. However, most patients (73%) report improvement postoperatively. Sex life improvement was associated with greater satisfaction with surgery. Lower BMI was predictive of improved sex life. In older patients—in addition to lower BMI—lower ASA grade and higher education were predictive of improvement.

Abstract Abstract 3660 Background: Evidence based guidelines for management of acute coronary syndrome (ACS) in patients (pt) with congenital hemophilia A & B (HA/HB) and von Willebrand disease (VWD) are lacking and confined to case reports and expert opinion (Schutgens et al, 2009). Aims: To review the management of ACS in patients with HA/HB and VWD followed at the Mayo Comprehensive Hemophilia Center. Methods: All pt with HA/HB and VWD who presented with symptoms of ACS to our institution between 2000 and 2010 were retrospectively identified using the hemophilia center database. Medical notes were reviewed, focusing on types of intervention and bleeding complications. Results: Ten pt, HA = 3 and VWD=7, experienced 13 ACS or suspected ACS events. Median age at time of event was 74 years (45 – 80 years), with M:F = 7:3. All 13 events presented with chest pain. 6/13 events presented to the emergency department (ED), 4/13 events presented to a Mayo outpatient clinic, 2/13 events occurred in hospitalized pt and 1 event was a direct referral from a non-Mayo outpatient clinic to our Cardiology in-patient service. ED pt received 325 mg aspirin (HD-ASA) in 5/6 events and intravenous unfractionated heparin (UFH) in 4/6 events, per ACS management guidelines. One ED pt did not receive either ASA or UFH due to atrio-venous malformation (AVM)-related gastrointestinal (GI) bleed (Hg 6 g/dL). Of the inpatients, one received HD-ASA while the other was already on daily low-dose aspirin (LD-ASA); neither received UFH. The pt admitted directly to the Cardiology in-patient service received HD-ASA but not UFH. Of the outpatients, one was started on LD-ASA while another was already on LD-ASA; none received UFH as they were considered low-risk for ACS but warranted further diagnostic evaluation. Coronary angiography (CA) via a right femoral arterial approach was performed in 12/13 events; of which 5 received prophylactic factor concentrate prior to CA. One pt (no prior prophylaxis) experienced minor bleeding at the puncture site, requiring factor concentrate replacement post-CA. Another patient continued to receive prophylactic factor concentrate for 4 days post-CA. Major bleeding or bleeding requiring red blood cell (RBC) transfusion did not occur. Following CA, in 2/12 events, pt underwent bare metal stent (BMS) placement and glycoprotein 2b/3a inhibitor infusion, with no bleeding complications. In 4/12 events, pt proceeded to coronary artery bypass grafting (CABG) and received prophylactic factor concentrate; of which one required multiple post-operative RBC transfusions due to ongoing AVM-related GI bleed. The remaining 6 events were managed medically. The 1 pt who did not undergo CA experienced a post-total knee replacement ACS and was medically managed. On discharge, in 5/13 events, pt were started on daily ASA (HD-ASA, n=2; LD-ASA, n=3). 2 of these received a month of clopidogrel, in addition to LD-ASA, due to BMS placement and were not placed on prophylactic factor concentrate for the duration of dual anti-platelet agent therapy; there were no bleeding complications. Daily ASA was continued in 4/13 events (HD-ASA, n=1; LD-ASA, n=3), with 1 patient receiving both LD-ASA and a month of warfarin for DVT prophylaxis post-orthopedic surgery. In the remaining 4 events, pt were dismissed without ASA, due to bleeding complications (n=2) or the perceived risk of bleeding outweighed the benefit (n=2). During long term follow-up, 1 patient had to stop HD-ASA after 2 years due to GI bleed, while another patient stopped LD-ASA due to episodic epistaxis requiring nasal packing. Conclusion: In this small series of patients, outcomes of management of ACS did not result in significant acute bleeding complications. In addition, long-term treatment with anti-platelet agents appears to be safe and should be strongly considered for all patients with coronary artery disease. