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Introduction Notable advances have been made in multiple myeloma management (MM) in recent years. The monoclonal antibodies daratumumab (dara) and elotuzumab (elo) are integral in the management of relapsed/refractory MM and are moving into the frontline setting for transplant ineligible patients. Despite many trials evaluating the efficacy of these agents, there is no consensus on the optimal integration of these agents into the current paradigm of MM management. There is a paucity of data to guide the selection of one antibody over the other, and little is known about whether the use of one prior antibody alters the efficacy of other agents in subsequent lines of therapy. We retrospectively analyzed MM patients treated with both elo and dara during the course of their disease to assess whether the sequence of elo followed by dara or dara followed by elo led to better outcomes. Methods We reviewed the records of MM patients ≥ 18 years old who received both dara and elo at any time during treatment at MD Anderson Cancer Center. We evaluated the time to next treatment (TTNT), defined as the start date of one treatment to the start of the next treatment, and the overall response rate (ORR) (partial response or greater) to dara and elo. TTNT and ORR were calculated for dara when administered as the first antibody during treatment and to dara when administered as the second antibody (elo given during prior lines of treatment). We evaluated TTNT and ORR when elo was administered as the first antibody during treatment and to elo when administered as the second antibody (dara given during prior lines of treatment). The association with categorical patient variables (age, race, immunoglobulin class, number of prior lines of therapy, agent co-administered with the second monoclonal antibody given) was analyzed using Fisher exact tests. Outcomes were estimated using the Kaplan-Meier method and differences in survival among groups were assessed using two-sided log-rank tests. Results We identified 56 patients treated with both dara and elo. We excluded 6 for missing data; 56% of the 50 patients were male; 70% were Caucasian; 56% with IgG subclass paraprotein; 66% kappa light chain restricted. Patients were heavily pre-treated; most with >5 lines of therapy prior to initiation of dara or elo. Elo was the first agent received in 64% of patients. Independent of treatment order, the ORR to elo and dara were 72% and 88% respectively. When elo was administered prior to dara (elo first), the ORR was 78%, and 61% when administered after dara (elo second). When dara was administered prior to elo (dara first), the ORR was 89%, and 88% when administered after elo (dara second). There was no statistical difference in ORR (78% vs 89%) for the initial antibody given, but there was a significant difference in ORR (61% vs. 88%) to the agent given second (p=0.04). Of the variables assessed, only the antibody class had a statistically significant association with outcomes; IgG was associated with better responses when elo was administered as the second agent. TTNT analysis included 47 (of 50) evaluable patients. With elo given first, median TTNT was 6.28 months, and 2.23 months when given second. With dara given first, median TTNT was 8.97 months and 4.60 months when given second. There was no statistically significant difference in TTNT for either the first or second agent administered. There was a statistically significant improvement in TTNT in Caucasian patients compared to other races when elo was given first, but no other clinical factor association was statistically significant. Conclusions Our data, though retrospective and single-center, demonstrate that responses to dara are similar whether administered as the first or second monoclonal antibody used in the treatment of MM. However, prior treatment with dara negatively impacts responses to elo in subsequent lines of therapy. Similarly, independent of the sequence of administration, TTNT was prolonged with dara compared to elo. Our findings suggest that elo followed by dara may be the preferred sequence of monoclonal antibody therapy as responses to elo decreased when administered after dara, but responses to dara were stable irrespective of elo administration. These findings warrant further investigation particularly as dara is now being used more often in the frontline setting. Further evaluation is also needed to determine any association with additional patient factors such as cytogenetics. Disclosures Lee: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Thomas:Amgen Inc: Research Funding; Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding. Orlowski:Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Poseida: Research Funding.

Background The introduction of multiple novel agents and regimens for NDMM and relapsed/refractory MM (RRMM) has improved outcomes while increasing the complexity of treatment selection and disease management. The real-world effectiveness of many novel-agent-based regimens remains to be elucidated. INSIGHT MM (NCT02761187) is the largest global, prospective, observational MM study to date. It aims to understand global NDMM/RRMM disease and pt characteristics, treatment patterns, and clinical outcomes, as well as regional variations. Here we report data for 1056 NDMM pts enrolled from July 1, 2016 to April 27, 2018. Methods INSIGHT MM is enrolling ~4200 adult pts with NDMM/RRMM (1-3 prior therapies) from 15 countries; 9 in Europe (EU), 3 in Latin America (LA), the United States (US), and 2 in Asia. Pts will be followed prospectively for ≥5 yrs. Data are collected from hospital/clinic records at baseline (MM-specific disease characteristics, prior therapies) and every 3 mos (disease management, effectiveness, safety). Results At data cut-off, 1056 NDMM pts had been enrolled from 14 countries, including 495 (47%) from EU, 361 (34%) from the US, 112 (11%) from LA, and 88 (8%) from Taiwan. Median age at enrollment was 64 (range 32-89) yrs and 139 (13%) pts were aged >75 yrs (14%/12%/11%/13% in EU/US/Taiwan/LA); 57% of pts were male (60%/58%/61%/39% in EU/US/Taiwan/LA); 72%, 13%, and 8% were White/Caucasian, Asian, and Black/African American, respectively. Overall, 62% of pts were treated at academic centers and 38% in community settings. Based on accrual at data cut-off, regional differences were observed, with more pts treated at academic centers in EU/Taiwan (88%/91%) vs the US/LA (30%/25%). 87% of pts were treated outside of clinical trials (88%/82%/95%/98% in EU/US/Taiwan/LA). Bone pain (32%, including 33%/28%/40%/37% in EU/US/Taiwan/LA), weakness/fatigue (anemia; 11%, including 12%/10%/6%/18% in EU/US/Taiwan/LA), and kidney problems (5%, including 3%/3%/17%/2% in EU/US/Taiwan/LA) were the most common reasons for pts seeking care; 32% (36%/32%/22%/24% in EU/US/Taiwan/LA) were asymptomatic at diagnosis. At diagnosis, 27%/26%/31% of pts had physician-reported ISS Stage I/II/III MM, and 88% had ECOG PS 0-1; 8% of pts had hypercalcemia, 34% creatinine clearance 3 bone lesions. The most common reasons for initiating therapy were the presence of CRAB criteria, e.g. bone involvement (54%) and anemia (37%). At start of treatment, fixed-duration therapy, treat-to-best-response, and treat-to-progression approaches were planned for 38%, 29%, and 31% of pts, respectively. The most frequently administered regimens are shown in the Table; 20%/66% of pts received a doublet/triplet. V-based regimens were the most frequently used. Regional differences in regimen selection are emerging: among IMiDs, T is most commonly prescribed in EU, Taiwan, and LA; R is more common in the US. After a median follow-up of 9.3 mos, 72 (7%) pts had discontinued the study, most often due to death (57%), consent withdrawal (14%), or change of treatment provider (11%). At data cut-off, data for 236 (22%) pts who received 1st-line ASCT were available (median age 60 yrs; 12%/63%/25% of pts aged 65 yrs). Of these, 64% received ASCT at academic centers; 42% of pts each in EU and the US received ASCT vs 11% in Taiwan and 4% in LA. The most frequently administered regimens in ASCT-eligible (n=429) vs ASCT-ineligible (n=571) pts were VC±d (21% vs 21%), VR±d (19% vs 17%) and VT±d (17% vs 10%). At data cut-off, 115 NDMM pts had progressed to 2nd-line therapy; 99 pts received a PI with 1st-line therapy, of whom 33 (33%) then received a PI-based regimen in 2nd line; 61 pts received an IMiD with 1st-line therapy, of whom 35 (57%) then received an IMiD-based regimen in 2nd line. Among 1st/2nd-line pts, 2%/12% received monoclonal antibody therapy. Conclusions PIs and IMiDs remain the global backbones of MM therapy, with V-based regimens most commonly used in NDMM pts, regardless of intended transplant status. These data from INSIGHT MM are beginning to elucidate regional differences in disease presentation and treatment selection, including higher numbers of pts receiving ASCT in the US/EU vs Taiwan/LA, which are likely reflective of differences in healthcare systems and access to MM treatments in the participating countries. Future studies will evaluate the impact of these regional variations on outcomes. Table. Table. Disclosures Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Hungria:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Leleu:Karyopharm: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; BMS: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Davies:Abbvie: Consultancy; Janssen: Consultancy, Honoraria; Takeda: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; ASH: Honoraria; MMRF: Honoraria. Costello:Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Rifkin:Takeda: Consultancy; EMD Serono: Consultancy; McKesson: Equity Ownership; Celgene: Consultancy; Amgen: Consultancy; Sandoz: Consultancy; Boehringer Ingelheim: Consultancy. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Chari:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, 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, Research Funding; The Binding Site: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Berdeja:Teva: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Zonder:Takeda: Honoraria; Coelum: Honoraria; BMS: Research Funding; Celgene: Consultancy, Honoraria; Alnylam: Honoraria; Janssen: Honoraria; Pharmacyclics: Other: DSMC. Abonour:Prothena: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Omel:Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Demers:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Ren:Takeda Pharmaceuticals International Co.: Employment. Skacel:Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Terpos:Novartis: Honoraria; Celgene: 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, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding.

