Citations

Background: Overexpression of the anti-apoptotic BCL-2 protein promotes multiple myeloma (MM) cell survival. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis and has shown synergistic activity with bortezomib (B) and dexamethasone (d). Phase 1 studies in relapsed/refractory (RR) MM demonstrated encouraging clinical efficacy of Ven + d in t(11;14) MM and in a broader patient (pt) population in combination with Bd. Recent results from the Phase 3 BELLINI study of Ven vs placebo (Pbo) + Bd in pts with RRMM demonstrated that pts treated with Ven + Bd had improved clinical response rates and progression-free survival (PFS) vs Pbo, although the overall survival (OS) result was in favor of Pbo. Subgroup analyses showed different efficacy and survival outcomes based on tumor cytogenetics and BCL-2 expression. Results of pre-specified subgroup analyses and additional retrospective correlative biomarker analyses in the Phase 3 BELLINI study are described herein. Methods: BELLINI (NCT02755597) was a randomized, double-blind, multicenter Phase 3 study of Ven or Pbo + Bd in pts with RRMM who received 1-3 prior therapies and were either sensitive or naïve to PIs. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo + Bd. The following biomarker analyses were performed by central laboratory assessments of pre-treatment tumor samples: BCL-2 protein expression by immunohistochemistry (IHC) analysis of bone marrow (BM) core biopsies; BCL2 gene expression by quantitative PCR (qPCR) and cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH) analysis of CD138-enriched BM mononuclear cells. Correlation between BCL-2 (protein and gene) expression, cytogenetics, and outcomes were examined by Kruskal-Wallis tests and by hazard ratio (HR) using the Cox proportional hazard model. Results: As of the data cut-off of 18 Mar 2019, 291 pts were randomized, 194 to the Ven arm and 97 to the Pbo arm. Out of the 291 pts randomized, 177 pts (61%) were evaluable by IHC, 257 pts (88%) by qPCR, and 262 pts (90%) by FISH. A broad range of BCL2 gene expression was observed (median 2-DCt: 0.212 [range: 0-5.21]), which strongly correlated with protein expression (median 2-DCt 0.115 in BCL-2 IHC Low vs 0.277 in BCL-2 IHC High, p=0.0021). t(11;14) MM had the highest levels of BCL-2 expression (23/23 BCL-2 High by IHC; median 2-DCt 0.406 vs 0.212 in t(11;14) negative, p=0.0132), however high BCL-2 expression was not limited to the t(11;14) subgroup. Univariate analyses showed higher BCL2 expression in pt tumor samples with del(13q) (median 2-DCt 0.333 vs 0.159 in pts without del(13q), p=0.0008) and gain(1q) (median 2-DCt 0. 295 vs 0.180 in pts without gain(1q), p=0.0059). Bootstrapping and aggregating thresholds from trees (BATTing) was used retrospectively to identify an estimated threshold value for BCL2 expression (2-DCt ≥0.323) that could provide optimum selection of pts with maximum improvement in PFS when treated with Ven+Bd. Biomarker subgroups with the greatest PFS improvement were t(11;14) (HR=0.10; 95% CI: 0.02-0.46, p=0.003) and High BCL2 by qPCR (HR=0.26; 95% CI: 0.13-0.51, p<0.001; Table 1). Since the t(11;14) and High BCL2 patient populations do not completely overlap (20% of High BCL2 pts were t(11;14) and 54% of t(11;14) were High BCL2), a combined subgroup analysis was performed. For pts with t(11;14) or High BCL2, the median PFS was not reached in the Ven arm vs 9.9 mo in Pbo (HR=0.26, 95% CI: 0.14-0.48, p<0.001; Table 1). Higher overall response (ORR, 88% vs 70%), very good partial response or better (≥VGPR, 73% vs 33%), and complete response or better (≥CR, 42% vs 3%) rates were observed in the Ven vs Pbo arm (Table 2). Minimal residual disease negativity (MRD-, 10-5) rate was also higher for t(11;14) or High BCL2 pts in the Ven vs Pbo arm (19% vs 0%). Median overall survival (OS) was not reached in either arm but was similar between treatment arms for the combined group with t(11;14) or High BCL2 pts (HR=0.92, 95% CI=0.39-2.16, p=0.85). In contrast, in the t(11;14) negative and Low BCL2 pts, OS favored Pbo (HR=3.13, 95% CI=1.2-8.13, p=0.019; Table 1). Conclusions: Adding Ven to Bd demonstrates significant efficacy in pts with RRMM harboring either t(11;14) or tumor cells expressing high levels of BCL2. The benefit-risk profile appears to be favorable in these subsets of pts and additional studies to gain further safety and efficacy information are warranted. Disclosures Harrison: GSK: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Celgene: Consultancy, Honoraria, 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, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De La Rubia:AMGEN: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Other: travel, accommodations, expenses. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Hungria:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Amgen: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Takeda: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Spencer:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics Australia: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: 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; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; GlycoMimetics Inc: Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garg:Janssen: Honoraria; Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses. Punnoose:Roche: Other: Stock/stock options; Genentech, Inc.: Employment. Jalaluddin:AbbVie: Employment, Other: Stock/stock options. Jia:AbbVie: Employment, Other: Stock/stock options. Yang:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Ward:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

Background Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multi-system organ dysfunction. The most frequently involved organs are the heart and kidney (individually or together), with advanced cardiac involvement conferring particularly poor outcomes. Achievement of hematologic response and improved organ function result in better outcomes. There are currently no approved treatments for AL amyloidosis; multiple myeloma (MM) treatment strategies are used for these pts. Active, tolerable treatment options specific for AL amyloidosis are needed. The oral proteasome inhibitor (PI) ixazomib (ixa) is active and approved in combination with lenalidomide (L)-dexamethasone (Dex) for the treatment of MM pts who have received ≥1 prior therapy. Methods RRAL pts with measurable disease and major organ involvement (cardiac/renal) who required treatment after 1-2 prior therapies (and were not refractory to prior PI therapy) were randomized to ixa (4.0 mg, d 1, 8, 15) plus Dex (20 mg, d 1, 8, 15, 22) or physician's choice (Dex alone or plus melphalan [M], cyclophosphamide [C], thalidomide [T], or lenalidomide [L]) in 28-d cycles until disease progression or unacceptable toxicity (or best response plus 2 cycles or maximum 18 mos therapy/600 mg total dose for MDex). Randomization was stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure. Primary endpoints were 1) overall hematologic response rate (ORR) centrally adjudicated, and 2) death or vital organ deterioration at 2 yrs. Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate; other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety. Results 168 pts were randomized to ixa-Dex (n=85) or physician's choice (n=83; 47 LDex, 24 MDex, 10 CDex, 2 TDex); median age was 65 (range 38-84) vs 66 (33-82) yrs, 60% vs 55% were male, 56% vs 63% had cardiac and 66% vs 58% had renal involvement (33% vs 23% had both) at initial diagnosis (plus 9% vs 12% liver, 12% vs 18% gastrointestinal tract, and 11% vs 10% peripheral nerve involvement), 47% vs 47% had prior bortezomib, and 47% vs 37% had prior transplant. Median time since diagnosis was 14.7 vs 15.9 mos. Hematologic responses were seen in 45 (53%) vs 42 (51%) pts receiving ixa-Dex vs physician's choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762). Higher CR rates were seen with ixa-Dex vs physician's choice (26% vs 18%). Overall survival, overall/hematologic/vital organ PFS, time to vital organ deterioration/death, DOR, time to treatment failure, and time to subsequent therapy data all favored pts treated with ixa-Dex vs physician's choice (Figure). Vital organ response rates were 36% in the ixa-Dex arm vs 11% with physician's choice (cardiac response rate: 18% vs 5%; renal response rate: 28% vs 7%). At data cut-off, pts had received a median treatment duration of 11.7 vs 4.9 mos with ixa-Dex vs physician's choice, and 21% vs 6% of pts remained on treatment. Grade ≥3 adverse events (AEs) were seen in 59% vs 56% of pts, including 33% vs 41% with drug-related grade ≥3 AEs, 45% vs 33% had serious AEs, 25% vs 20% had AEs resulting in discontinuation, and there were 6% vs 5% on-study deaths. AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (25% vs 15%), nausea (24% vs 14%), pneumonia (22% vs 16%), and peripheral neuropathy (20% vs 15%). Common (≥5% overall) grade ≥3 AEs were fatigue (9% vs 9%), anemia (2% vs 10%), cardiac failure, dyspnea (each 6% vs 4%), peripheral edema, and pneumonia (each 5% vs 5%). Conclusions Treatment with ixa-Dex significantly prolonged duration of composite survival and vital organ function, PFS, and time to subsequent therapy vs physician's choice. Moreover, ixa-Dex resulted in an improved CR rate and DOR and, although the primary endpoint of hematologic response was not met, all clinically relevant time-to-event endpoint data favored ixa-Dex vs physician's choice. Ixa-Dex was generally well tolerated and associated with a doubling of treatment duration vs physician's choice; no new safety signals were seen. TOURMALINE-AL1 is the first phase 3 trial in RRAL to show significant outcome improvements, suggesting ixa-Dex represents a new option for RRAL pts, who have limited access to therapies. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Wechalekar:Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Ono: Research Funding; Celgene: Honoraria; Janssen: Honoraria. Comenzo:Takeda: Research Funding; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Liu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faller:Phoenicia Biosciences: Equity Ownership; Briacell Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Viracta Pharmaceuticals: Equity Ownership; Boston University: Employment. Off Label Disclosure: Investigation of the oral proteasome inhibitor ixazomib in combination with dexamethasone versus physician's choice (of which there are no approved treatment options) for the treatment of relapsed/refractory primary systemic amyloidosis.

Abstract SPECC1L mutations have been identified in patients with rare atypical orofacial clefts and with syndromic cleft lip and/or palate (CL/P). These mutations cluster in the second coiled-coil and calponin homology domains of SPECC1L and severely affect the ability of SPECC1L to associate with microtubules. We previously showed that gene-trap knockout of Specc1l in mouse results in early embryonic lethality. We now present a truncation mutant mouse allele, Specc1lΔC510, that results in perinatal lethality. Specc1lΔC510/ΔC510 homozygotes showed abnormal palate rugae but did not show cleft palate. However, when crossed with a gene-trap allele, Specc1lcGT/ΔC510 compound heterozygotes showed a palate elevation delay with incompletely penetrant cleft palate. Specc1lcGT/ΔC510 embryos exhibit transient oral epithelial adhesions at E13.5, which may delay shelf elevation. Consistent with oral adhesions, we show periderm layer abnormalities, including ectopic apical expression of adherens junction markers, similar to Irf6 hypomorphic mutants and Arhgap29 heterozygotes. Indeed, SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves. Finally, we wanted to determine if SPECC1L deficiency also contributed to non-syndromic (ns) CL/P. We sequenced 62 Caucasian, 89 Filipino, 90 Ethiopian, 90 Nigerian and 95 Japanese patients with nsCL/P and identified three rare coding variants (p.Ala86Thr, p.Met91Iso and p.Arg546Gln) in six individuals. These variants reside outside of SPECC1L coiled-coil domains and result in milder functional defects than variants associated with syndromic clefting. Together, our data indicate that palate elevation is sensitive to deficiency of SPECC1L dosage and function and that SPECC1L cytoskeletal protein functions downstream of IRF6 in palatogenesis.

