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Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant. Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of "lenalidomide containing regimen". In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles. Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829). 55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324). Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue. Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologous transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. Figure 1 Figure 1. Disclosures Badros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

Introduction: Patients with hematologic malignancies are at an increased risk of morbidity and mortality from COVID-19 disease (Vijenthira, Blood 2020). This is likely a result of combination of immunodeficiency conferred by the disease and the therapeutics. The immunogenicity of the COVID-19 vaccines in patients with exposure to CD19 directed Chimeric Antigen Receptor (CAR)-T cell therapy is not established. CD19 CAR-T cell therapies cause B-cell aplasia, which in turn can affect humoral immune response against novel antigens. Herein, we present results from our prospectively conducted clinical study to evaluate immune responses against mRNA based COVID-19 vaccines in patients with lymphoma who have received CD19 directed CAR-T cell therapy. Methods: All patients and healthy controls were enrolled in a prospective clinical study evaluating immune responses against commercial COVID-19 RNA vaccines in patients with hematologic malignancies. Plasma samples were generated from heparinized peripheral blood of 4 heathy controls (HCs) receiving the same vaccines and 19 B cell lymphoma patients treated with CD19 CAR- T cells. Samples from ~4 weeks post second dose of the vaccine (d56) were available for 14 CAR-T patients, for 5 CAR-T patients samples were available from ~4 weeks after the first dose (d28). Plasma samples were analyzed in an enzyme-linked immunosorbent assay (ELISA) using different full-length recombinant SARS-CoV-2 proteins and control proteins. Neutralizing activity was measured using the cPass Neutralization Antibody Detection Kit (GenScript Biotech). Results: Results from 4 healthy controls and 19 patients (12 males and 7 females) with lymphoma are reported. Median age for the lymphoma patients is 65 years. Eleven patients had large B cell lymphoma, 5 had follicular lymphoma and 3 had mantle cell lymphoma as primary diagnoses. Seventeen patients had advance stage disease (III/IV stage) and had received a median of 3 prior lines of therapy. All patients received CD19 directed CAR-T cell therapy. Ten patients received Moderna vaccine and 9 received Pfizer vaccine. Median time between CAR-T infusion and first COVID-19 vaccine was 258 days. While the peripheral blood plasma from 3/4 HCs already showed substantial SARS-CoV-2 neutralizing activity at ~4 weeks after the first dose of COVID-19 mRNA vaccine, none of the 5 CD19 CAR-T patients analyzed evidenced any antibody-mediated neutralizing activity in their blood at the same point in time (Figure 1A). Around 4 weeks after receiving the second dose of the vaccine, all 4 HCs tested evidenced complete or almost complete neutralizing activity (Figure 1B). In marked contrast, only 1 out of 14 CAR-T patients analyzed evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity in their blood (Figure 1B). Interestingly, when we asked whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CAR-T patients, we found that that was clearly not the case since anti-Flu, -TT, and -EBV responses were equivalent to the ones observed in HCs (Figure 2A). However, while at ~4 weeks post second dose of the vaccine the HCs showed marked antibody titers against all the viral spike proteins including their "delta" variants (Figure 2B), that was not the case for our CAR-T patients. The vast majority of our CAR-T patients did not evidence IgG antibody responses against any of the SARS-CoV-2 proteins analyzed such as S1, S1 delta, RBD, RBD delta, or S2 (Figure 2B). Conclusion: In this prospectively conducted clinical study, 18 of 19 patients with lymphoma who have received CD19 CAR-T therapy had poor immunogenicity against mRNA based COVID-19 vaccines as measured by neutralization assays and antibody titers. The antibody titers against B.1.617.2 (delta variant, S1 and RBD protein) were also demonstrably poor. The antibody response to common pathogens (flu, EBV, TT) were preserved, suggesting impaired immune response against novel antigens. Long-term follow-up of this study is ongoing. APR and DJ contributed equally Figure 1 Figure 1. Disclosures Dahiya: Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Research Funding; Miltenyi Biotech: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees.