Background: Recent studies with autologous chimeric antigen receptor (CAR)-redirected T-cells against CD19 have demonstrated long-term durable remissions in patients with B-cell leukemia and lymphoma, indicating that CAR T-cell therapy is a promising approach for refractory malignancies. Signaling lymphocytic activation molecule F7 (SLAMF7, also called CS1) is highly expressed on multiple myeloma (MM) tumor cells and is present in only a subset of hematopoietic cells among normal tissues. Because of its high expression on MM tumor cells and restricted expression in normal cells, SLAMF7 is a potential target for CAR T-cell therapy approach in MM. We had previously demonstrated that allogeneic “off-the-shelf” CAR T-cells lacking the ability to induce graft versus host disease could be generated for universal use by inactivating the TCRα constant (TRAC) gene using TALEN® gene editing technology. We also demonstrated that to minimize the risk of fratricide of SLAMF7-specific CAR+ T-cells, SLAMF7 could be inactivated by TALEN® in the T-cells prior to introduction of the CAR construct (Galetto et al., ASH 2015, Abstract 116). Here, we report the efficacy of these double KO (TRAC and SLAMF7) SLAMF7-specific universal CAR T cells (UCARTCS1) against MM in in vitro and in vivo studies. Methods: We tested the efficacy of UCARTCS1 cells against MM cell lines and primary tumor cells from MM patients for their capacity to specifically a) degranulate when co-cultured with MM tumor cells as determined by CD107a assay, b) lyse MM cell lines and primary MM cells in in vitro cytotoxicity assay, c) produce cytokines in culture supernatants, d) proliferate in presence of MM cells as determined by CFSE proliferation assay, and e) eradicate primary MM tumors in a patient-derived xenograft model as determined by serum tumor immunoglobulin (M-protein) levels and survival analysis. Results: UCARTCS1 but not control double KO T-cells (lacking SLAMF7 CAR) specifically lysed the MM cell line, MM.1S (median, 93% lysis; range, 78-98% with UCARTCS1 vs. median, 17%; range, 15-47% with control T-cells; n=10). UCARTCS1 cells similarly induced significant lysis of tumor cells from primary MM samples (n=10) (median 59%; range, 20-90%) compared to control T cells (median 9%; range, 0-36%). In agreement with this, we observed specific degranulation in both CD4+ and CD8+ UCARTCS1 cells but not control T-cells in presence of MM.1S cells and primary MM tumor cells. In addition, significant and specific proliferation of both CD4+ and CD8+ UCARTCS1 cells but not control T-cells was observed when they were co-cultured with MM.1S or primary MM tumor samples (n=8). Analysis of culture supernatants for ten cytokines (IFN-γ, GM-CSF, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, and TNF-α) showed that UCARTCS1 cells primarily produced IFN-γ and GM-CSF in presence of primary MM tumor cells (n=6), indicating a Th1/Tc1 response. To test the efficacy of UCARTCS1 cells in vivo, we injected 1x106 primary MM tumor cells into human fetal bone implanted under the skin of NSG mice. After the tumor has been established for 6 to 8 weeks and the serum M-protein was sufficiently elevated, mice were treated intravenously with either 10x106 total cells/mouse of UCARTCS1 or control T-cells. Mice treated with control T-cells developed gradual increase in M-protein levels (median, 339 µg/ml; range, 100-700 µg/mL) whereas the M-protein levels rapidly became undetectable in the mice treated with UCARTCS1 cells and remained undetectable until they were euthanized at approximately 50 days after adoptive transfer. Conclusion: Our results demonstrated that UCARTCS1 cells were highly cytotoxic against primary MM tumor cells in both in vitro and in vivo studies. In addition, UCARTCS1 cells specifically degranulated, produced Th1/Tc1 cytokines, and proliferated in response to primary MM tumor cells. These data provide a rationale for evaluating UCARTCS1 cells as a universal “off-the-shelf” allogeneic CART product in patients with MM. This abstract is also being presented as Poster A46. Citation Format: Rohit Mathur, Zheng Zhang, Jin He, Roman Galetto, Agnes Gouble, Isabelle Chion-Sotinel, Stephanie Filipe, Annabelle Gariboldi, Tanooha Veeramachaneni, Elisabet Manasanch, Sheeba Thomas, Hans C. Lee, Krina Patel, Donna Weber, Richard Eric Davis, Robert Orlowski, Julianne Smith, Jing Yang, Sattva S. Neelapu. Targeting multiple myeloma with universal SLAMF7-specific CAR T-cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR01.

8044Background: MM follows a clinical course leading to refractoriness and limited treatment options in RRMM. Aggressive NDMM needs rapid cytoreduction for disease control, which may not be possibl...

8049Background: Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are monoclonal gammopathies that precede multiple myeloma (MM). Although considered asymptomatic, patients diagnosed with these conditions are at greatly increased risk of developing MM. There is currently limited to no information on quality of life (QOL) or cancer worry/anxiety burden for patients with MGUS and SMM. Methods: We implemented a longitudinal QOL and cancer-related worry assessment in an observational cohort study of MGUS and SMM patients at MD Anderson Cancer Center (expected total enrollment of N = 200). Questionnaires included the QLQ-C30 cancer QOL tool and the MY20 myeloma-specific module, as well as questions to measure cancer worry. In this preliminary data analysis, a total of 46 patients completed the baseline questionnaires (MGUS = 17; SMM = 29). Results: Overall, individuals with MGUS have a worse QOL compared to SMM patients with MGUS patients reporting a > 12 point lower Gl...

8054Background: Plasma cell leukemia (PCL) is a rare and aggressive disease characterized by a clonal proliferation of plasma cells in bone marrow and blood. PCL can present as de novo disease with...

Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) and after myeloablative AuSCT in patients (pts) with multiple myeloma (MM) (Attal et al. NEJM 2012, McCarthy et al. NEJM 2012,). Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of pts with MM who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report preliminary results of the primary (PFS) and secondary (overall survival and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 28 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2 and q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=27 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until progression. LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC < 1000/mL, platelet count < 100,000/ml). For the 1st 8 weeks, pts The primary endpoint of the study is PFS, defined as the time from AuSCT to clinical progression or death (whichever occurs first), or the time of last contact. Secondary objectives include best response, overall survival, incidence of second primary malignancies and adverse event (AE) profile. Total enrollment of 100 pts is planned. Pts will be followed for 48 months after the last patient is enrolled in the trial. Eligible pts had received no more than 2 lines of induction therapy, and were between 60-210 days post-AuSCT. Results: Patients (n=55) have been treated for a median of 14 cycles (2-30). At study entry, 13 pts (24%) had complete response (CR), 27 (49%) had very good partial remission (VGPR), 14 (25%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 28 pts (51%), VGPR in 23 pts (42%) and PR in 4 pts (7%). For those who have converted to CR on study, median time to CR has been 5 months. Of 14 pts in CR who have been tested for MRD while on study, 13 are negative by flow cytometry (minimum of 2 million cells evaluated; sensitivity 10 -4-10-5). Two of these 13 have converted from VGPR to MRD negativity at 4 and 14 months on study, respectively. With a median follow up of 21 months, 95% of pts (n=52) remain alive. Three pts (all with high risk disease) had disease progression at 4 (del 17p), 9 (t [4;14]), and 13 (gain 1q) months; of these, 2 have died of progressive disease while receiving salvage therapy. One patient, in VGPR, died on study after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Two pts withdrew for logistical reasons; 2 have been taken off study per physician discretion (prolonged cytopenias (1), drug rash (1)). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 35% (16), thrombocytopenia 9% (4), febrile neutropenia 7% (3), and anemia 7% (3). Grade 3-4 non-Hematologic AEs (no. of pts): diarrhea 17% (8), fatigue 17% (8), pneumonia 15% (7), other infections 15% (7), peripheral neuropathy 11% (5), myalgias 9% (4), nausea/vomiting 7% (3), maculopapular rash 4% (2), dizziness 4% (2), edema 2% (1), memory impairment 2% (1). Renal cell carcinoma was diagnosed in 1 patient, 15 months after removal from study for disease progression. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 44% of 55 pts have had improvement in quality of response while on therapy, including 28% who have converted to CR and 24% who have tested MRD negative. The number of pts who have experienced improvement on study may, in fact, be underestimated in this analysis due to elotuzumab interference with measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Disclosures Thomas: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Shah: Kayopharm: Employment. Lee: Pimera Inc: Consultancy; Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Manasanch: merck: Research Funding; adaptive biotechnologies: Consultancy; sanofi: Research Funding; celgene: Consultancy; takeda: Consultancy; quest diagnostics: Research Funding. Patel: Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Purpose: Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin lymphoma and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein–Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection. Experimental Design: We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide, and dexamethasone (LTD) combination. Results: Treatment of EBV-infected B-cell lines with LTP at physiologically relevant concentrations induced the immediate early gene BZLF1, the early gene BMRF1, and the late proteins VCA and BCFR1. This occurred in the potency order pomalidomide > lenalidomide > thalidomide, and the nucleoside analogue ganciclovir enhanced the cytotoxic effects of lenalidomide and pomalidomide in Burkitt lymphoma cells in vitro and in vivo. EBV reactivation was related to PI3K stimulation and Ikaros suppression, and blocked by the PI3Kδ inhibitor idelalisib. Combinations of lenalidomide with dexamethasone or rituximab increased EBV reactivation compared with lenalidomide alone and, importantly, lenalidomide with melphalan produced even greater reactivation. Conclusions: We conclude LTP may reactivate EBV-positive resting memory B cells thereby enhancing EBV lytic cycle and host immune suppression. Clin Cancer Res; 22(19); 4901–12. ©2016 AACR.

This paper presents an overview of our work towards building socially intelligent, cooperative humanoid robots that can work and learn in partnership with people. People understand each other in social terms, allowing them to engage others in a variety of complex social interactions including communication, social learning, and cooperation. We present our theoretical framework that is a novel combination of Joint Intention Theory and Situated Learning Theory and demonstrate how this framework can be applied to develop our sociable humanoid robot, Leonardo. We demonstrate the robot's ability to learn quickly and effectively from natural human instruction using gesture and dialog, and then cooperate to perform a learned task jointly with a person. Such issues must be addressed to enable many new and exciting applications for robots that require them to play a long-term role in people's daily lives.

Proteasome inhibitors now form the backbone of many myeloma therapeutic regimens in either the upfront or relapsed settings, but both innate and acquired drug resistance have emerged as significant clinical challenges. The second-generation proteasome inhibitor carfilzomib recently received regulatory approval after showing promising activity in bortezomib-resistant preclinical models and human studies. Although similar to its predecessor in targeting the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome, carfilzomib has distinct mechanistic and structural properties. These allow it to bind irreversibly and provide a more sustained target inhibition than bortezomib, which is characterized by slowly reversible binding kinetics, and may in part contribute to its ability to overcome proteasome inhibitor resistance. Numerous clinical studies with carfilzomib are now underway investigating its use in various clinical settings and in combination with other novel agents that will provide valuable insight on its optimal use. However, despite the important advance in myeloma therapeutics that carfilzomib represents, cross-resistance between proteasome inhibitors remains a significant problem. This highlights the need for a better understanding of proteasome inhibitor resistance biology to inform the design of next-generation proteasome inhibitors and the development of rational drug combinations to overcome such resistance.

Background: The ubiquitin-proteasome system (UPS) has been validated as a target in multiple myeloma (MM) through the success of proteasome inhibitors such as bortezomib, but drug resistance is an emerging challenge. Targeting some of the upstream components of the UPS, such as the E1 ubiquitin activating enzyme (UAE), could therefore be a promising alternative. TAK-243 (MLN7243) specifically blocks the ubiquitin conjugation cascade through the formation of a TAK-243-ubiquitin adduct, thereby inhibiting the UAE. Our aim was to explore the effectiveness of TAK-243 against pre-clinical myeloma models, and to understand some its mechanisms of action. Methods: We performed pre-clinical studies in myeloma cell lines and mouse models using TAK-243. Downstream effects were evaluated using viability, apoptosis assays, western blotting, gene expression profiling (GEP), and Reverse Phase Protein Array (RPPA) techniques. Results: MM1.S and MOLP-8 TP53 wild-type cell lines were sensitive to TAK-243, with median inhibitory concentrations (IC50) of 25 nM at 24 hours based on viability assays. In otherwise isogenic cell lines in which TP53 was suppressed using genome editing techniques, the IC50 was ~40 nM, but higher TAK-243 concentrations of 100 nM overcame resistance due to TP53 inactivation. Similarly, TAK-243 was able to overcome resistance to both conventional (dexamethasone) and novel (bortezomib, lenalidomide) drugs in paired sensitive and resistant cell line models. After treatment with TAK-243, Annexin V and TO-PRO3 staining determined that viable MM1.S cells were induced into early or late apoptosis. This was accompanied by a significant increase in cleaved caspase-3, -8, and -9 as detected by flow cytometry, and in cleaved caspase-7 detected by RPPA and western blot. Exposure to TAK-243 reduced the cellular content of ubiquitin-protein conjugates, and did not enhance expression levels of a fusion protein degraded by the proteasome in a ubiquitin-independent manner, indicating the lack of direct proteasome inhibition. GEP analysis and RPPA detected enhanced expression of p53-pathway related proteins, including MDM2, TP53, and p21 in TAK-243 treated MM1.S cells. Several mRNAs and proteins in the ER stress pathway, including ATF6, ATF4, IRE1a and XBP1 were also elevated, as were many non-coding RNAs and DNA-damage related genes. Combination experiments in MM cell lines demonstrated synergy between TAK-243 and lenalidomide, pomalidomide, panobinostat, melphalan and doxorubicin. Finally, TAK-243 demonstrated in vivo antitumor activity against MM1.S and MOLP-8 xenograft models when dosed at 12.5 mg/kg IV twice-weekly for 2 weeks (tumor growth inhibition of 60% and 73%, respectively). Elevation of BiP, ATF4, XBP1s and cleaved-caspase 3 was detected within the first 24 hrs after dosing in the sensitive MM1.S xenografts. In contrast, RPMI 8226 cells, which showed a 2000 nM IC50 in cell culture, were also resistant to TAK-243 in vivo, with no tumor growth inhibition detected. Conclusions: TAK-243 is a UAE inhibitor that is active against myeloma cells in vitro and in xenograft models in vivo, overcomes conventional and novel drug resistance, and its action is associated with stimulation of the TP53 and ER stress pathways. Thus, it may deserve further evaluation as an anti-myeloma agent. Disclosures Berger: Takeda Pharmaceuticals: Employment. Hyer:Takeda Pharmaceuticals: Employment. Chattopadhyay:Takeda Pharmaceuticals: Employment. Syed:Takeda Pharmaceuticals: Employment. Shi:Takeda Pharmaceuticals: Employment. Yu:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Shinde:Takeda Pharmaceuticals: Employment. Kreshock:Takeda Pharmaceuticals: Employment. Tirrell:Takeda Pharmaceuticals: Employment. Menon:Takeda Pharmaceuticals: Employment. Orlowski:Takeda Pharmaceuticals: Research Funding.