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: The anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Bortezomib (BTZ) can inhibit MCL-1 activity by stabilizing the MCL-1 antagonist, NOXA. Venetoclax is an orally bioavailable, highly selective BCL-2 inhibitor, which enhances BTZ efficacy in MM xenograft models. This Phase 1 study evaluates venetoclax with BTZ and dexamethasone (Dex) in patients (pts) with relapsed/refractory MM. Methods: Objectives include safety, pharmacokinetics, preliminary efficacy and maximum therapeutic dose of venetoclax with BTZ and Dex. A fixed dose of venetoclax ranging from 50 to 800 mg PO daily, according to dose cohort assignment, was given in combination in cycles (C) 1-11 and alone in C12 and beyond. Dose escalation decisions were made using the continual reassessment method. Pts received BTZ (1.3 mg/m2 SC, days [D] 1, 4, 8, 11) and Dex (20 mg PO, D1, 2, 4, 5, 8, 9, 11, 12) in cycles (C)1-8 (21D), then BTZ + Dex (D1, 8, 15, 22) in C9-11 (35D). Results: Forty-one pts were enrolled as of June 15, 2015 (pts in each cohort: 50 mg, n=3; 100 mg, n=5; 200 mg, n=6; 300 mg, n=7; 400 mg, n=6; 500 mg, n=7; 600 mg, n=5; 800 mg, n=2). Median age was 65 (38-79); 15/26 F/M. 14 were ISS stage I, 11 stage II, 11 stage III, 5 missing. Median (range) number of prior lines of therapy was 5 (1-15). Thirty-five pts had received prior BTZ (10 refractory), 34 prior lenalidomide (22 refractory); 29 had undergone stem cell transplantation. Based on FISH analysis, 5 pts had MM with t(11;14); 3 with t(4;14), 20 with del 17p, and 10 with del 13q. Treatment-emergent AEs occurring in ≥20% of pts were constipation (37%), diarrhea (37%), thrombocytopenia (32%), asthenia (29%), insomnia (29%), anemia (27%), peripheral neuropathy (27%), dyspnea (24%), peripheral edema (22%), and nausea (20%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (20%), and anemia (17%). SAEs occurred in 18 pts; SAEs in ≥2 pts were cardiac failure, embolism, pyrexia, respiratory failure, sepsis, thrombocytopenia (n=2 each, no SAEs were venetoclax-related). Twenty-nine pts have discontinued treatment: 23 due to PD, 2 due to AEs [adenocarcinoma; cardiac and respiratory decompensation attributed to Dex (DLT at 300 mg)], and 4 withdrew consent. Three deaths occurred (all due to PD). No TLS occurred. In preliminary PK analyses (n=41), dose-normalized venetoclax exposure when given with BTZ+Dex was similar when compared to venetoclax monotherapy in MM as well as CLL and NHL pts. Forty of 41 pts were evaluable for efficacy. All responses occurred in BTZ sensitive or naïve pts. Median (range) duration or response was 5.9 (0-14.1) months in all pts, 8.5 (2.3-11.4) months in BTZ naïve pts, and 4.7 (0-14.1) months in BTZ-sensitive pts. Conclusions: Venetoclax with BTZ and Dex has an acceptable safety profile in heavily pretreated MM pts; no new safety signals were identified compared to other venetoclax studies. These early data suggest the combination of proteasome and BCL-2 inhibition resulted in anti-tumor activity. Responses were observed only in pts naïve or sensitive to prior BTZ (ORR = 100% and 58%, respectively) and occurred in all dose cohorts. The study is currently enrolling pts in the 1000 mg dose escalation cohort. Figure 1. Figure 1. Disclosures Moreau: Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Agarwal:Amgen, Millennium: Consultancy; Celgene, Onyx: Speakers Bureau; AbbVie: Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Touzeau:AbbVie: Research Funding. Darden:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Verdugo:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; AbbVie: Research Funding.