Abstract Background: The Checklist for Early Recognition and Treatment of Acute Illness and Injury (CERTAIN) study is a before-and-after clinical quality improvement study involving 20 countries. Our aim was to describe the challenges and solutions for study implementation across various intensive care units.Methods: After local institutional review board approval, each study center had a setup period before patient data were collected. Each center was required to accomplish 4 stages: baseline data collection, remote simulation training, local implementation, and postimplementation data collection and maintenance of process of care. We measured the time required to complete each study stage and used the Define, Measure, Analyze, Improve, and Control (DMAIC) framework to identify the challenges encountered during each stage and guide improvement strategies to facilitate implementation of CERTAIN.Results: Between June 2012 and December 2017, 55 centers from 20 countries were recruited to participate. The time to complete each stage at different centers varied significantly. The most common domains in which challenges occurred were 1) leadership support and team building, 2) communication, 3) work environment culture, 4) language barriers, 5) infrastructure and technology, and 6) sustainability. Obstacles in these 6 areas delayed reaching major milestones of the study. Different strategies were deployed to overcome these barriers: engaging leadership for support, using native-speaking clinicians during training sessions, using various communication platforms, providing personal computers to local hospitals, making in-person site visits, offering flexible training time, and supporting local centers’ grant applications. Centers that enrolled during the control phase, compared with those that enrolled earlier, had significantly shorter times and less variation in times for each study stage and for the total study time.Conclusions: By using the DMAIC method, we identified the predominant 6 domains in which challenges occurred during implementation of the global CERTAIN study and developed targeted strategies to overcome the challenges and shorten the duration of the study. The DMAIC method would be useful in improving the efficiency of other large-scale multinational quality improvement projects.

Background: Despite treatment advances, multiple myeloma (MM) remains a condition with high unmet medical need as patients (pts) relapse and become resistant to therapy. MM pts experience a range of serious disease-related symptoms and side effects impacting their functioning and health-related quality of life (HRQL). The median overall survival (OS) has improved with the advent of new treatments in the last two decades, however, the impact of newer combination treatments on pt quality of life remains unknown (Beckner, N et al. Cancer Res. 2011;183:25; Bharat, N et al. J Clin Oncol 2019;37:15(suppl):8039). Venetoclax is a novel, orally bioavailable small molecule inhibitor of BCL-2 activity in MM. In the Phase 3 double-blind, randomized clinical trial (M14-031, BELLINI) progression free survival (PFS) was studied in relapsed/refractory (RR) MM pts receiving venetoclax or placebo in combination with bortezomib and dexamethasone. In addition, patient-reported outcomes (PRO) data focused on physical functioning, pain, and fatigue from BELLINI were evaluated to better understand the overall impact on pt HRQL of adding venetoclax to bortezomib and dexamethasone-based doublet therapy. Methods: The BELLINI Phase 3 study (NCT01794520) enrolled patients ≥18 y old with R/R MM who had received 1-3 prior lines of therapy. The study met its primary endpoint of PFS (HR 0.63, 95% CI=0.44-0.89) but higher risk of death (HR 2.027, 95% CI=1.04-3.95) was observed in the treatment arm compared with placebo, although the OS data are not yet mature (Kumar, S et al. EHA Library. Jun 16 2019;273254:LB2601). The secondary HRQL endpoints included in this study were pain severity, fatigue, physical functioning (PF), and global health status, which were measured using the Brief Pain Inventory-Short Form (BPI-SF), PROMIS Fatigue Short Form surveys, and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Change from baseline to day 1 of each cycle visit (up to 25 cycles or last treatment visit) was assessed for each measure in both the treatment and placebo groups. Summary analyses compared mean and median scores between arms at each cycle. The treatment effect was evaluated in a mixed effect model controlling for the patient's baseline score, total visits (or cycles of treatment), age (<65 or ≥65), prior therapy lines, and prior proteasome inhibitor exposure. The model also included an interaction term examining treatment by visits. Results: The intention-to-treat (ITT) dataset included 194 pts (median age: 66y; 53% with 2 or 3 