Introduction: Despite the introduction of highly effective novel agents, the outcome of patients with relapsed and refractory multiple myeloma (RRMM) remains poor, particularly in those with disease refractory to both proteasome inhibitors (PI) and immunomodulatory agents (IMiDs). Limited available data suggests that autologous hematopoietic stem cell transplantation (auto-HCT) may be an effective therapy in this patient population. Methods: We retrospectively analyzed all patients with RRMM who underwent first auto-HCT at our center between March 2000 and October 2015. RRMM was defined as never achieving a response (stable disease [SD]) or having progressed while on therapy or within 60 days after discontinuation of therapy. Patients with disease refractory to at least one PI and at least one IMiD either in combination or administered separately were classified as double refractory (DR-MM). Results: 233 patients with RRMM were identified. Of these, 105 (45%) had DR-MM. The remaining 128 (55%) patients were classified as refractory (R)-MM and included all patients with RRMM but without history of being double refractory. Median age at auto-HCT was 59 years (DR-MM 60 vs. 56 years in R-MM, p=0.005). High-risk cytogenetics (IMWG criteria) were noticed in 67 of 140 (48%) patients (DR-MM, 35/89 [39%] vs. R-MM, 32/51 [63%], p=0.009). Median number of prior lines of therapy was 2 (range 1 - 7) (DR-MM, 2 (1 - 7) vs. R-MM, 1 (1 - 5), p Conclusions: Our findings highlight that auto-HCT is an effective and safe therapy in patients with RRMM including those who are refractory to an IMiD and PI Figure 1 Progression Free Survival Figure 2. Overall Survival Figure 1. Progression Free Survival Figure 2. Overall Survival Figure 2 Figure 2. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

Introduction Multiple myeloma (MM) is a disease of elderly with median age of diagnosis 66-years. Autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for eligible patients with newly diagnosed MM, however, it is not offered to many elderly patients due to concerns of excessive toxicity. We have previously reported that auto-HCT can be safely performed in myeloma patients aged ≥ 70 years (Bashir et al. L&L 2012). Here we report the results of a retrospective analysis of MM patients aged ≥ 75 years who underwent auto-HCT at our center. Methods All myeloma patients aged ≥ 75 years who underwent auto-HCT at our institution between 1/1/2000 and 12/31/2015 were retrospectively analyzed. Frequencies of toxicities were compared using Fisher's exact test. The cumulative incidence (CI) of non-relapse mortality (NRM) was assessed using the competing risks method. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Differences in survival between groups were assessed using the log-rank test. The association between survival and patient subgroups of interest was determined using univariate and multivariable Cox proportional hazards regression models. Results 72 patients (median age 76 years; 58% male) were included in the study. Thirty percent (n=19/63) were ISS stage I, 43% (n=27/63) were stage II and 27% (n=17/63) stage III. Seventy-eight percent (n=56) were considered standard-risk (IMWG criteria) and 22% (n=16) had high-risk cytogenetics. Sixty-three percent (n=45) received conditioning with melphalan (MEL) 140 mg/m2, while 38% (n=27) received MEL >140. Seventy-five percent (n=54) of the patients received auto-HCT as part of first line therapy and 85% (n=61) had at least partial response (PR) at auto-HCT. Median time from diagnosis to auto-HCT was 7.6 months. Half of the patients (n=36) received post transplant maintenance. Median follow-up time for all survivors (n=48) was 25.5 months. Grade II-IV toxicity was seen in 74% (n=53) of patients, gastrointestinal being most common (49% of all patients). There was no difference in toxicity between MEL 140 vs. MEL >140. The median time to neutrophil and platelet engraftment was 11 and 12 days, respectively. The CI of NRM was 1% at Day 100 and 6 months and 4% at the end of the assessment period. Day 100 response rate (at least PR) was 92% (n=66), with 36% (n=26) achieving near complete remission (nCR) or better. Median PFS was 31.4 months (95% CI: 22.6, 36.6, Figure 1). Seventy-five percent of the patients were event free at one year after transplant and 23% were event free at 5 years. Median OS was 72.8 months (95% CI: 45.7, 86.2, Figure 2). The OS rates at 1 year and 5 years post transplant were 93% and 58%, respectively. On multivariable analysis, high-risk cytogenetics and ISS stage III disease were associated with significantly worse PFS and OS. Conclusion Auto-HCT in myeloma patients aged ≥ 75 years is feasible with response rate and survival comparable to that seen in younger patients. Age alone should not be used to determine eligibility for auto-HCT. Figure 1 Progression-free survival (all patients). Figure 1. Progression-free survival (all patients). Figure 2 Overall survival (all patients). Figure 2. Overall survival (all patients). Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

Multiple myeloma (MM) refractory to both proteasome inhibitors and immunomodulatory agents (IMiDs; double-refractory myeloma) has a poor prognosis. With the more frequent use of these agents as part of initial therapy, and then in the maintenance setting until disease progression, such drug resistance is an emerging problem of great significance. New therapeutic strategies are clearly needed for this patient population, including the development of more potent agents within existing antimyeloma drug classes, exploration of rational combinations of both novel and conventional drugs, and validation of new myeloma drug targets. Several approaches have shown substantial promise, including use of the second-generation proteasome inhibitor carfilzomib and the third-generation IMiD pomalidomide, which led to the recent regulatory approval of both agents. In addition, the kinesin-spindle protein KSP inhibitor ARRY-520 has shown activity as a first-in-class drug in myeloma therapeutics, whereas the histone deacetylase (HDAC) inhibitors vorinostat and panobinostat have demonstrated efficacy when used in rational combinations. This overview provides a summary of novel agents that have shown activity in double-refractory myeloma in recent phase II and III clinical trials, and a framework for future studies that will help to improve outcomes in this patient population.