Introduction:Chimeric antigen receptor T-cell (CAR-T) therapy has become an important treatment modality for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, many of these patients have aggressive disease and require a form of bridging therapy (BT) for disease control during CAR-T manufacturing. There is limited data in the literature on the most appropriate form of BT and the impact of BT on clinical outcomes. Methods:We retrospectively analyzed data on 75 patients that received CAR-T therapy at our institution. BT was defined as therapy administered between apheresis and CAR-T infusion. 52 patients received bridging therapy (BT) and 23 did not receive BT (NBT). BT included 10 high dose (HD) steroids, 28 chemotherapy-based regimen (CT), and 14 radiation therapy (RT). CT included cytotoxic chemotherapy, immunotherapy, and targeted therapy. IRB approval was obtained for this study. Statistical analysis was conducted with SAS v9.4. Univariate analysis Cox proportional hazard model was used and p-values for response rate were generated from Fisher's exact test. The methods of generalized linear model and logistic regression were used to associate the toxicity grades and cytopenias with BT, respectively. Results:Many patient and disease characteristics between BT and NBT groups were similar, with minor, non-statistically significant differences (See Fig. 1a). Although while the incidence of stage III/IV patients in the BT and NBT group was comparable (p=0.79), in subgroup analysis, there were significantly more stage III/IV patients in the CT subgroup and NBT than in the RT and HD steroids subgroups (p=0.03). There was a higher incidence of bulky disease (≥10cm) in the BT and all BT subgroups versus (vs) NBT, although this was not significant (p=0.58 and p=0.92). The number of prior lines of therapy was comparable between the BT and NBT groups (p=0.99). However, in subgroup analysis there were significantly more patients in the CT subgroup and NBT that received ≥4 lines of therapy compared with RT and HD steroids subgroups (p=0.02). There was no significant difference in overall response rate (ORR) at last follow up between BT vs NBT and BT subgroups vs NBT with approximately 50% being in complete remission in all cases (p=0.48 and p=0.54). Progression free survival (PFS) and overall survival (OS) were similar in the BT vs NBT (one-year rates of 67% vs 64% and 83% vs 75%, respectively) and this was not statistically significant (p=0.52 and 0.89), see Fig. 1b and 1c. In subgroup analysis PFS was comparable in the BT subgroups (CT 69% and HD steroids 68%) vs NBT group (67%) while RT was lower (51%), although this was not statistically significant (p=0.54). In subgroup analysis OS was slightly worse in the BT subgroups (CT 77%, RT 76%, and HD steroids 72%) vs NBT group (83%) although was not statistically significant (p=0.93). The development of cytokine release syndrome (CRS) was comparable in the BT vs NBT group and in BT subgroups vs NBT (p=0.18 and p=0.53). The median grade of immune effector cell-associated neurotoxicity syndrome (ICANS) was higher in BT than NBT (grade 2 vs 0) and trended towards statistical significance (p=0.09). The development of cytopenias at day +180 following CAR-T therapy was significantly higher in BT (50%) vs NBT (13.3%) and was statistically significant (p= 0.038). Subgroup analysis also showed significantly increased cytopenias at day +180 in CT (58.3%) and RT (57.1%) subgroups (p= 0.04). Conclusion:In our single-institution experience, BT prior to CAR-T therapy is feasible and may preserve CAR-T candidacy in patients with rapidly progressive LBCL. BT does not appear to significantly affect ORR, PFS, and OS. The incidence of CRS was comparable, although there was a higher incidence of ICANS in BT, which trended towards significance, and could be contributed to higher tumor bulk in the BT group. BT patients receiving CT and RT for BT were more likely to experience prolonged cytopenias, likely due to the myelosuppressive impact of BT and previous lines of chemo-immunotherapy agents. In conclusion, in high-risk patients with advanced and/or aggressive disease, BT may provide disease stabilization to CAR-T with a similar toxicity profile compared to NBT patients, although BT patients are more likely to experience prolonged cytopenias after CAR-T therapy. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics:Other: Advisory Board.Hardy:Incyte Corporation:Other: Advisory Board Member;American Gene Technologies:Other: DSMB Member;Kite/Gilead:Other: Advisory Board Member.

