Equity Holder Research Articles

G-CSF/Plerixafor Dual-Mobilized Donor Derived CD33CAR T-Cells As Potent and Effective AML Therapy in Pre-Clinical Models

There are currently no known acute myeloid leukemia (AML) specific antigens. Genetic ablation of CD33 using CRISPR/Cas9 engineering of the hematopoietic stem cell (HSC) transplant (VOR33) represents a synthetic biology approach to generating a leukemia-specific antigen in the transplant recipient. VOR33 enables anti-CD33 CAR-T cell killing of AML cells while sparing normal myeloid lineage development and function, thereby potentially avoiding myelosuppression and increasing the therapeutic index of anti-CD33 CAR-T therapy. Mobilized leukapheresis product represents an attractive starting material for the generation of both a CD33 null HSC transplant and a complementary CD33CAR T-cell product. In this study, we sought to determine the impact of dual mobilization with Granulocyte-Colony Stimulating Factor (G-CSF) and plerixafor (mozobil) on immune cell composition, T cell phenotype, and the functionality of these T cells to control AML tumor growth upon chimeric antigen receptor (CAR) transduction.Mobilized (mob) peripheral blood mononuclear cells (PBMCs) were collected from healthy donors injected with G-CSF (10µg/kg/day, 5 consecutive days) and plerixafor (240µg/kg, on day 4 and 5). Non-mobilized (non-mob) PBMCs, collected from the same donors, were used as controls. Cells were analyzed by flow cytometry for immunophenotyping and T cell characterization including differentiation and bone marrow homing markers, as well as responses to T cell activation with anti-CD3 (OKT3) and IL-2. Non-/mob PBMC populations were also analyzed by single-cell next generation sequencing (CITEseq) using 127 immune cell phenotypic markers in combination with extensive transcriptome and T cell receptor repertoire analysis. In addition, lentiviral transduction of anti-CD33 CAR constructs enabled functional comparisons of mob- and non-mob-CAR T-cells in AML cell co-cultures as well as AML mouse models.Ex vivo immunophenotyping of PBMC from a total of over 30 healthy donor samples showed that mobilization decreases the overall percentage of CD3 + T cells but increases that of naïve T cells (CD45RA +/CCR7 +), at the expense of T effector-memory (CD45RA -/CCR7 -) and central-memory (CD45RA -/CCR7 +) populations. Bone marrow homing factors (e.g.: CXCR4) were increased in mob compared to non-mob T cell samples. As expected, higher percentages of monocytes (CD14 +) were detected in mob compared to non-mob donor samples, but this difference disappeared after culture under T cell activation conditions. T cell activation also led to similar increases in CD25, CD69 and CD137 expression, and a decrease in CD62L expression. Single cell sequencing analyses confirmed mobilization-induced increases in naïve T cells as well as changes in monocytes/macrophages, CD4 + T cells and NK cells percentages. Notably, functional in vitro cytotoxic assays demonstrated that mob-CD33-CAR T-cells are as effective as non-mob-CD33-CAR T-cells in killing CD33 + AML cells, with reduced ‘bystander’ activation of non-transduced T cells. Furthermore, results from in vivo AML mouse models indicate that mob-CD33-CAR T-cells are equally effective in clearing CD33 + tumors as non-mob-CD33-CAR T-cells.Our analysis showed phenotypical ex vivo differences between mob and non-mob PBMCs, which disappeared upon activation, indicating similar responses to T cell-specific stimulation. These findings are corroborated by similar in vitro cytotoxicity profiles of non-/mob-CAR T-cells. Non-transduced T cells in the mob-CAR T-cell population showed limited ‘bystander’ activation, indicating a potentially favorable clinical toxicity profile. Additional in vivo assessment of mob-CAR T-cell function shows effective tumor clearance, which supports further efforts towards their clinical use in combination with engineered HSCs for the treatment of AML patients. DisclosuresCanesin: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Hoyt: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Williams: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Silva: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Chng: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Cummins: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Ung: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Qiu: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Shin: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Hu: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Ge: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Scherer: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Chakraborty: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Kassim: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company.

High Prevalence of CHF and Diabetes in AML Long-Term Survivors - a Patient Forever?

Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved over the past decades, the fraction of patients surviving long-term is increasing. Information on long-term somatic and psycho-social health consequences of AML and its treatment is sparse. Previous studies suggested a higher prevalence of cardiovascular diseases in AML survivors, especially those treated with allogeneic stem cell transplantation (alloHSCT). The aim of our study was to perform a multi-dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on somatic, especially cardiovascular, morbidity in AML-LTS. Overall and health-related quality of life are reported separately (Telzerow et al.).Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessment by the patients' physicians, and medical and laboratory reports. An age- and sex-matched control cohort was derived from German population-based health surveys (Robert Koch Institute, DEGS1 survey; n=6013; persons diagnosed with leukemia [n=11] were excluded).Results: 427 AML-LTS, aged 28 to 93 years, participated in this study. Data on somatic health status is available for 355 survivors, 5 to 19 years after their AML diagnosis. Thirty-eight percent of survivors were treated with chemotherapy with or without an autologous transplant (autoHSCT), whereas 62% had undergone alloHSCT. Focusing on cardiovascular diseases and risk factors, we found that that 49% of AML-LTS had hypertension, 33% had hypercholesterolemia, 15% had type 1/2 diabetes, 10% had congestive heart failure (CHF), and 9% had coronary artery disease (Figure A). The mean body-mass index (BMI) of AML-LTS was 26.7, similar to the DEGS1 cohort (mean BMI, 26.8).Next, we compared the prevalence of cardiovascular diseases and risk factors between AML-LTS and the general German population (represented by the DEGS1 sample), using multivariate models adjusting for age and sex (Table B). Compared to persons not diagnosed with leukemia, AML survivors had similar risks of hypertension, coronary heart disease and myocardial infarction. Prevalence of diagnosed hypercholesterolemia was higher in AML-LTS compared to non-AML controls. In addition, AML-LTS had a 2-fold higher risk of having type 1/2 diabetes, and a 3.5-fold increased risk of CHF compared to the general population.To identify factors associated with the increased risks of diabetes and CHF among AML-LTS, we constructed multivariate models incorporating patient- and treatment related covariables (age, sex, BMI, smoking, prior AML relapse, treatment [chemotherapy + autoHSCT vs. alloHSCT], and type of leukemia [de novo versus secondary / therapy-related]). We found an increased risk of CHF for AML-LTS who had had a relapse (OR, 3.16; 95% CI: 1.46 - 6.83; P=0.004) and, in trend, for patients with sAML or tAML (OR 2.19; 95%CI: 0.92 - 5.22, P=0.076). In addition, we found an increased risk of type 1/2 diabetes for AML-LTS who are smokers (OR: 3.43; 95% CI: 1.43 - 8.21; p: 0.006). Disease- or treatment-related factors did not significantly associate with any of the other comorbidities we studied.Conclusion: To the best of our knowledge, this is the largest analysis of somatic health outcomes in AML-LTS. Strengths of our study include the relatively large cohort representing a wide age range, the long follow-up period of 5 to nearly 20 years, and the heterogeneity regarding therapy regimens (chemotherapy + autoHSCT vs. alloHSCT). We found that, compared to the general population, AML-LTS have increased risks for CHF and diabetes, but not for hypertension or coronary artery disease. We identified AML relapse as a risk factor for the development of CHF, suggesting that cumulative chemotherapy exposure might be causally involved. On the other hand, we found no treatment- and disease-related risk factors that might explain the higher prevalence of diabetes in AML-LTS. Notably, AML-LTS who had undergone alloHSCT did not have increased risks of CHF, cardiovascular disease, hypertension or diabetes, compared to survivors treated with chemotherapy only. Our results may guide future recommendations for follow-up and inform personalized treatment decisions. [Display omitted] DisclosuresBerdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; AbbVie: Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Pfizer: Consultancy; Astellas: Honoraria.

Impact of the COVID-19 Pandemic on in-Person Visit Rates Among Patients with Hematologic Malignancies in the United States

Impact of the COVID-19 Pandemic on in-Person Visit Rates Among Patients with Hematologic Malignancies in the United States

Real-World Effectiveness of Bortezomib Plus Dexamethasone in Patients with t(11;14) Positive Multiple Myeloma

Real-World Effectiveness of Bortezomib Plus Dexamethasone in Patients with t(11;14) Positive Multiple Myeloma

Peripheral T-Cell Lymphoma Involvement of the Central Nervous System: Impact of Novel Therapeutics on Clinical Outcomes

Primary Central Nervous System (CNS) involvement of peripheral T-cell lymphoma (PTCL) is a rare phenomenon, with a reported incidence ranging from 2% to 16.7%. Similarly, secondary CNS lymphoma with PTCL phenotype is rare, with an approximately 2-6% incidence. Both clinical situations lead to dismal outcomes. Given the rarity of CNS involvement with PTCL, our understanding of this clinical manifestation is limited to retrospective studies, which have identified risk factors for CNS involvement such as extranodal involvement, stage III-IV disease, bone marrow involvement as well as ATLL subtype. Herein, we characterize CNS involvement of PTCL over a 26-year time period at a single institution, identify if there are any factors that have a positive impact on survival, and extrapolate risk factors for CNS involvement from this dataset.From the years 1996-2020, 222 patients were diagnosed with PTCL, of those, 25 patients developed CNS involvement. All patients had secondary CNS involvement. Baseline characteristics including first-line therapy are noted in Table 1. Four patients received intrathecal methotrexate for CNS prophylaxis, all of which were patients with an ATLL diagnosis. The median time from initial diagnosis to CNS involvement was 4.77 months (0-64 months). Upon CNS diagnosis, the median time to death was 1.13 months. With a median of 2 lines of treatment (range 1-5), 12 patients were exposed to novel therapeutic agents (HDAC inhibitors [HDACis], brentuximab vedotin, pralatrexate) and/or clinical trials investigating epigenetic combinations. Of these patients, 10 patients were exposed to novel therapeutics and/or epigenetic based clinical trials in the 2 nd line setting. There was a trend towards improved overall survival with exposure to novel therapeutics and/or treatment on epigenetic based clinical trials (p=0.1) (Figure 1). With the majority of patients surviving <6 months from CNS diagnosis, there were three excellent responders that survived >12 months, all of which were exposed to novel therapeutics. Two of the three excellent responders were diagnosed with CNS involvement upon initial diagnosis, while 1 patient relapsed in the fourth-line setting with CNS involvement. All three of the excellent responders were exposed to novel therapeutics, particularly pralatrexate as a commonality in the second line setting. Using logistic regression, an ATLL diagnosis, extranodal involvement, and a high ECOG score were associated with a higher risk of CNS involvement. Unlike other studies, a high IPI score was not associated with a predilection for CNS involvement.In conclusion, we describe one of the largest single-center collection of CNS PTCL involvement. CNS involvement of PTCL is rare, with a reported cumulative incidence in this cohort of 11.3% over a 26-year time period. Risk factors that were identified include an ATLL diagnosis, extranodal involvement, and poor performance status. Exposure to novel therapeutics leads to a trend towards improved outcomes possibly secondary to improved disease control, but overall, the majority of patients had dismal outcomes. Notably, of the novel therapeutics interrogated, romidepsin and pralatrexate have low penetrance into the CNS, while there is no current evidence to suggest brentuximab vedotin is able to cross the blood-brain barrier. The possibility of a disturbed blood-brain barrier to permit improved penetrance of these drugs is plausible, but further studies are warranted to support this. Although a small percentage of patients will suffer from CNS PTCL, there is a dire need to improve therapy for this patient population and to establish universal metrics to identify patients that are at risk of CNS involvement. Moreover, given the rarity of CNS PTCL involvement, a future endeavor would be to validate these findings in larger, multicenter initiative. [Display omitted] DisclosuresLue: AstraZeneca: Speakers Bureau; Kymera Therapeutics: Research Funding; TG Therapeutics: Consultancy; Epizyme: Consultancy; Kura Oncology: Consultancy. Marchi: Astex: Research Funding; Kyowa Kirin: Honoraria; Merck: Research Funding; BMS: Research Funding; Myeloid Therapeutics: Honoraria; Kymera Therapeutics: Other: Scientific Advisor. O'Connor: Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Servier: Research Funding; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Super-Enhancer Driven Regulation of CKS1B in Multiple Myeloma: Implications in Mediating Response to BET Inhibitor and Celmod Agent Combination

Introduction: The Myeloma Genome Project (MGP) characterized the genomic landscape of patients with newly diagnosed multiple myeloma (NDMM) (Walker BA, et al. Blood 2018; 132[6]:587-597). Using a multi-omics unsupervised clustering approach, 12 molecularly-defined disease segments were identified (Ortiz M, et al. Blood 2018; 132[suppl 1]:3165). Here, we performed experimental validation of CDC28 Protein Kinase Regulatory Subunit 1B (CSK1B) that was identified as a putative target from the disease segment with poorest clinical outcome. CKS1B was selected for in-depth validation due to their role in cell cycle pathways associated with high-risk disease, biological mechanisms of chromosome 1q amplification and druggability.Methods: Association of CKS1B with outcomes was analyzed in NDMM patients, across relapses and with clinical outcome datasets from MGP and Mayo clinic. Inducible shRNAs of CKS1B and bromodomain containing protein 4 (BRD4, a member of the BET [bromodomain and extra terminal domain] family) were generated in MM cell lines. BRD4 and Aiolos ChIP-seq datasets were analyzed for binding on CKS1B gene. BRD4 inhibitors JQ1 and CC-90010 were utilized for inhibition studies in MM cell lines.Results: Higher expression of CKS1B was associated with significantly poorer PFS, OS, disease severity and relapse. Knock-down of CKS1B in MM cells led to a significant decrease in proliferation (P<0.001) and enhanced apoptosis in MM cell lines. BRD4-ChIP sequencing studies revealed that the expression of CKS1B was regulated by super-enhancer (SE) associated elements. As expected, two BRD4 inhibitors, JQ1 and CC-90010 and inducible BRD4 shRNAs downregulated the expression of CKS1B resulting in decreased proliferation, cell cycle arrest and apoptosis in MM cell lines. Furthermore, MM cell lines harboring chromosome 1q gain/amp showed higher sensitivity to BRD4 inhibition compared to cell lines with normal 1q copy number. Mechanistic studies revealed that BRD4inh and BRD4 shRNAs downregulated the expression of Aiolos and Ikaros in MM cell lines. Interestingly, Aiolos ChIP-sequencing studies demonstrated the binding of Aiolos at the transcriptional start sites of CKS1B with the transcriptional activation mark. The immunomodulatory agent (IMiD ®) pomalidomide (Pom) transcriptionally downregulated CKS1B in Pom-sensitive cells downstream of Aiolos, Ikaros degradation. Based on these mechanisms, IMiD agents, lenalidomide, Pom and the novel Cereblon E3 ligase modulating degrader (CELMoD ®) agent CC-92480 in combination with BRD4inh promoted a synergistic decrease in proliferation, cell cycle arrest and increase in apoptosis in both Pom-sensitive and -resistant cell lines. The combination of IMiD or novel CELMoD agent with BRD4inh also promoted deeper downregulation of CKS1B, Aiolos, Ikaros, c-Myc and survivin proteins with enhanced levels of apoptotic marker cleaved Caspase 3 as compared to single agents alone.Conclusions: In summary, we have identified CKS1B as a key target associated with poor outcome in MM patients. Translational studies suggest a profound downregulation of CKS1B and key pro-survival effector proteins following combination treatment with BRD4inh and IMiD agents/novel CELMoD agents resulting in synergistic anti-tumor effects. These data provide rationale for testing these agents in the clinic for high-risk and IMiD-relapsed patients.Figure: Changes in cell proliferation and protein levels of key signaling mediators were studied in K12PE cell line treated with increasing doses of Lenalidomide, Pomalidomide and CC-92480 in combination with JQ1. [Display omitted] DisclosuresAhsan: BMS: Current Employment, Current equity holder in publicly-traded company. Polonskaia: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hsu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund: BMS: Current Employment, Current equity holder in publicly-traded company. Ortiz Estevez: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Towfic: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bahlis: Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Pourdehnad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: No royalty. Flynt: BMS: Current Employment, Current equity holder in publicly-traded company. Ahsan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