The clinical challenge posed by p53-deficiency in hematological malignancies needs novel therapeutic strategies. ONC201, a first-in-class small molecule, was discovered as a p53-independent activator of apoptosis with a benign preclinical safety profile (Allen et al, Sci Transl Med 2013). Here we report that ONC201 exerts anti-tumor effects in hematological malignancies and leukemia stem cells (LSC) via the induction of ATF4 in the integrated stress response (ISR). ONC201 induced p53-independent apoptosis in cell lines and primary patient samples from mantle cell lymphomas (MCL) and acute myeloid leukemias (AML), independent of genetic alterations that correlate with poor prognosis (e.g., TP53 mutation, FLT3-ITD, or complex karyotype). ONC201 also induced apoptosis in LSC, while sparing normal bone marrow progenitors, as measured in vitro and after transplantation. Specifically, we recovered unfractionated LSC-containing populations of AML cells (t(9;11)(p22; q23), CEBPA and ATM mutant) from secondarily-engrafted mice and cultured them in vitro for 48 hr in two groups, ONC201-treated (5 uM) or Control. For both groups, the same number of Trypan Blue-negative cells was then re-transplanted. The frequency of human CD45+ cells 4 weeks after transplantation was 38.09 ± 2.59 % of tibial BM cells in untreated mice and 0.10 ± 0.05% in treated mice (n = 3 for each, p < 0.01). The survival of the treated group was dramatically prolonged (Figure 1). Gene Set Enrichment Analysis (GSEA) of gene expression profiling (GEP) data of Jeko-1 and Z-138 cells treated with ONC201 implicated up-regulated Endoplasmic Reticulum (ER) stress-related genes, such as targets of the ER stress-induced transcription factor CHOP (DDIT3; FDR q = 0.016), and ER component proteins (FDR q = 0.039). We confirmed the ONC201-induced increased mRNA levels of DDIT3, GADD34, DR5 and TRIB3, and increased protein levels of CHOP, ATF4 and IRE1-a in Jeko-1 cells. Knockdown of ATF4 and IRE1-a revealed that ATF4 is an essential protein for ONC201-induced apoptosis in most AML cells and MCL cells, while IRE1-a is only necessary for apoptosis in MCL cells. However, unlike other ER stress inducers, ONC201 did not cause phosphorylation of an eIF2a kinase PERK, a hallmark of classical ER stress. Importantly, ONC201 was also effective in lymphoma cells resistant to bortezomib, an ER stress inducer, supporting the notion that ONC201 uses a unique mechanism to trigger the ISR. In addition, ONC201 inhibited mTORC1 signaling, likely secondary to ATF4 activation via the induction of DDIT4, a negative regulator of mTORC1, which presumably increases the cytotoxicity of ONC201 by global translation inhibition. Investigating the type of apoptosis induced by ONC201, we examined protein levels of anti-apoptotic BCL-2 family members (BCL-2, BCL-XL and MCL-1) after ONC201 treatment. MCL-1 was reduced most notably after 12 hr. We then tested the effect of ONC201 on cells with overexpression or knockdown of BCL-2 family proteins. MCL-1 knockdown in OCI-AML3 cells increased their sensitivity to ONC201 only slightly, but ONC201 efficacy was dramatically reduced in BCL-2-overexpressing HL-60 cells, even more so than in BCL-XL-overexpressing HL-60 cells. Therefore, we investigated whether ONC201 sensitivity could be increased by ABT-199, a small-molecule BH3 mimetic that specifically inhibits BCL-2, and is known to be ineffective in cell lines with MCL-1 overexpression; accordingly, the combination of ONC201 and BCL-2 antagonist ABT-199 was highly synergistic (Figure 2). In conclusion, ONC201 induces p53-independent apoptosis and abrogates LSC function by ATF4 induction, via the ISR. By suppressing MCL-1, ONC201 can also increase the effectiveness of the Bcl-2 inhibitor ABT-199. These findings suggest that ONC201 may provide promising novel therapeutic strategies for TP53 -wild type and TP53 -mutant hematological malignancies. Phase I/II clinical trials have been initiated at the MD Anderson Cancer Center in leukemias and lymphomas to determine safety, efficacy and further characterize mechanism of action. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ishizawa: Karyopharm: Research Funding. Allen:Oncoceutics, Inc: Employment, Equity Ownership. Orlowski:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding. Wang:Celgene: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Andreeff:Oncoceutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background: The role of dysregulation of the proto-oncogene MYC in both early and late myeloma progression events is well established. Among key MYC -downstream targets is upregulation of ribosomal biogenesis, resulting in increased protein translational capacity and biomass accumulation that is characteristic of neoplastic cells. Thus, given the relationship between myeloma pathobiology, MYC dysregulation, and ribosomal biogenesis, we hypothesized that selective targeting of ribosomal RNA (rRNA) transcription with the small molecule RNA polymerase (pol) I inhibitor CX-5461 (Senhwa Biosciences) may represent a novel therapeutic strategy in myeloma. Methods: Studies with CX-5461 were performed in human myeloma cell lines, isogenic p53 wild-type (wt) and knock-out (KO) p53 cells generated using sequence-specific zinc-finger nucleases, drug-resistant cell lines, primary patient samples, and myeloma murine xenograft models using NOD-SCID IL2Rgnull mice. Results: CX-5461 treatment of p53 wt (MM1.S, MOLP-8) and p53 mutant (U266, RPMI-8226) myeloma cell lines demonstrated a time- and dose-dependent decrease in cell proliferation with a median inhibitory concentration (IC50) at nM levels after 72 hours. A corresponding increase in cleaved-PARP, cleaved caspase-9, and cleaved caspase-3 expression was seen on Western blot as well as increased Annexin V staining on flow cytometry analysis, although this was more pronounced in p53 wt versus mutant cell lines. CX-5461 also retained activity in a panel of cell lines resistant to standard myeloma therapeutic agents (bortezomib, carfilzomib, lenalidomide, and doxorubicin) and in primary patient samples, including a heavily pretreated relapsed/refractory patient and a de novo plasma cell leukemia patient with del 17p. In vivo studies using a systemic isogenic MM1.S p53 wt and KO myeloma murine xenograft model demonstrated significant improvement in median overall survival in the CX-5461-treated p53 wt cohort (41 days vs. not reached, P .05), although outcomes were more modest in the p53 KO cohort with only a trend towards improved survival (P.1) in the drug-treated mice. To probe the p53-independent effects of CX-5461, gene expression profiling and gene set enrichment analysis was performed on isogenic MM1.S and MOLP-8 p53 wt and KO myeloma cell lines treated with CX-5461 or vehicle. These results suggested downregulation of MYC downstream targets as one p53-independent effect of RNA pol I inhibition. qPCR and Western blot studies revealed rapid downregulation of MYC at the transcript level within 1-hour of CX-5461 treatment followed by decreases in MYC protein levels. Previous studies have suggested ribosomal biogenesis is tightly controlled by an auto-regulatory feedback mechanism in which ribosomal proteins such as RPL5 and RPL11 can bind to the 3'UTR of MYC mRNA and facilitate its degradation through the RNA-induced silencing complex (RISC). Because RNA pol I inhibition is known to induce a nucleolar stress response and increase the availability of free ribosomal proteins, RISC-mediated degradation of MYC mRNA was explored as one possible mechanism of CX-5461-mediated MYC downregulation. Indeed, treatment with CX-5461 led to increased pull-down of RPL5 when immunoprecipitated with the RISC subunit TAR (HIV-1) RNA Binding Protein 2 (TARBP2) compared to vehicle-treated controls, and RNA immunoprecipitation assays with the catalytic RISC subunit, Argonaute 2 (AGO2), demonstrated enrichment of MYC mRNA with CX-5461 treatment. These results suggest that CX-5461 may induce degradation of MYC through the cooperative binding of ribosomal proteins, RISC subunits, and MYC mRNA. Finally, to evaluate the role of MYC expression and ribosomal biogenesis in relation to CX-5461 sensitivity, MYC was overexpressed in the H1112 myeloma cell line, which at baseline does not harbor a MYC translocation. MYC overexpression in H1112pCDH-myc cells led to increased basal pre-rRNA transcript levels compared to H1112pCDH cells, and furthermore, led to enhanced sensitivity to CX-5461. Conclusion: RNA pol I inhibition by CX-5461 is a promising target in myeloma therapy, with downregulation of MYC representing one mechanism of action. Moreover, increased MYC expression enhances sensitivity to CX-5461, providing rationale for the clinical translation of CX-5461 for the treatment of myeloma and other MYC-driven cancers. Disclosures O'Brien: Senhwa Biosciences, Inc.: Employment. Keats:Translational Genomic Research Institute: Employment. Orlowski:Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy; Genentech: Consultancy; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding.