P-BCMA-101 and P-BCMA-ALLO1, autologous and allogeneic BCMA targeting CAR-T cell therapies respectively, are manufactured using a novel transposon-based system called piggyBac (PB). They comprise a high percentage of desirable stem cell memory T-cells associated with efficacy and safety. Single agent P-BCMA-101 data was previously reported showing marked efficacy and minimal toxicity (PRIME study), and exploratory combination cohorts have also been evaluated. P-BCMA-ALLO1 is expected to be first assessed in patients by the time of this presentation. Here we report results for P-BCMA-101 exploratory cohorts and P-BCMA-ALLO1. PRIME is a Phase 1/2 clinical trial to assess the safety and efficacy of P-BCMA-101 in patients with RRMM (≥ 3 prior lines, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory) (NCT03288493). Patients undergo apheresis to harvest T cells and P-BCMA-101 is then manufactured. Patients then receive a 3-day cyclophosphamide (300 mg/m 2/day) / fludarabine (30 mg/m 2/day) lymphodepletion (LDC) regimen. Following 2 days of rest, patients received a single administration of P-BCMA-101 in escalating doses starting at 0.75 x 10 6 CAR-T cells/kg. Similar P-BCMA-101 dose escalation was performed in combination cohorts with rituximab (Rit) or lenalidomide (Len). During the study, use of a nanoplasmid (NP) vector in CAR-T manufacturing was implemented to improve transposition efficiency and cell quality. As of June 30 th, 2021, 90 unique patients have been treated with P-BCMA-101 in 5 dose levels of single agent P-BCMA-101, 3 dose levels of P-BCMA-101 with Rit and 2 dose levels of P-BCMA-101 with Len. The median age is 61 years and 66/37% were M/F. Patients were heavily pre-treated with a median of 6 prior regimens (range 3-18), 100% had received prior PI and IMiD, 74% daratumumab and 63% ASCT. 13 patients were treated in combination with Rit and 9 in combination with Len. Like prior reports of P-BCMA-101, the safety profile compares favorably to other CAR-T. No dose limiting toxicities (DLT) were observed in the single agent or the combination cohorts. The addition of Rit or Len did not increase toxicity. Grade 1-2 CRS was seen in 25% (no G3/4) of patients and ICANS in 7% (2% G3). Tocilizumab was used in 11% of patients. There were no treatment related deaths or unexpected/off-target toxicities. The most common treatment emergent adverse events were cytopenias, infections and constitutional symptoms (≥ G3 neutropenia 74%, thrombocytopenia 30%, anemia 35%), as expected with CAR-T and LDC. The overall response rate (ORR) with the Rit and Len combinations was 73% and 71% respectively. The favorable safety profile allowed outpatient treatment in 23 (25%) patients. Founded on the P-BCMA-101 data, an allogeneic CAR-T (P-BCMA-ALLO1) using a similar PB construct was created and demonstrated excellent preclinical safety and efficacy leading to the initiation of a Phase 1 clinical trial (NCT04960579). P-BCMA-ALLO1 CAR-T cells are generated from healthy donor T-cells using Cas-CLOVER to knockout Beta-2 microglobulin to prevent host vs graft rejection, TCRβchain for graft vs host disease prevention. Proprietary booster molecules are utilized to increase manufacturing yield and cell quality. The CAR binding domain is a novel anti-BCMA VCAR that produced superior efficacy in tumor models. These constructs contain the same PB transposon transgene cassette, DHFR for gene selection and an iCasp9-based safety switch, successfully assessed in the PRIME study. The primary objective of the P-BCMA-ALLO1 phase 1 trial is to assess the safety and maximum tolerated dose (MTD) based on DLT in RRMM patients who have received a PI, IMid and CD38 mAb. Secondary objectives will assess the anti-myeloma effect of P-BCMA-ALLO1 and biomarkers. The protocol is designed to treat 40 RRMM patients in a standard 3+3 dose escalation with a P-BCMA-ALLO1 starting dose of 0.75 X 10 6 cells/kg. Patients will receive P-BCMA-ALLO1 following LDC with cyclophosphamide (300 mg/m 2/day) / fludarabine (30 mg/m 2/day X 3 days. In conclusion, transposon generated autologous CAR-T cells demonstrate excellent clinical activity with a favorable toxicity profile in RRMM, can be safely combined with Len and Rit, and