Abstract Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM. Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS). Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax. Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table). Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable. Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. Figure 1. Figure 1. Disclosures Kumar: Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

Abstract Introduction: In multiple myeloma, randomized trials of maintenance therapy using thalidomide or lenalidomide following autologous transplant (ASCT) demonstrated prolonged progression-free survival (PFS), but overall survival benefit was inconsistent. The MY.10 trial (n=332) demonstrated improved PFS with thalidomide-prednisone maintenance therapy, but quality of life was inferior and overall survival was not improved. As a randomized trial with a no-treatment control arm and biospecimen collection, MY.10 provides a unique opportunity to identify predictors of benefit from therapy that could be used to personalize treatment. Immunomodulatory drug action is mediated in part through binding to cereblon (CRBN) and downregulation of IRF4. Candidate single nucleotide polymorphisms (SNPs) were selected from the CRBN/IRF4 pathway and other genes previously associated with myeloma prognosis, drug response and toxicity from literature review. The aim of this study was to investigate associations between candidate SNPs and benefit from immunomodulatory compound-based maintenance therapy, as well as prognostic impact. Methods: Genomic DNA was extracted from samples preserved in Trizol¨. SNPs were genotyped using TaqMan¨ genotyping assays on the ViiA7 qPCR platform. Analysis was performed on 187 patients with available samples and clinical data (86 in treatment arm; 101 in observation arm). Cox regression models were performed using SAS clinical 2.0 for prognostic impact of a single SNP on PFS, assessed with and without adjusted covariates (age, stage, performance status and response to ASCT). In treatment benefit analysis, PFS was modeled with genotype, treatment assignment and their interaction term. Results: SNPs with significant prognostic impact for PFS in all 187 patients were found in CRBN (rs1672753) (HR 0.59, 95%CI 0.4-0.86; p=0.006) and the following SNPs which had been found to be prognostic in prior studies were validated: CYP1A1 (rs1048943) (HR 1.98, 95%CI 1.19-3.27; p=0.008), CYP1B1 (rs1056836) (HR 0.72, 95%CI 0.52-0.99; p=0.043), and trend toward significance for SNP in CYP1A2 (rs2069514) (HR 2.02, 95%CI 0.98-4.15; p=0.057). Of these, only the CYP1A1 SNP was found to be possibly predictive of greater benefit from maintenance therapy. A SNP in ABCA1 (rs363717), previously associated with thalidomide-induced neuropathy,‎ was prognostic in this study (HR 1.44, 95%CI 1.03-2.02; p=0.033) but not predictive of treatment benefit. Table 1 lists SNPs associated with a differential level of benefit from maintenance therapy, including SNPs in FAM179a and ICAM1 that were possibly associated with harm from maintenance therapy. Table 1. SNPs and treatment interaction with significant impact on PFS. HR represent hazard ratio of treatment versus observation for a given genotype group. Asterisk Indicates trend toward significance. Wildtype Heterozygote & mutant p-value interaction Gene dbSNP ID SNP HR 95% CI HR 95% CI FAM179A rs1053667 T>C 0.46 0.33, 0.66 2.28 0.78, 6.65 0.003 ICAM1 rs1799969 G>A 0.51 0.36, 0.73 1.75 0.83, 3.70 0.007 CASP3 rs1049216 A>G 0.82 0.54, 1.25 0.41 0.25, 0.69 0.029 IRF4 rs12203592 C>T 0.69 0.47, 1.02 0.38 0.21, 0.69 0.062* CYP1A1 rs1048943 A>G 0.62 0.44, 0.87 0.11 0.02, 0.52 0.079* Conclusion: Previously identified SNPs in drug metabolism and drug efflux genes were validated to be prognostic in this cohort. The prognostic but not predictive significance of a SNP in CRBN suggests a possible role for CRBN in multiple myeloma disease biology independent of immunomodulatory therapy. SNPs predictive of differing degrees of benefit from immunomodulatory maintenance were found in genes involved in immunomodulatory activation, drug action and cell adhesion mediated drug resistance; SNPs in FAM179A and ICAM1 were possibly associated with harm from thalidomide maintenance and could potentially be used to identify patients unsuitable for immunomodulatory maintenance therapy. These results may be applicable to lenalidomide and pomalidomide, since immunomodulatory compounds exhibit similar chemical structures and mechanisms of action. Validation of these SNPs in prospective clinical trials involving other immunomodulatory can test this hypothesis. Further studies are needed to confirm our findings. Disclosures Off Label Use: thalidomide and prednisone maintenance for multiple myeloma. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Johnson & Johnson: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Celgene Canada: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Seftel:Celgene: Honoraria, Research Funding. Howsen-Jan:Celgene: Honoraria, Research Funding. Reece:Amgen: Honoraria; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Onyx: Consultancy; Millennium Takeda: Research Funding; Lundbeck: Honoraria; Otsuka: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Shepherd:Celgene: Honoraria, Research Funding. Chen:Celgene: Honoraria, Research Funding. Djurfeldt:Celgene: Research Funding. Reiman:Soricimed Biopharma Inc: Consultancy, Other: Scientific Advisory Board for Soricimed.