Introduction: Multiple myeloma (MM) is characterized by malignant plasma cell (PC) proliferation. Gene expression profiling (GEP) of CD138+ bone marrow PC has emerged as a new way to identify patients with worse clinical outcomes so that an individualized treatment approach can be undertaken in the clinic. The majority of data with GEP come from clinical trials. We aimed to evaluate the use of GEP in a standard clinical setting. Methods: We retrospectively searched our database of newly diagnosed MM patients with GEP completed prior to initial treatment. 35MM patients from April 2014 until June 2015 were identified and included in our analysis. GEP was performed through MyPRS® (Signal Genetics, Little Rock, AR). Fisher's exact test was used to evaluate the associations between complete response status and other categorical variables. The Wilcoxon rank sum test was used to evaluate the difference in continuous variables between patients that achieved a complete remission after 6 months of initial treatment and those who did not. Responses were assessed using IMWG criteria. Results: Median age was 60 (38-76). Patients presented with lytic lesions (60%), anemia (80%), kidney dysfunction (11%) and hypercalcemia (20%). All patients with known initial therapy were treated with bortezomib (n=29) or carfilzomib (n=1) based therapy. 10 patients had upfront autologous stem cell transplant. 18 patients had available response at 6 months. 37% (n=13) of patients were characterized as high risk by GEP, of which 46% (n=6) had the proliferation (PR) subtype. Most low risk patients had hyperdiploidy (HY) subtype (n=12, 55%). Patients with high risk GEP presented more often with complex karyotypes whereas low risk GEP patients most often had normal or hyperdiploid karyotypes. FISH abnormalities that are usually present in high risk myeloma were also present in patients classified as GEP low risk (Table 1). At 6 months after diagnosis, lower baseline total protein, serum M-spike, serum free light chain ratio and serum kappa light chain levels were significantly associated with achieving a stringent complete response (sCR) (p Conclusion: In a standard clinical setting, GEP seems to identify MM patients that are at higher risk of adverse clinical outcomes early after diagnosis. GEP may be an adjunct to cytogenetics/FISH in MM risk stratification, as high risk FISH abnormalities were also found in low risk GEP patients. Larger studies with longer follow up may help address the particular role of GEP in the individualized treatment of MM. Figure 1. Figure 1. Disclosures Orlowski: Array BioPharma: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding.

survivors. Design: Retrospective study from 1992-2011. Setting: Data from Surveillance Epidemiology and End Results-13 registry. Patients: 15,517 FL patients. Main Outcome Measures: 1. Risk of SPM, developing 6 months after the diagnosis of FL, using Standardized Incidence Ratio (SIR) and Absolute Excess Risk (AER). 2. Poisson multivariate regression to study the impact of different variables on the risk of SPM. Results: At 71 months (range 5 -239 months) follow-up, 1766 patients (11.4%) developed SPM with SIR of 1.23 (95% CI 1.18-1.29; p

This paper presents an overview of our work towards building humanoid robots that can work alongside people as cooperative teammates. We present our theoretical framework based on a novel combination of joint intention theory and collaborative discourse theory, and demonstrate how it can be applied to allow a human to work cooperatively with a humanoid robot on a joint task using speech, gesture, and expressive cues. Such issues must be addressed to enable many new and exciting applications for humanoid robots that require them to assist ordinary people in daily activities or to work as capable members of human-robot teams.

Background Ribosomal RNA (rRNA) forms a major component of ribosomes, which play a critical role in cellular growth and proliferation through regulation of protein synthesis. Increased rRNA transcription and ribosomal biogenesis have been associated with tumorigenesis, and recent reports have suggested that inhibition of rRNA transcription by CX-5461 (Senhwa Biosciences), a novel selective small-molecule inhibitor of RNA polymerase (pol) I, induces cell death in several human tumor types by both p53-dependent and independent mechanisms. These findings led to our hypothesis that selective RNA pol I inhibition with CX-5461 could be a rational new approach to therapy for both wild-type (wt) and mutant p53 multiple myeloma models. Methods Studies with CX-5461 were performed in wt p53 and mutant p53 cell lines, zinc-finger nuclease (ZFN) p53 knock-out (KO) isogenic myeloma cell lines, and bortezomib and carfilzomib-resistant myeloma cell lines. Results Treatment of wt p53 (MM1.S, MOLP8) and mutant p53 (U266, RPMI-8226) myeloma cell lines demonstrated a time and dose dependent decrease in cell proliferation after exposure to CX-5461 with a median inhibitory concentration (IC50) range of 50-100 nM after a 72-hour incubation. A corresponding increase in cleaved PARP, cleaved caspase-9, and cleaved caspase-3 expression was seen on Western blot, as well as increased Annexin V staining on flow cytometry analysis. Notably, the degree of Annexin V staining was less in the p53 mutant cell lines compared to the wt p53 cells at any given drug concentration, but strong apoptotic signaling could be induced in mutant p53 cell lines when using higher concentrations of CX-5461. In addition, co-culturing myeloma cells with GFP+ HS5 stromal cells to mimic the bone marrow microenvironment did decrease the therapeutic effect of CX-5461, but again could be overcome with higher drug concentrations [250-500 nM]. Similar results were seen when isogenic MM1.S ZFN p53 KO cells were used, whose sensitivity to CX-5461 was comparable to that of wt p53 cells. Finally, CX-5461 was also tested on drug-resistant myeloma cell lines that were generated by exposing cells to low concentrations of bortezomib (RMPI-8266, KAS-6/1, ANBL-6) or carfilzomib (KAS-6/1) over time. These drug-resistant cell lines showed sensitivity to CX-5461 with an IC50 in the 100-250 nM concentration range. Gene expression profiling (GEP) of isogenic MM1.S ZFN p53 KO and wt cells revealed that gene expression perturbations by CX-5461 were primarily p53-independent. Additional GEP and pathway analysis in other isogenic ZFN p53 wt and KO cell lines is currently ongoing, with a particular interest in p53-independent mechanisms that may explain the efficacy of CX-5461 in both wt and mutant p53 myeloma models. Conclusion RNA pol I inhibition by CX-5461 is a promising approach to myeloma therapy, with low nanomolar drug activity seen in wt p53, mutant p53, and drug-resistant myeloma cell line models, providing a rationale for translation of CX-5461 into the clinic for the treatment of multiple myeloma. Disclosures: O'Brien: Senhwa Biosciences, Inc: Employment. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