Real-World Evidence on Treatment Utilization in Lower-Risk Myelodysplastic Syndromes: Findings from a Medical Record Review in the United States

Introduction: Patients diagnosed with myelodysplastic syndromes (MDS) are at an increased risk for developing infections, bleeding events, cardiopulmonary complications, and progressing to acute myeloid leukemia (AML). Patients with lower-risk MDS experience a mean life-year loss of about 6 years, and the main focus of treatment is on management of cytopenias, in particular anemia. Currently, limited real-world evidence exists on prevailing treatment patterns and outcomes in lower-risk MDS in the United States (US).Methods: In this retrospective, non-interventional review of medical records, eligible patients (≥ 18 years of age) with diagnosis of lower-risk MDS (with or without ring sideroblasts and with single-lineage or multilineage dysplasia) between July 1, 2013 and September 30, 2018, were identified by participating clinicians. Patients with prior history of AML or other malignant neoplasms were excluded. This is an ongoing study in the US and interim data are described. Study measures descriptively summarized patient demographics, clinical characteristics at MDS diagnosis, and utilization of medication treatments for the management of anemia.Results: Data from medical records of 50 patients with lower-risk MDS were abstracted by 26 hematologist-oncologists in the US. Participating clinicians had been managing treatment for hematology/oncology patients for an average (standard deviation [SD]) of 16.3 (6.7) years, 53.9% practiced in an academic hospital or cancer center, and 46.2% practiced in a community setting. The mean (SD) age for patients with lower-risk MDS at diagnosis was 64.2 (9.9) years, 64.0% were male, 70.0% were White, and 60% were insured primarily through Medicare. Most patients (54.0%) had Low-risk MDS (as categorized by Revised International Prognostic Scoring System) followed by Very low-risk (28.0%), and Intermediate-risk (18.0%) at initial diagnosis. The most common gene mutations observed were JAK2 (22.0%) and ASXL1 (8.0%). The most common karyotype abnormalities observed were del(5q) (28.0%), −Y (14.0%), and del(7q) (12.0%). During the 12 months before diagnosis of lower-risk MDS, cardiac complications were observed among 18.0% of patients, and 58.0% of patients were either current or former smokers at the time of diagnosis of lower-risk MDS. At the time of data abstraction, mean (SD) follow-up time was 39.6 (21.6) months, and 46 (92.0%) patients had received ≥ 1 line of treatment for MDS-associated anemia. Of these 46 patients, 93.5% received first-line treatment with an erythropoietin-stimulating agent (ESA). In the first-line, most patients received ESA monotherapy (n = 37; 80.4%) followed by ESA-based combination therapy (n = 6; 13.0%), lenalidomide only (n = 2; 4.4%), and azacitidine (n = 1; 2.2%). All 18 patients who received a second-line treatment had received an ESA-based first-line treatment. Second-line treatments received were ESA-based treatment (n = 5; 27.8%), lenalidomide only (n = 5; 27.8%), luspatercept only (n = 4; 22.2%), azacitidine only (n = 3; 16.7%), and filgrastim only (n = 1; 5.6%). Third-line treatment was only observed in 3 patients.Conclusions: In this ongoing study, current analysis for 50 patients with lower-risk MDS in the US showed ESA-based regimens were the most common first-line therapy. ESA-based treatment was again utilized as second-line therapy among some patients who were previously treated with ESA. DisclosuresGerming: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding. Goyal: RTI Health Solutions: Other: Full-time employee of RTI Health Solutions, which is business unit of RTI International, a non-profit research organization, which received funding from BMS to conduct this study.. Yucel: BMS: Current Employment, Current holder of individual stocks in a privately-held company. Parikh: RTI-Health Solutions: Other: Full-time employee of RTI-HS, which received funding to conduct this study from BMS.. Jimenez: RTI Health Solutions: Current Employment. Sluga-O'Callaghan: RTI Health Solutions: Current Employment. Tang: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hughes: BMS: Current Employment. Diez-Campelo: Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

OM301, a Synthetic Polypeptide Containing the p53TA (Transactivation) Domain, Impairs Mitochondrial Activity and Survival of Myeloma Cells