prior lines of therapy) in the treatment group and 97 pts (median age: 65y; 55% with 2 or 3 prior lines of therapy) in the placebo group (2:1 randomization). There was no clear evidence for an independent effect of treatment on PF (P=0.522). Pain scores across multiple measures showed a similar trend, with a statistically non-significant improvement of unadjusted average "Worst Pain" scores for the venetoclax group (P=0.289; Figure B). Non-inferiority in pain results were replicated by the pain subscale of the QLQ-30 (P=0.778), the BPI pain severity index (P=0.418), and the related BPI pain interference subscale score (P=0.603). Fatigue scores likewise demonstrated no significant differences between treatment arms whether using PROMIS Cancer Fatigue t-scores (P=0.442), raw scores (P=0.568), or the 3-item QLQ-C30 subscale (P=0.959), although there was a positive trend across cycle summary scores for the treatment group compared with the placebo group. Unadjusted QLQ-C30 PF subscale scores showed declines from baseline that were generally worse in the placebo group across 25 treatment cycles, although differences were smaller and non-significant in the adjusted model (Figure A). Conclusions: Comparable HRQL in pain severity, fatigue, and PF was observed in RRMM pts receiving venetoclax in combination with bortezomib and dexamethasone compared to pts receiving bortezomib and dexamethasone. The summary scores showed outcomes that were comparable or slightly improved for those randomized to the venetoclax combination. Results of concurrent measures of the same or associated concepts reinforced confidence in these results. Additional analyses of subgroups are ongoing (eg, t(11;14), BCL-2 expression status) and may provide further insights surrounding HRQL in these populations. Figure Disclosures Gasparetto: BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Popat:Takeda: Honoraria, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, 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, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Sanofi: Honoraria, Other: Travel or accommodations; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Maciel:Amgen: Other: funding for travel, teaching, participation in advisory boards; Janssen: Other: funding for travel, teaching, participation in advisory boards. Moreau:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Harrison:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jia:AbbVie: Employment, Other: Stock/stock options. Karve:AbbVie: Employment, Other: stock/stock options. Ma:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Devine:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Benjamin:AbbVie: Employment, Other: stock/stock options.

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells and has shown synergistic activity with the proteasome inhibitor (PI) bortezomib (B) and dexamethasone (d). Ven ± d had encouraging clinical efficacy in both t(11;14) MM and in pts irrespective of genetic background when administered with B, with a tolerable safety profile in Phase 1 studies. Here, we provide updated efficacy and safety of Ven vs placebo (Pbo) + Bd in pts with relapsed/refractory (RR) MM, including subgroup analyses, in the BELLINI study. Methods: BELLINI (NCT02755597) was a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo + Bd in pts with RRMM who received 1 - 3 prior therapies and were either sensitive or naïve to PIs. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo + Bd. Cycles 1-8 were 21-day with B 1.3 mg/m2 on Days 1, 4, 8, 11 + d 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12. Cycles 9+ were 35-day with B 1.3 mg/m2 on Days 1, 8, 15, 22 + d 20 mg Day 1, 2, 8, 9, 15, 16, 22, 23. The primary endpoint was progression-free survival (PFS) by independent review committee (IRC). Results: A total of 291 pts were randomized, 194 to the Ven arm and 97 to the Pbo arm. Median age was 66 (range, 36 - 87); 53% had ISS II/III disease; 54% received 2 or 3 prior lines of therapy; 59% had prior stem cell transplant; 70% had prior PI, 68% had prior immunomodulatory drug, 41% had both. Among pts with evaluable results, 18% had high-risk cytogenetics, 13% had MM positive for t(11;14), and 79% had high levels of BCL-2 protein by immunohistochemistry (IHC). In the primary endpoint analysis per IRC, the median PFS was 22.4 months (m) in Ven vs 11.5 m in Pbo (HR=0.630, p=0.01), with a median follow-up of 18.7 m (as of 26 Nov 2018). As of updated analysis based on a data cut-off of 18 March 2019, the median PFS (per investigator [INV]) was 22.9 m in Ven vs 11.4 m in Pbo (HR=0.587, p=0.001; Table 1), with a median follow-up of 22.7 m. Per INV, higher overall response (ORR, 84% vs 70%, p=0.009) and very good partial or better response (≥VGPR, 61% vs 40%, p<0.001; Table 2) rates were observed in Ven vs Pbo. Minimal residual disease