administered in the outpatient setting. Allogeneic CAR-T cells generated from this platform represent a further advance. Current data from both clinical studies will be presented. Disclosures Derman: Sanofi: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy. Ali: BMS: Research Funding; Aduro: Research Funding; Poseida: Research Funding; Aduro: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; BMS: Consultancy; Janssen: Consultancy. Dholaria: Pfizer: Research Funding; MEI: Research Funding; Poseida: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Angiocrine: Research Funding; Jazz: Speakers Bureau; Celgene: Speakers Bureau. Berdeja: Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Lilly: Research Funding; Abbvie: Research Funding; EMD Sorono: Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy; Servier: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Vivolux: Research Funding; Cellularity: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CURIS: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Teva: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Bluebird: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; Genentech: Research Funding; Kesios: Research Funding. Cohen: GlaxoSmithKline: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy; BMS/Celgene: Consultancy; Novartis: Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Patel: Oncopeptides: Consultancy; BMS Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy. Siegel: Karyopharm: Honoraria; Amgen Inc.: Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Celularity: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. McArthur: Poseida: Current Employment, Current equity holder in publicly-traded company. McCaigue: Poseida: Current Employment, Current equity holder in publicly-traded company. Martin: Poseida: Current Employment, Current equity holder in publicly-traded company. Ghoddusi: Poseida: Current Employment, Current equity holder in publicly-traded company. Namini: Poseida: Current Employment, Current equity holder in publicly-traded company. Ostertag: Poseida: Current Employment, Current equity holder in publicly-traded company. Spear: Poseida: Current Employment, Current equity holder in publicly-traded company. Belani: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Shah: Indapta Therapeutics: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Bluebird Bio: Research Funding; Precision Biosciences: Research Funding; Karyopharm: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Sanofi: Consultancy; CSL Behring: Consultancy; Kite: Consultancy; GSK: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding.

Introduction: CD19 Chimeric Antigen Receptor T-cell (CAR-T) therapy is now a commonly used treatment for relapsed/refractory (R/R) Large B-cell Lymphoma (LBCL). However, predictors of long-term response remain poorly defined. In particular, partial response (PR) at first tumor assessment at Day 28 (D28) is a source of uncertainty both for clinicians and patients. In the pivotal CAR-T trials for LBCL, approximately half of these patients eventually achieved a complete remission (CR), while the other half experienced progressive disease (PD) (Neelapu et al, NEJM 2017). Herein, we present real-world data on 24 patients achieving a PR on D28 by PET/CT imaging following CAR-T therapy for R/R LBCL. We explore whether differences between baseline and D28 PET/CT imaging might predict progression free survival (PFS), overall survival (OS), best overall response rate (B-ORR), or last overall response rate (L-ORR). Methods: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 24 (32%) as achieving a PR on D28. Two independent radiologists collected baseline (pre-CAR-T therapy) and D28 PET/CT Standard Uptake Value (SUV) max and Total Tumor Metabolic Volume (TMV, in cm 3) using ROVER software. The Intraclass Correlation Coefficients (ICC) as a measure of absolute agreement between two readers was 0.99 for SUV the 0.97 for TMV. There was a strong absolute agreement between the two radiologists. For simplicity of data interpretation and given this concordance we present the results of one reviewer. Univariable Cox regression model was used to calculate PFS and OS. All statistical tests were 