Abstract 4209 Background: Recurrence of disease remains a significant cause of morbidity and mortality in patients who undergo allogeneic SCT for AML and MDS. Low-dose azacitidine is currently under investigation in the post-transplant setting with the goal of prolonging disease-free survival and decreasing relapse rates. It is unclear if there is potential pharmacologic interaction between azacitidine and dose-adjusted tacrolimus used to prevent post-transplant graft-versus-host disease (GVHD), a clinically relevant question since any resultant tacrolimus under- or over-dosing may lead to increased risk of GVHD or drug toxicity, respectively. We hypothesized that azacitidine does not significantly interact with tacrolimus levels and performed a retrospective analysis to test this hypothesis. Patients and Methods: We reviewed tacrolimus daily doses and serum drug levels of 62 AML and MDS patients who received azacitidine maintenance therapy (n=30) or no maintenance therapy (n=32) following allogeneic stem cell transplantation at MD Anderson Cancer Center between 2008–2012. Patient characteristics are summarized in the Table. Patients in the maintenance cohort received subcutaneous azacitidine at 32 mg/m2 on days 1–5 repeated every 28 days starting at a median time of post-transplant day +65 (range 43–100). Tacrolimus doses and serum levels were averaged for 28 days for each patient before and after initiation of azacitidine maintenance and at day +66 in the non-maintenance cohort. Differences between the two cohorts in their mean change of tacrolimus doses and serum drug levels were assessed using a Student's t-test. Results: Mean (SD) oral tacrolimus doses pre- and post-maintenance therapy were 2.61 (2.13) mg daily and 2.44 (2.15) mg daily in the azacitidine group and 2.54 (1.86) mg and 2.23 (1.39) mg daily in the non-azacitidine cohort. This resulted in a mean change in tacrolimus dosing of -0.17 (1.16) mg daily in the azacitidine patients and -0.31 (1.10) mg daily in the non-maintenance group (p=0.62). Mean (SD) serum tacrolimus levels pre- and post-maintenance therapy were 8.07 (1.16) ng/mL and 7.58 (2.32) ng/mL in the azacitidine group and 8.23 (1.49) ng/mL and 7.10 (1.69) ng/mL in patients on no maintenance therapy. This resulted in a mean change in serum tacrolimus levels of -0.49 (2.75) ng/mL in the azacitidine cohort and -1.13 (2.04) ng/mL in the non-maintenance group (p=0.30). Conclusion: Maintenance azacitidine therapy following allo-SCT for AML and MDS does not appear to affect concurrent tacrolimus dosing or serum drug levels. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML. Champlin:Otsuka: Research Funding. De Lima:Celgene: Research Funding.

Abstract 742 AZA has immunomodulatory properties that may affect donor lymphocytes favorably, potentially leading to less GVHD after HSCT. We have been investigating low-dose AZA (32 mg/m2 daily for 5 days) to prevent AML/MDS relapse after HSCT. Interestingly, in our dose finding phase I study (Cancer, 2010) there was a suggestion of less cGVHD with longer AZA treatments. We then hypothesized that this approach leads to less cGVHD, and performed a comparison of patients that received AZA to prevent relapse versus historic controls that did not receive the drug. Major objective of this analysis is to determine the cumulative incidence of cGVHD with versus without AZA. Methods. Patients received AZA based on high risk of relapse disease, starting at a median of 45 days from transplant (range, 17–149). AZA effect on aGVHD was not studied since the drug was started after most cases of aGVHD had already occurred or/and had resolved or improved. Patients with active acute GVHD (aGVHD) were not eligible to receive AZA. Median dose was 32 mg/m2 (range, 8–40). Median number of AZA cycles was 3 (range, 1–54), and median time on AZA for patients that received >3 cycles (n=37) was 144 days (range, 93–1329). Using a computer algorithm, we randomly selected from our departmental database a control group consisting of patients who had received HSCT within the same time period, and had similar GVHD prophylaxis, stem cell source, and comparable low risk of grade II-IV aGVHD (Table). Two hundred and thirty patients were identified fulfilling these criteria. The rate of cGVHD was compared between the AZA group (grouped as 1–3 cycles and >3 cycles) and the control group, in a landmark analysis starting at 6 months after HSCT. Leukemia relapse or death in remission before cGVHD onset were considered as competing risks in this analysis. Results. Median follow-up was 25 months (range, 1–99) in the AZA group, and 31 months (range, 1.5–117) in the control group. 29, 24, and 115 patients in the >3 AZA cycles, 1–3 AZA cycles, and the control group were evaluable for the 6-month landmark analysis, respectively. The numbers of patients developing cGVHD and the HR at 2 years in this analysis were as follows: 53 of 115 controls (reference group), 11 of 24 patients who received 1–3 AZA cycles (HR at 2 years, 0.9; P=NS), and 6 of 29 patients who received >3 AZA cycles (HR at 2 years, 0.4; 95% confidence interval (CI), 0.1–0.8; P=0.02) developed cGVHD. Similarly, in a landmark analysis, the cumulative incidence of cGVHD was significantly lower in the subgroup that received >3 AZA cycles (figure). Conclusion. Low-dose AZA appears to reduce the likelihood of developing cGVHD. We are investigating if this effect is associated with preservation or improvement of the graft-versus-leukemia effect in an ongoing, randomized study. Download : Download high-res image (26KB) Download : Download full-size image Figure . Cumulative incidence of cGVHD. 6-month landmark analysis. Table . Controls (n=230) AZA AZA>3 cycles (n=37) P (controls X AZA>3 cycles Median age 52 60 52 0.9 Ablative preparative regimen 63% 25% 30% Disease status (remission (CR1/CR2)/ active disease) 64%/36% 31%/69% 41%/59% 0.01 AML/MDS 95% 96% 86% 0.07 Second allo HSCT 7% 15% 22% 0.01 Peripheral blood graft 86% 75% 70% 0.02 4% 11% 13% P=NS Tacrolimus-based GVHD prophylaxis 98% 92% 89% 0.01 aGVHD incidence (grade II-IV/III-IV) 10%/2% 17%/11% 25%/3% 0.01 (gd II-IV) Disclosures: de Lima: Celgene: Research Funding. Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML. garcia Manero: celgene: Research Funding.

Abstract 2360 Peripheral T-cell lymphomas (PTCL) represent a rare and heterogeneous group of lymphoproliferative disorders characterized by poor prognosis. For relapsed and refractory disease, treatment options remain limited, and recent data has suggested that patients with PTCL beyond first remission (CR2/PR2+) do not benefit from autologous hematopoietic stem cell transplantation (HSCT) (Chen et al. Biol Blood Marrow Transplant. 2008; 14:741-747). The role of allogeneic HSCT in this patient population is not well defined, although several recently published retrospective analyses have shown promising results. We examined the outcomes of 27 patients with PTCL who underwent allogeneic HSCT for relapsed or primary refractory disease at Washington University between 1997–2008. PTCL subtypes in this cohort included PTCL not otherwise specified (NOS,n=9), anaplastic large cell lymphoma (ALCL,n=9), angioimmunoblastic T-cell lymphoma (AILT,n=5), hepatosplenic gamma-delta T-cell lymphoma (n=2), subcutaneous panniculitis-like T-cell lymphoma (n=1), and extra-nodal NK T-cell lymphoma (n=1). Among the patients with ALCL, 1 patient had anaplastic lymphoma kinase (ALK) negative ALCL; however, ALK status was unavailable for the other 8 patients in this group. Median age was 45 years (range 19–61) and 37% were female. 23 patients underwent myeloablative conditioning regimens with the majority receiving total body irradiation and cytoxan (74%). 4 patients received nonmyeloablative conditioning regimens consisting of fludarabine and anti-thymocyte globulin. 14 patients had HLA-identical related donors, 8 patients had HLA-identical unrelated donors, and the remaining 5 patients had unrelated mismatched donors. In general, patients were heavily pre-treated with an average of 3.3 chemotherapy regimens preceding allogeneic HSCT, and 7 patients (26%) had undergone prior autologous HSCT. 7 patients were transplanted at CR1/PR1, 14 patients at CR2/PR2+, and 6 patients had refractory disease at the time of transplant. Of the patients that were transplanted at CR1/PR1, 6 out of 7 were refractory to their first-line chemotherapy. 1-year, 3-year, and 5-year overall survival (OS) rates were 59%, 50%, and 50%, respectively. Corresponding progression free survival (PFS) rates were 56%, 51%, and 51%, and non-relapse mortality (NRM) rates were 15%, 15%, and 15%. Median OS was 27 months, and median follow-up time was 22 months. Univariate analysis demonstrated similar rates of OS (p=0.5), PFS (p=0.5), and NRM (p=0.8) between the CR1/PR1 and CR2/PR2+ subgroups, and a trend towards lower OS and PFS in patients with refractory disease at transplant. There was no statistical difference in OS (p=0.6), PFS (p=0.6), or NRM (p=0.6) between different PTCL histological subtypes, and no clear trend favoring any particular subtype. We conclude that allogeneic HSCT can provide durable remission and survival for patients with relapsed and refractory PTCL, with acceptable treatment-related mortality. Future prospective trials are needed to further define the role of allogeneic HSCT in this patient population. Disclosures: No relevant conflicts of interest to declare.