negativity rate (by next-generation sequencing) was also higher in the Ven arm vs Pbo (MRD- [10-5], 13% vs 1%). Median duration of response was 23.4 m for Ven and 12.8 m for Pbo. In the overall population, median overall survival (OS) was not reached in either arm but continued to favor Pbo (HR 1.474, 95% CI=0.870-2.498). A total of 70 deaths have been reported, 51 (26%) in the Ven arm and 19 (20%) in the Pbo arm. In the safety population (N=289), the most common treatment-emergent adverse events (TEAEs; Ven/Pbo) were diarrhea (59%/48%), nausea (37%/22%), constipation (35%/31%), and fatigue (31%/32%). The most common Grade 3/4 TEAEs were neutropenia (18%/8%), pneumonia (17%/12%), anemia (16%/15%), thrombocytopenia (15%/30%), and diarrhea (15%/12%); 23%/12% discontinued Ven due to a TEAE. The rates of serious AEs (51%/51%) and serious infections (30%/28%) were comparable between arms. There were 69 deaths in the safety population: in the Ven arm, 14 were treatment-emergent (TE; treatment start to 30 days after discontinuation) and 36 were non-TE (>30 days after treatment discontinuation); in the Pbo arm, 1 was TE and 18 were non-TE. In the t(11;14) subgroup, median PFS has not been reached for pts receiving Ven, but was 9.3 m for Pbo (HR=0.095; per INV). In the t(11;14)-negative (neg) subgroup, median PFS was 22.4 m and 10.7 m for Ven and Pbo, respectively (HR=0.627; per INV). Median OS has not been reached in either arm for the t(11;14) and t(11;14)-neg subgroups, although the HR favored Ven in t(11;14) pts, and Pbo in t(11;14)-neg pts. Analyses indicate that low BCL-2 expression by IHC and high-risk cytogenetics (defined as t(4;14, t(14;16), or del(17p)) were associated with decreased PFS and OS in the Ven arm (Table 1). In the high-risk cytogenetics pts, median PFS was 11.4 m in both arms (HR=0.99), and median OS has not been reached in either arm but favors Pbo (HR=10.6). In the subgroup with low BCL-2 expression by IHC, median PFS was 11.7 m and 17.0 m for Ven and Pbo, respectively (HR=1.42), and median OS was 21.3 m in the Ven arm and not reached in Pbo (HR=4.58). Conclusions: Updated analysis of BELLINI continue to reflect a favorable benefit-risk profile in t(11;14) pts, with meaningful clinical responses and improvement in PFS, as well as a positive trend in OS in this subgroup when treated with Ven + Bd. Disclosures Moreau: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Harrison:Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. De La Rubia:Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; Takeda: Honoraria, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Hungria:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Amgen: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Janssen Cilag: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Gay:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: 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: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mikala:Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Punnoose:Genentech, Inc.: Employment; Roche: Other: Stock/stock options. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Sood:AbbVie: Employment, Other: Stock/stock options. Jalaluddin:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Ward:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

AbstractThe role of long noncoding RNAs (lncRNAs) in the epithelial‐mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify an lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA. Expression profiling of lncRNAs revealed that highly upregulated in liver cancer (HULC) was highly expressed, and induced, by transforming growth factor‐β in PDAC cells and their EVs. Knockdown of HULC decreased PDAC cell invasion and migration by inhibiting the EMT. Thus, HULC could be transferred by EVs, and promote EMT, invasion, and migration in recipient PDAC cells. To assess the roles of HULC, PDAC cell xenografts in nude mice were established. Knockdown of HULC in PDAC cells implanted in mice inhibited tumor growth. Moreover, microRNA‐133b suppressed PDAC cell invasion and migration by inhibiting the EMT through targeting HULC. Furthermore, serum samples were obtained from 20 PDAC and 22 intraductal papillary mucinous neoplasm (IPMN) patients, as well as 21 healthy individuals. Analysis of serum EV HULC expression by digital PCR showed that HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. Additionally, HULC showed good predictive performance for discriminating PDAC, suggesting that the analysis of EV‐encapsulated HULC would contribute to the diagnosis for human PDAC. Extracellular vesicle‐transported HULC promotes cell invasion and migration by inducing the EMT, and microRNA‐133b suppresses the EMT by targeting HULC. Extracellular vesicle‐encapsulated HULC could be a potential circulating biomarker for human PDAC.