2-sided and conducted at the 0.05 level of significance. Results: Of the 24 patients with PR on D28 PET/CT, median follow-up time was 1.9 years with 17 patients (71%) still alive at last follow-up (see Fig 1a). Median age was 51 years-old, 46% were female, 66.7% had stage III/IV disease, all patients had ECOG ≤2, 58% received bridging therapy, and half had ≥3 lines of prior therapy (see Table 1A). Results of the univariable Cox regression model revealed that a lower D28 SUV max (p=0.004), lower TMV at both baseline (p=0.03), and at D28 (p=0.01) may be predictive of better OS. Longer PFS was found with lower D28 SUV max (p=0.002) and lower TMV at both baseline (p=0.01), and D28 (p=0.04). In analysis of B-ORR achieved by PET/CT, half of patients in PR at D28 ultimately achieved a CR (see Table 1B). OS was significantly lower in those with a B-ORR of PR vs CR (p In analysis of outcome by L-ORR by PET/CT, 11 patients were in CR, while 13 had PD (see Table 1C). The median SUV max at baseline was 14 in those in CR vs 15 in PD (NS); at D28 median SUV max was 5 in those with CR vs 6 in PD (NS). The median baseline TMV was 298 in those with CR vs 591 in PD (NS); the median TMV at D28 was 15 in those with CR vs 21 in PD (NS). There was no significant difference in absolute or percent change between baseline and D28 of either SUV max or TMV based on L-ORR. Conclusion: In this analysis of patients in PR at D28 following CD19-directed CAR-T therapy, D28 but not baseline SUV max was significantly higher in those with a B-ORR of PR; and, in our modeling, lower D28 SUV max may predict favorable PFS and OS. Lower TMV, both at baseline and D28, may also be predictive of longer PFS and OS. Collectively, these findings suggest that for patients achieving a PR at D28, the best predictive factor by imaging for ultimately achieving a CR is lower SUV max at D28 and lower TMV at baseline and D28. These characteristics were also associated with longer PFS and OS. These findings indicate that there may be an intrinsic quality to the tumor itself (e.g. FDG-avidity and metabolic volume) that determines the ultimate outcome from a D28 PR. While further study is warranted, we demonstrate that patients with such characteristics should be identified, monitored closely for relapse, and perhaps be considered for further early intervention. Figure 1 Figure 1. Disclosures Hardy: InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees.

Programmed death 1 (PD-1) receptor and its ligand (PD-L1) facilitate immune evasion in multiple myeloma (MM). We hypothesized that pembrolizumab, PD-1-antibody, can enhance antimyeloma cellular immunity generated by pomalidomide, leading to improved clinical responses. In this single-center, phase 2 study, 48 patients with relapsed/refractory MM (RRMM) received 28-day cycles of pembrolizumab, 200 mg IV every 2 weeks, pomalidomide 4 mg daily for 21 days, and dexamethasone 40 mg weekly. Patients had a median of 3 (range: 2-5) lines of therapy, median age 64 (range: 35-83) years, and had received both an immune modulatory drug (IMiD) and proteasome inhibitor: (35 [73%] of 48) were refractory to both; (31 [70%]) had received an autologous transplant, and (30 [62%]) had high-risk cytogenetics. Adverse events grade 3 to 4 occurred in (19 [40%] of 48 patients), including hematologic toxicities (19 [40%]), hyperglycemia (12 [25%]), and pneumonia (7 [15%]). Autoimmune events included pneumonitis (6 [13%]) and hypothyroidism (5 [10%]), mostly ≤ grade 2. Objective responses occurred in (29 [60%] of 48) patients, including stringent complete response/complete response (4 [8%]), very good partial response (9 [19%]), and partial response (16 [33%]); median duration of response was 14.7 months. At median follow-up of 15.6 months, progression-free survival (PFS) was 17.4 months and overall survival was not reached. Analyses of pretreatment marrow samples revealed a trend for increased expression of PD-L1 in responding patients and longer PFS with increased T-lymphocyte infiltrates, irrespective of PD-1 expression. Pembrolizumab, pomalidomide, and low-dose dexamethasone have acceptable safety and durable responses in RRMM patients. This trial was registered at www.clincialtrials.gov as #NCT02289222.