Abstract Early response to therapy, including assessment of MRD is a powerful prognostic factor in childhood ALL. However, there are many other known prognostic factors, and the precise relationship among these and MRD has been incompletely explored. In COG protocol P9900, patients were assigned to one of 3 risk-directed therapies based on NCI risk group, as well as TEL-AML1 translocations (TEL) and simultaneous trisomies of chromosomes 4 and 10 (DT). Infants and Ph+ patients were excluded. Good risk patients (9904) comprised NCI SR patients with either TEL or DT without CNS disease. Poor risk patients (9906) included a subset of NCI HR patients with particularly unfavorable risk factors based largely on age and white count, while 9905 had both NCI SR and HR patients not eligible for 9904 or 9906, including NCI HR patients with TEL or DT. MRD was satisfactorily measured with at least .01% sensitivity by 4-color flow cytometry in the marrow at end of induction (D29) or in blood at Day 8 (D8). D29 MRD was associated with poor outcome in all studies, and in both HR and SR patients on 9905 as shown: Study 4 y EFS ± SE (n) p value MRD <.01% MRD >.01% 9904 Overall 94±1%(668) 75±6%(105) <.0001 TEL-AML1 94±2%(367) 68±12%(38) <.0001 DT 95±1%(316) 80±7%(69) <.0001 9905 NCI-Standard Risk 89±2%(462) 63±6%(119) <.0001 9905 NCI-High Risk 83±4%(292) 49±9%(73) <.0001 9906 74±6%(156) 39±8%(84) <.0001 The proportion of D29 MRD positive DT(17.9%) patients was higher than that of TEL patients (9.4%) but MRD was also prognostic when each group was considered separately; similar findings were seen in HR TEL and DT patients. TEL or DT was associated with a significantly better prognosis in both HR and SR patients who were MRD negative, but were not favorable factors in MRD positive patients. D8 blood MRD was also prognostic in all studies, with higher MRD levels generally associated with poorer outcome. Patients who were both D29 and D8 MRD negative had a good outcome overall (93% 4 y EFS); combining all favorable risk factors, including TEL, DT, NCI risk group, D8 and D29 MRD identified a group of patients (about 13% of B-precursor ALL patients) with 98± 1% 4 y EFS. In multivariate analysis, D29 MRD was the most important prognostic factor. NCI Risk group, DT and D8 blood were also significant, but TEL and day 8 morphologic assessment of marrow were not. We conclude that MRD is a major prognostic factor in childhood ALL even accounting for other risk factors. The prognostic significance of TEL and DT depends on MRD status. The combination of good risk clinical and genetic factors, and absence of MRD in both D8 blood and D29 marrow identifies a group of patients with outstanding outcome on limited therapy.

Abstract Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA). Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P&lt;0.0001); estimated 12-month PFS rates were 72% vs 28%, respectively. ORR was 88% with DVd vs 70% with Vd (P=0.0040), with ≥very good partial response (VGPR) rates of 72% vs 42% (P&lt;0.0001), and ≥complete response (CR) rates of 30% vs 20% (P=0.1199), respectively. For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P&lt;0.0001). Estimated 12-month PFS rates were 55% vs 27%, respectively. ORR was significantly higher with DVd vs Vd (80% vs 60%; P=0.0001), along with significantly higher rates of ≥VGPR (52% vs 22%; P&lt;0.0001) and ≥CR (13% vs 3%; P=0.0019). Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P&lt;0.0001) and ≥CR (20% vs 5%; P=0.0261). Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting. Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. Figure Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Figure. Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.