INTRODUCTIONAlthough the treatment of patients with multiple myeloma (MM) has dramatically improved, those with high-risk characteristics, including the deletion or mutation of the master tumor suppressor gene TP53 on chromosome 17, experience limited survival. OM301 is a synthetic polypeptide containing the p53TA (transactivation) domain, which prevents p53 degradation through inhibition of MDM2. Here, we demonstrate that OM301 has strong anti-MM activity in vitro and in vivo. RESULTSWe first assessed the cytotoxic effects of OM301 in MM cell lines with varying TP53 status (TP53 wild type: MM.1S, H929; TP53 mutated/null: L363, RPMI-8226, U266, JJN3, KMS11) and found that OM301 exerts significant cytotoxic effects at a concentration of ~5 µM in all cell lines we tested, while it was minimally toxic to human peripheral blood mononuclear cells. Next, using immunocompromised NSG mice models injected with MM.1S, we determined the in vivo efficacy of OM301 in three different studies. Many potent anticancer agents, particularly of peptide origin, show prominent anti-tumor effects but fail to sustain similar effects when given intraperitoneally because of poor absorption, distribution, metabolism and excretion properties. OM301 at an intraperitoneal dose of 20 mg/kg/body weight twice a day induced significant reduction in tumor size with respect to vehicle control, suggesting the stability of OM301 without any loss of its activity (n=7, p<0.0001). Accordingly, we investigated its effect in a disseminated NSG/MM.1S model and found that it significantly increased survival (p<0.0001) (see Figure).Because OM301 was designed to simulate the p53 interaction domain with MDM2, we first determined its effect on p53-MDM2 crosstalk using a p53-MDM2 co-Immunoprecipitation (co-IP) assay and compared it with effects from Nutlin-3a, a known inhibitor of p53-MDM2. The co-IP data showed that, unlike Nutlin-3a, OM301 does not inhibit the p53-MDM2 interaction. Thus, to confirm our findings, we first overexpressed MDM2 in HeLa cells, and, using MDM2-IP and p53-MDM2 co-IP, found similar observations. Additionally, OM301 also failed to induce endogenous upregulation of genes activated by p53, such as MDM2 and p21, as opposed to results from Nutlin-3a. RNA sequencing data also showed a distinctive OM301signature, as compared to Nutlin-3a in MM cells. While treatment of Nutlin-3a induced expression of p53-activated canonical genes, OM301-treated cells showed alterations in genes involved in inflammatory responses, c-Myc regulated genes, fatty acid metabolism, glucose metabolism, and oxidative phosphorylation, among others.Next, to dissect its underlying mechanism, we dual-tagged OM301 with fluorophores at the 3' and 5' ends to study its localization and its stability in MM cells. Indeed, OM301 was found to be stable and mainly localized in the cytosol. We then modified OM301 by biotinylation of its penetratin end and first verified its cytotoxic effect in different MM cell lines, which was similar to that of native OM301. The biotinylated OM301 was then immunoprecipitated using streptavidin beads. The streptavidin pull-down and subsequent proteomic analysis confirmed that OM301 does not interact with MDM2 but interacts with c-Myc and with proteins localized in mitochondria, including Bcl-2 and Bcl-2 family members such as Bclaf1, Bcl2L13, and Bcl2L1. Pull-down experiments and immunoblot analysis validated Bcl-2/OM301 interactions. To further evaluate the relative binding potentials of OM301, we performed molecular docking studies using the HPEPDOCK server (Yan et al., Nat Protoc. 2020;15:1829). Post-docking, the calculated docking scores for OM301 was -281, suggesting that OM301directly interacts with Bcl-2. Thus, we evaluated the effects of OM301 on mitochondrial function and physiology. Treatment with OM301 decreased mitochondrial membrane potential in different MM cell lines. OM301 also increased mitochondrial superoxide production and induced mitophagy and mitochondrial fission as seen by electron microscopy. CONCLUSIONHere, we report for the first time that OM301, although designed for p53-selective cells, may instead interact with Bcl-2, which in turn induces mitochondrial dysfunction, leading to cell death irrespective of their TP53 status. Our data suggest that OM301 may be a novel and effective therapeutic option for MM. [Display omitted] DisclosuresKrishnan: REGENERON: Consultancy; MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings.

Sustained Improvement in Health-Related Quality of Life in Patients with Hemophilia A with or without Inhibitors Treated with Fitusiran Prophylaxis

BACKGROUNDFitusiran is an investigational, subcutaneous (SC), prophylactically administered small interfering RNA (siRNA) therapeutic. It targets antithrombin and restores thrombin generation sufficient to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. Long-term exposure to fitusiran is being studied in a Phase 1/2, 6-year open-label extension study (NCT02554773) in patients with hemophilia (PwH) A or B with or without inhibitors. Improvement in the health-related quality of life (HRQoL) as measured by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) total score, and specifically in the physical health domain was previously reported by von Mackensen et al. for PwHA with inhibitors (NCT02554773, N=17, von Mackensen et al. Blood 2020;136(1):23-24). This analysis aimed to present HRQoL changes from baseline to last available measure (LAM), as measured by the Haem-A-QoL total score and domains (filtered by actual treatment exposure following 2 voluntary dosing holds) in PwHA, with or without inhibitors, who continued into the Phase 2 open-label extension study.METHODSParticipants who completed the Phase 1 study (NCT02035605) were eligible to participate in Phase 2 long-term exposure study (NCT02554773). All participants received fixed monthly doses of 50 mg (N=9) or 80 mg (N=18) of fitusiran. HRQoL data were collected in 3-month lapse periods. Mean changes from baseline to LAM were calculated for the Haem-A-QoL (total score and domains).RESULTSAs of February 2021, 26 severe and 1 moderate PwHA (13 with, 14 without inhibitors) with mean baseline age (SD) 37.3 (9.7) were treated for up to mean (SD) 33.32 (17.06) months. For the total Haem-A-QoL score and each of 10 domains, mean improvements from baseline to LAM (lower scores denoting better HRQoL) were consistently observed in PwHA (except for the sport & leisure domain that was higher in the non-inhibitor group). Mean estimated reductions (SD) in the Haem-A-QoL total score were -8.33 (13.84) and -9.16 (14.55) while that in the physical health domain score were -13.21 (25.07) and -7.14 (22.80), for PwHA with and without inhibitors respectively (Table 1). When comparing Haem-A-QoL domains in inhibitor to non-inhibitor participants, results suggest a modest favorable trend for non-inhibitor patients (greater reductions in 4 vs 6 domains, respectively).CONCLUSIONSMean improvements in the Haem-A-QoL total scores and 9 out of 10 domains suggest sustained HRQoL improvements in PwHA. Small sample size and outlying results might limit the interpretation. Further research in HRQoL for fitusiran will include a larger population on the new 50 mg every other month dose regimen, and notably Phase III results from NCT03549871 (open-label study in patients switching to fitusiran from previous prophylaxis or bypassing agents) and NCT03754790 (open-label, long-term safety and efficacy study of fitusiran) in various subpopulations. [Display omitted] DisclosuresCano: Sanofi Genzyme: Current Employment, Current equity holder in publicly-traded company; Takeda: Ended employment in the past 24 months. Bartelt-Hofer: Sanofi: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Hu: Sanofi: Current Employment. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Dasmahapatra: Sanofi: Current Employment, Current equity holder in publicly-traded company. Von Mackensen: Biomarin: Speakers Bureau; Novo Nordisk: Consultancy; Sanofi: Consultancy; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; University Medical Centre Hamburg-Eppendorf: Current Employment; CSL Behring: Speakers Bureau; Chugai/Roche: Membership on an entity's Board of Directors or advisory committees.