Background: Noninvasive electrocardiographic imaging (ECGi) is used clinically to map arrhythmias before ablation. Despite its clinical use, validation data regarding the accuracy of the system for the identification of arrhythmia foci is limited. Methods: Nine pigs underwent closed-chest placement of endocardial fiducial markers, computed tomography, and pacing in all cardiac chambers with ECGi acquisition. Pacing location was reconstructed from biplane fluoroscopy and registered to the computed tomography using the fiducials. A blinded investigator predicted the pacing location from the ECGi data, and the distance to the true pacing catheter tip location was calculated. Results: A total of 109 endocardial and 9 epicardial locations were paced in 9 pigs. ECGi predicted the correct chamber of origin in 85% of atrial and 92% of ventricular sites. Lateral locations were predicted in the correct chamber more often than septal locations (97% versus 79%, P =0.01). Absolute distances in space between the true and predicted pacing locations were 20.7 (13.8–25.6) mm (median and [first–third] quartile). Distances were not significantly different across cardiac chambers. Conclusions: The ECGi system is able to correctly identify the chamber of origin for focal activation in the vast majority of cases. Determination of the true site of origin is possible with sufficient accuracy with consideration of these error estimates.

Abstract Abstract 627 Myeloproliferative diseases (MPD) are clonal hematologic disorders that present with increased numbers of functional, mature, terminally differentiated myeloid elements. Even though genetic, biochemical and functional studies have provided important insights into the pathogenesis of MPDs, the role of epigenetic changes in disease pathobiology is not well elucidated. We performed the HELP assay to study genome-wide methylation patterns in cases of Polycythemia Vera (PV), Essential Thrombocytosis (ET) and Idiopathic Myelofibrosis (IMF) and compared it with normal matched controls. The HELP assay uses differential methylation specific digestion by HpaII and MspI followed by amplification, two color labeling and hybridization to quantitatively determine individual promoter CpG methylation of 25636 loci. Analysis of 26 MPD neutrophil samples comprising 9 cases of ET, 6 cases of PV and 11 Cases of IMF was performed and compared to normal healthy controls. Unsupervised clustering based on global methylation profiles showed that IMF cases formed a distinct epigenetic cluster, while PV and ET cases were more similar to the normal controls. Further analysis of epigenetic differences between these groups showed that PV and ET samples were characterized by aberrant hypermethylation when compared to controls and had 143 genes that were uniformly hypermethylated. These genes are involved in pathways regulated by the NF-Kb and HNF-4alpha transcription factors. IMF on the other hand was characterized by both aberrantly hyper (n=162) and hypomethylated (n=95) loci when compared to controls. The pathways affected by hypomethylated genes were involved in cytokine cell signaling and MAP kinases. We subsequently validated these observations in an independent set of 8 IMF cases compared to 8 age matched controls. Methylation profiles obtained from whole blood by the HELP assay were able to clearly separate IMF cases from controls demonstrating the validity of our observations. These changes were quantified on a whole genome level by the Luminometric methylation assay (LUMA) that also revealed significantly more hypomethylation in IMF when compared to PV and ET cases (49% hypomethylation in IMF vs. 38% in PV/ET, p<0.05). Selected changes were validated by Mass Array sequencing. We next wanted to determine the epigenomic effects of Jak2V617F mutation and compared methylation profiles of MPD cases with and without the mutation. We observed that cases with Jak2 mutation had a higher number of differentially hypomethylated loci. This striking difference was seen by the LUMA assay also with 67% hypomethylation seen in mutant cases when compared to 48% in those without the mutation (p=0.02). This observation was validated in vitro in a cell line (FDCP) that expressed wither WT or mutant Jak2 kinase. We observed that expression of the mutant kinase led to global hypomethylation. This observation builds on recent data demonstrating nuclear binding of the mutant Jak2 kinase and its effects on the histone epigenetic machinery. In conclusion, we report that MPDs are characterized by various novel epigenetic alterations that affect important functional pathways and IMF is grossly epigenetically distinct from ET and PV. The Jak2 mutation also affects the methylome and leads to global hypomethylation that potentially contributes to the genomic instability and disease pathobiology. Disclosures: No relevant conflicts of interest to declare.