Personal robots for human entertainment form a new class of computer-based entertainment that is beginning to become commercially and computationally practical. We expect that the principal manifestation of the robots' entertainment capabilities will be socially interactive game playing. We describe this form of gaming and summarize our current efforts in this direction on our lifelike, expressive, autonomous humanoid robot. Our focus is on teaching the robot via playful interaction using natural social gesture and language. We detail this in terms of two broad categories: teaching as play and teaching with play.

Abstract 3075 Background: Allogeneic stem cell transplantation (allo-SCT) is a potential curative therapy for patients with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the risk for disease recurrence following transplant remains high. The ability to identify patients likely to relapse may allow for preemptive interventions in high-risk patients. The goal of hematopoietic transplantation is to eradicate the recipient myeloid leukemia cells and restore hematopoiesis and immunity with donor cells. Donor lymphoid cells mediate an important graft-vs.-leukemia effect. Post transplant peripheral blood (PB) chimerism analysis represents one potential tool for predicting disease recurrence, although the relationship between mixed chimerism and disease relapse is not well defined. Methods: We conducted a retrospective review of patients with AML/MDS who underwent allo-SCT with fludarabine/busulfan based conditioning regimens at The University of Texas MD Anderson Cancer Center between 2001 and 2011. PB chimerism was assessed between post-transplant days +90–120 using a multiplex PCR-based microsatellite polymorphism assay. Cox's proportional hazards regression was used on univariate and multivariate (MV) analysis to evaluate the impact of chimerism of T-lymphocytes and myeloid cells in PB, as well as patient-, disease-, and transplant-related variables on the rate of disease progression and progression-free survival (PFS). Survival and PFS were assessed in landmark analysis starting on day +120. The cut off levels for assessment of chimerism were based on the respective quartiles of distribution of T-lymphocytes and myeloid cells in the study population. Results: 483 patients who underwent allo-SCT for AML/MDS with fludarabine/busulfan based conditioning regimens between 2001–2011 were analyzed. Within this cohort, 378 patients were alive and without evidence of disease progression on day +120 and were eligible for study evaluation. Patients with disease progression or death within 3 weeks of chimerism assessment were excluded from analyses assessing the impact of chimerism on outcomes. 158 patients were in CR1, 66 in CR2, and 154 had active disease at the time of transplantation. PB T-lymphocyte and myeloid donor cell chimerism data between days +90–120 were available for 265 (70%) and 286 (76%) patients, respectively. The median follow-up time among surviving patients was 54 months (range, 5–126). Progression-free survival from day +120 was 56% (95% CI 39–52) at 3 years, and 46% (95% CI 39–52) overall. On univariate analysis, mixed T-lymphocyte chimerism of ≤87% (HR=1.8, P 0.03, Figure 1) and myeloid chimerism ≤98% (HR=2.4, P 0.005, Figure 2) were significantly associated with a higher rate of 3-year disease progression. These cut-off points were based on the 25th percentile of the respective distributions of T-lymphocyte and myeloid chimerism in the study population. Additional adverse factors included poor-risk cytogenetics (HR=1.5, P 0.04) and disease status other than first or second remission at the time of transplant (HR=2, P 0.002). All factors remained significant on MV analysis, with the exception of myeloid chimerism, which became only marginally significant (HR=1.96, P 0.06). Mixed T-lymphocyte (HR=1.5, P 0.05) and myeloid (HR=1.9, P 0.02) chimerism were also associated with significantly lower 3-year PFS on univariate analysis, but were no longer significant (HR=1.5, 95% CI 0.95–2.3 and HR=1.6, 95%, CI 0.9–2.8, respectively) after adjustment for disease status at transplant. Disease status other than first or second remission at transplant was the only significant predictor of 3-year PFS on MV analysis (HR=1.6, P=0.03). Stem cell source (PB vs. BM), donor type (match-related donor vs. other), age (>50 vs. ≤50 years), and diagnosis (AML vs. MDS) did not impact the rate of disease progression or disease free survival. Conclusion: Mixed T-lymphocyte and myeloid chimerism assessed on day +120 post SCT are associated with the rate of disease progression independently of disease status at transplant. The use of chimerism assessments may be useful in selecting patients at high-risk for relapse for preemptive therapeutic approaches. Disclosures: Champlin: Otsuka: Research Funding.

8032 Background: The impact of t(11;14) (16%–24% of MM pts) on prognosis is not fully understood. Consensus is lacking on the effects of induction treatment (tx) on outcomes with t(11;14). The Connect MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with NDMM designed to examine real-world diagnostic patterns, treatment (tx) patterns, clinical outcomes, and HRQoL pt-reported outcomes in pts with NDMM. The impact of t(11;14) on tx outcomes are reported. Methods: Analysis included data from pts from 250 community, academic, and government sites in cohort (C) 1 (9/2009–12/2011) and C2 (12/2012–4/2016), who completed first-line (1L; induction) tx and were tested for t(11;14) by FISH or cytogenetics. Primary end points (progression-free survival [PFS] and overall survival [OS]) were measured from start of 1L tx to earliest event (PFS, death or progression; OS, death), loss to follow-up, or data cutoff, adjusted for baseline (BL) risk factors. A sensitivity analysis excluding pts with concomitant cytogenetic abnormalities [del 17p, t(4;14), t(14;16), 1q+] was also performed. Results: By 1/2018, 3011 pts were enrolled; 2938 were treated. Of 1574 enrolled pts tested for t(11;14), 378 were t(11;14)+ and 1196 were t(11;14)−. More pts in C2 vs C1 were t(11;14)+ (60% vs 40%). BL characteristics were similar between groups. t(11;14) status did not affect PFS ( P= NS) or OS ( P= NS; Table). Pts in C1 and C2 received similar 1L txs (IMiD agent + proteasome inhibitor [PI], 30% vs 42%; PI only, 42% vs 43%; IMiD agent only, 17% vs 11%). Results were similar when pts with concomitant abnormalities were excluded. Conclusions: Results of this analysis suggest that t(11;14) does not affect PFS and OS outcomes in NDMM pts. Clinical trial information: NCT01081028. [Table: see text]