The Role of Hemoglobin and Hemolysis on Transcranial Doppler Velocities in Children with Sickle Cell Disease: Data from a Natural History Cohort

Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events that can impact neurocognitive development and quality of life (Colombatti 2016). Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). High TCD velocities are an indication to start disease-modifying treatments or consider disease-curative options in children with SCD (Khemani 2019). However, real-world pediatric data on the correlation between hematological variables and TCD results are scarce (Salama 2020). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments.Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1,2009, to December 31, 2020 (censoring date). Standard care includes annual TCD from 2 years of age. We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Only complete exams with right and left measures available for both vessels were included. Hematological, clinical, and treatment variables were available from the natural history cohort database. Patients were divided according to genotype: HbSS/HbSβ 0 or HbSC/HbSβ +.Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chi-square tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb.Results: Of the 182 SCD patients in the cohort, 169 had assessments of cerebral vasculopathy, and 155 had evaluable TCDi (583 exams). The median follow-up of the entire cohort was 79.8 months (range: 2.1-298.6 months) (interquartile range [IQR]: 36.9-126.3 months). The median age at the censoring date was 13.4 years (IQR: 9.1-17.5 years); 130 were HbSS/HbSβ 0, and 25 were HbSC/HbSβ +. Basic demographic characteristics of the cohort are in Table 1. The distribution of TCDi results was significantly different between genotypes (P<0.0001): in the HbSC/HbSβ + group (70 exams), 14 were normal (20.0%), and 56 were low (80.0%); in the HbSS/HbSβ 0 group (513 exams), 8 were abnormal (1.6%), 56 were conditional (10.9%), 311 were normal (60.6%), and 138 were low (26.9%). Only 37/138 (26.8%) low TCDi results were confirmed as stenosis at the nearest MRA. Patients with abnormal/conditional TCDi results had lower Hb (8.4 vs 8.9 g/dL, P≤0.0001) and higher reticulocyte counts (317,766 vs 262,750/mm 3, P≤0.0001), lactate dehydrogenase (843 vs 690 U/L, P=0.0012), and aspartate aminotransferase (61 vs 54 U/L, P=0.0007) compared with patients with normal/low results.We detected a linear correlation between TICA/MCA TAMMVs and Hb (Figure 1A and 1B). Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064).Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV. Disease-modifying therapies increasing Hb and reducing hemolysis could be helpful in reducing TAMMV in children with SCD.Funding: This study was supported by Global Blood Therapeutics. [Display omitted] DisclosuresAgodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Beaubrun: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding.

A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

Quality of Life, Psychological Distress, and Prognostic Awareness in Caregivers of Patients with Multiple Myeloma

Quality of Life, Psychological Distress, and Prognostic Awareness in Caregivers of Patients with Multiple Myeloma

Safety and Anti-Tumor Activity of Plamotamab (XmAb13676), an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Subjects with Relapsed/Refractory Non-Hodgkin's Lymphoma

Safety and Anti-Tumor Activity of Plamotamab (XmAb13676), an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Subjects with Relapsed/Refractory Non-Hodgkin's Lymphoma

Treatment with DC/AML Fusion Vaccine and CD3xCD123 Bi-Specific T-Cell Engager (CD123-CODV-TCE) for Treatment of Acute Myeloid Leukemia

Treatment with DC/AML Fusion Vaccine and CD3xCD123 Bi-Specific T-Cell Engager (CD123-CODV-TCE) for Treatment of Acute Myeloid Leukemia

Impact of Dosing Frequency of Oral Oncolytics on Refill Adherence Among Patients with Hematological Malignancies

Background: With advances in oral oncolytics for hematologic malignancies, it is important to consider dosing frequency and treatment (tx) adherence, as prior data have shown poor adherence to oral cancer medications may result in inferior tx outcomes (Huang WC, Expert Rev Anticancer Ther, 2016; Muluneh B, J Oncol Pract, 2018). There is limited evidence regarding the impact of dosing frequency on tx adherence among patients with hematological malignancies treated with oral oncolytics. The objective of this study was to characterize real-world demographic and clinical characteristics, and compare refill adherence, among patients with hematological malignancies receiving once-daily (QD) versus twice-daily (BID) oral oncolytics.Methods: This retrospective cohort study used multi-year (2012-2020) commercial claims data from Optum's de-identified Clinformatics ® Data Mart Database and included adults (≥18 yr) with a diagnosis of a hematological malignancy identified using ICD-9-CM and ICD-10-CM codes. The exposure of interest was receipt of an oral oncolytic, and the date of the first observed oral oncolytic (QD or BID) was considered the index date. All patients were required to have continuous health plan enrollment for ≥6 mo prior and ≥6 mo after the index date. The 6-mo period prior to the index date was considered the baseline period for determining patient demographics, clinical characteristics, and prior medication use. To minimize the effect of the differences in observable baseline patient characteristics between the QD and BID groups on refill adherence, 1:1 propensity score (PS) matching was used. Tx refill adherence to QD and BID oral oncolytics was measured using two established metrics: proportion of days covered (PDC) and medication possession ratio (MPR). PDC, a conservative measure of refill adherence, was considered for primary analysis as it measures total days of drug coverage within a pre-specified follow-up period; whereas MPR which was included for sensitivity analysis, measures total drug supplied within the pre-specified follow-up period. PDC and MPR were measured at pre-defined time periods of 3 and 6 mo, and from the index date until the end of the follow-up period (variable-length follow-up). Patients with drug coverage for ≥80% (PDC or MPR ≥0.8) of pre-defined time periods were considered tx refill adherent.Results: The study identified 5,874 adults with hematological malignancies, of whom 4,938 (84.1%) received QD oral oncolytics and 936 (15.9%) received BID oral oncolytics. Before 1:1 PS matching, there were significant differences between the two groups in terms of mean age (67.5 yr QD vs 61.6 yr BID, P<0.001), insurance type (Medicare, 65.4% QD vs 46.8% BID, P<0.001), being previously untreated (67.6% QD vs 63.7% BID, P=0.019), and Charlson's comorbidity score (mean: 1.61 QD vs 1.44 BID, P<0.001). After 1:1 PS matching, demographics, baseline comorbidities, cancer histology, and line of therapy were well-balanced. The matched cohort comprised 936 patients receiving QD oral oncolytics and 936 patients receiving BID oral oncolytics. Table 1 summarizes refill adherence among patients with hematological malignancies receiving QD versus BID oral oncolytics. The proportion of patients with ≥80% of drug coverage during follow-up was higher for QD versus BID recipients at 3 mo: numerically higher by PDC (70.8% vs 66.9%, P=0.065) and statistically significantly higher by MPR (72% vs 67.8%, P=0.049). The proportion of adherent patients was significantly higher for QD vs BID for both PDC and MPR at 6 mo (PDC: 62% vs 56.8%, P=0.024; MPR: 62.7% vs 57.5%, P=0.021) and at variable-length follow-up (PDC: 82.4% QD vs 77.7% BID, P=0.011; MPR: 84.9% QD vs 80.9%, P=0.020). These results suggest QD dosing is associated with improved tx adherence to oral hematological oncolytics compared to BID dosing.Conclusions: This study demonstrates significantly higher refill adherence in patients receiving QD versus BID oral hematological oncolytics at 6 mo and variable-length follow-up, highlighting the potential benefit of dosing convenience in improving adherence to oral oncolytics in the real-world setting. As suboptimal tx adherence may result in reduced tx effectiveness, real-world characterization of refill adherence rates of oral oncolytics can better inform on tx effectiveness outside of a controlled clinical trial environment. [Display omitted] DisclosuresChallagulla: Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Kebede: Pharmacyclics LLC, an AbbVie Company: Consultancy; ObsEva: Other. Rege: Pharmacyclics LLC, an AbbVie Company (paid to institution): Consultancy. Volodarsky: AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Osei-Bonsu: AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia

Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the Connect ® Multiple Myeloma (MM) Disease Registry

Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the Connect ® Multiple Myeloma (MM) Disease Registry

High Rates of Remission with the Initial Treatment of Oral Azacitidine Plus CHOP for Peripheral T-Cell Lymphoma (PTCL): Clinical Outcomes and Biomarker Analysis of a Multi-Center Phase II Study

High Rates of Remission with the Initial Treatment of Oral Azacitidine Plus CHOP for Peripheral T-Cell Lymphoma (PTCL): Clinical Outcomes and Biomarker Analysis of a Multi-Center Phase II Study

Preferences and Perceptions Regarding Treatment Decision-Making for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL)

Patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) who are not eligible for transplantation face complex treatment-related decisions, many of which are preference-sensitive. Shared decision making (SDM) has the potential to improve patient experience, engagement, and treatment satisfaction; however, limited data exist on preferences for R/R DLBCL patients and how they want to be involved in their treatment decision-making, particularly with respect to 2 nd- and 3 rd-line treatment decisions. We conducted a primary qualitative research study to understand preferences and values that impact treatment decision-making among R/R DLBCL patients, their caregivers, and physicians that treat R/R DLBCL patients in the US.Qualitative 60-minute semi-structured interviews were conducted with R/R DLBCL patients, their caregivers, and oncologists that treat R/R DLBCL patients. Patients and caregivers were recruited as pairs; physicians and patients were not linked. Patient interview questions were designed to elicit feedback on: 1) perceptions of their level of involvement in treatment decision-making, 2) 2 nd- and 3 rd-line patient preferences and goals, and 3) treatment satisfaction. Caregivers were asked about their level of involvement in treatment-related decisions and current practices around SDM. We used template analysis to code transcripts, using 6 codes decided a priori, allowing for additional codes to emerge. Two interviewers double coded 4 interviews, ensuring interrater reliability >75% and reconciled differences, subsequently independently coding the remaining 26 interviews.We enrolled 14 R/R DLBCL patients, 8 caregivers, and 8 oncologists in this study. Overall, patients reported the shock from their diagnosis or from failing treatment constrained them from fully being involved in their treatment decisions. 71% of patients and 38% of caregivers perceived they had limited ability to be actively involved in treatment decision-making given that their treating physician had communicated that they were following a well-established standard of care. All physicians agreed that the limited 2 nd- and 3 rd-line treatment options available created limited opportunities for patients to make treatment decisions. Among 6 patients (43%), perceptions of autonomy in treatment decision-making improved as they experienced multiple lines of treatment, consistent with physician observations. 50% of patients shared that caregiver involvement was important for supplementing their understanding of 2 nd- and 3 rd-line treatment options; however, only 1 caregiver explicitly said that they had enough time to make an informed decision. Generally, physicians also said that they encourage caregivers to be included in treatment planning.5 patients (36%) reported that their physicians did not effectively communicate the full spectrum of 1 st-line treatment outcome possibilities. As a result, they did not feel prepared for the possibility of treatment failure or needing another line of treatment. 10 patients (71%) noted that their oncologists shared educational materials with them regarding treatment options; however, 5 physicians (62%) identified lack of patient understanding or education on treatment options as a major barrier to involving patients in decision-making.While 71% of patients felt satisfied with their treatment experience, some shared that they would have appreciated a more individualized approach. 4 patients (29%) shared that their physicians were not equipped to address ancillary health concerns (e.g., mental health) and 2 patients noted that existing resources did not address concerns for young adults (e.g., fertility).Results suggest that while 2 nd- and 3 rd-line treatment options may be limited for R/R DLBCL patients, preferences related to patient-centered outcomes can be discussed and incorporated into the long-term treatment planning process. Opportunities for improvement include developing tailored materials outlining caregiver responsibilities throughout the care journey, as they were consistently identified as a critical component of the treatment decision-making process by both patients and physicians. Further, developing physician tools that can support integration of patients' lived experiences (e.g., social needs) into their typical workflows can minimize duplicative patient interactions. [Display omitted] DisclosuresVukcevic: MorphoSys: Current Employment. Kurukulasuriya: MorphoSys: Current Employment, Current equity holder in publicly-traded company, Other: Support for attending meetings/travel.

Integrated Analysis of B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Relapsed and Refractory Multiple Myeloma Subjects By High-Risk Factors

Background: For relapsed and refractory multiple myeloma (RRMM), various clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell clinical trials are under way. For one such treatment, CT053, the Phase 1 investigator-initiated CG studies (NCT03380039, NCT03716856, NCT03302403) and the Phase 1 LUMMICAR STUDY 1 (NCT03975907) demonstrated deep and durable responses in heavily pretreated subjects with RRMM. Here we report integrated efficacy and safety of CT053 in Chinese subjects with RRMM based on high-risk factors.Methods: All subjects had received ≥2 prior therapies, including at least an immunomodulatory drug and a proteasome inhibitor. Subjects also could have had exposure to an anti-CD38 antibody. All subjects were refractory to the last therapy per International Myeloma Working Group criteria. After lymphodepletion, subjects received a dose of 0.5 (n=1), 1.0 (n=4), 1.5 (n=32), or 1.8 (n=1) ×10 8 CAR+ T cells. We performed an integrated subgroup analyses of efficacy and safety in subjects stratified by high-risk characteristics, including extramedullary disease (EMD), high-risk cytogenetics [del(17p), t(4;14), t(14;16), t(14;20) and gain 1q], and International Staging System (ISS) stage III.Results: A total of 38 subjects (LUMMICAR STUDY 1: n=14; CG studies: n=24) were treated with CT053 in Phase I studies in China. Of these, 31.6% subjects (12/38) had EMD, 47.4% (18/38) had high-risk cytogenetics, and 28.9% (11/38) had ISS stage III disease. After a median follow-up of 13.9 months, the objective response rate (ORR), complete response (CR) rate, median duration of response (mDOR) and median progression-free survival (mPFS) were 92.1%, 78.9%, 24.0 months [95% CI 13.3 months-not reached (NR)] and 22.7 months (95% CI 13.3 months-NR), respectively.The ORRs for subjects with EMD, high-risk cytogenetics, and ISS stage III were 91.7% (95% CI 0.62-1.00), 83.3% (95% CI 0.59-0.96), and 81.8% (95% CI 0.48-0.98), respectively. A lower CR rate and poorer mDOR and mPFS were observed in subjects with EMD compared to subjects without EMD (58.3% vs 88.5%, 9.2 months vs 24.0 months, and 9.3 months vs 25.0 months, respectively). Although high-risk cytogenetics and ISS stage III disease at baseline did not substantially affect the CR rate, they seemed to negatively impact the DOR and PFS. The mDOR and mPFS were 14.8 months (95% CI 8.5 months-NR) and 15.6 months (95% CI 6.2-25.0 months) respectively for subjects with high-risk cytogenetics, and 13.3 months (95% CI 7.6 months-NR) and 13.3 months (95% CI 0.9 months-NR), respectively for subjects with ISS stage III. The median DOR and median PFS had not been reached in subjects without these two high-risk factors (Figure 1).No dose limiting toxicity or CT053 treatment-related death occurred. The incidence of Grade 1/2 cytokine release syndrome (CRS) was 73.7%, and no ≥Grade 3 CRS occurred. Generally, CRS cases fully resolved after supportive care or tocilizumab. Only one subject with ISS stage III and EMD developed Grade 3 CAR T-cell-related encephalopathy syndrome (CRES), which fully resolved after methylprednisolone treatment. No other grade of CRES was observed in the studies.Conclusions: The results demonstrate that CT053 represents a promising treatment option for subjects with RRMM, including those with high-risk disease. Phase 2 trials are actively enrolling. [Display omitted] DisclosuresLI: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Zhao: CARsgen Therapeutics Corp: Current Employment.