P-BCMA-101 is an autologous chimeric antigen receptor-T cell (CAR-T) therapeutic targeting BCMA and comprised of a high percentage of desirable stem cell memory T cells. P-BCMA-101 is manufactured using a novel transposon-based system called piggyBac and is designed to increase efficacy while minimizing toxicity. A phase 1/2, clinical trial is being conducted in patients with r/r MM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory) to assess the safety and efficacy of P-BCMA-101 (NCT03288493). No pre-specified level of BCMA expression was required. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients intravenously (IV) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) lymphodepletion regimen. As of 30Jun20, 43 patients had been treated with P-BCMA-101 (M/F 67%/33%, median age 60 years). Patients were heavily pre-treated (median of 7 prior regimens; range 3-18), with 100% having received proteasome inhibitors and IMiD, 93% daratumumab and 58% ASCT. This study was initially conducted as a dose escalation trial of single infusions of P-BCMA-101 from 0.75-15 x 106 cells/kg, preceded by standard lymphodepletion. Subsequently, exploratory cohorts with novel therapeutic strategies were evaluated. Using a modified manufacturing process, a median dose of 0.75 x 106 cells/kg were administered in cohorts including: P-BCMA-101 infusions in biweekly cycles; the addition of rituximab or lenalidomide pre- and post- lymphodepletion to prevent anti-CAR antibody development and increase T cell robustness, respectively; and single administration. The safety profile across the entire group was excellent for a CAR-T cell product which was attributed the gradual expansion of the Tscm cells (2-3 weeks to peak versus 3-7 days for most CAR-T cells). Cytokine release syndrome (CRS) was only seen in 17% of patients, with only one being grade 3 and one case of possible neurotoxicity reported (transient increase in confusion). Likewise, peak elevations of CRS markers were modest (maximum IL-6 level reported in any patient was 1631 pg/mL, orders of magnitude lower than levels frequently associated with severe CRS with CAR-T products). Only 3 patients required tocilizumab and no patients required ICU admission, safety switch activation or other aggressive measures. Based on the safety results the protocol was amended to allow fully outpatient CAR-T cell administration. There have been no patient deaths, DLTs or unexpected/off-target toxicities related to P-BCMA-101. The most common adverse events otherwise were cytopenias/infections and constitutional symptoms (≥ grade 3 neutropenia 79%, thrombocytopenia 30%, anemia 30%), as expected in CAR-T cell studies with lymphodepleting chemotherapy. Consistent with the high percentage of Tscm, circulating P-BCMA-101 cells were detected in blood by PCR, peaking at 2-3 weeks after infusion, and remaining detectable up to 1.5 years (ongoing at last follow-up). Response was seen to correlate with the Cmax and AUC of cell expansion, none of which correlated with dose administered. The overall response rate (ORR) for evaluable subjects (n=34) treated with single administration during the initial dose escalation was 57%. As there was not a definite dose response curve, but indications of better response at lower doses, additional cohorts were implemented focusing on the lower end of the dose range using product from the modified manufacturing process. Four patients were subsequently treated with cyclic administration, rituximab, lenalidomide or single administration at the lowest dose level with this manufacturing process (all treated with P-BCMA-101 within ~2 months prior to the data cut-off date), and thus far all have rapidly responded (100% ORR) and all responses are ongoing. The safety profile in these patients (including multiply infused patients) was no different than the overall population, with minimal CRS reported. In conclusion, current clinical data are consistent with preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, with remarkably low toxicity allowing for outpatient administration. Low doses appear highly efficacious and the modifications to manufacturing appear to have notably improved efficacy. Disclosures Costello: Poseida Therapeutics: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cohen:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Patel:Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectis: Research Funding. Berdeja:Lilly: Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bioclinica: Consultancy; Glenmark: Research Funding; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird: Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Teva: Research Funding; Servier: Consultancy; Amgen: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Constellation: Research Funding. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Ganguly:Kadmon: Other: Ad Board; KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Yalamanchili:Poseida Therapeutics: Current Employment, Current equity holder in private company. Gregory:Kesios: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Celularity: Research Funding; Teva: Research Funding; Vivolux: Research Funding; Lilly: Research Funding; Constellation: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CRISP Therapeutics: Research Funding; CURIS: Research Funding; Acetylon: Research Funding; Incyte Corporation: Consultancy; Bluebird: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; EMD Sorono: Research Funding.

Introduction: Secondary hemophagocytic lymphohistiocytosis (HLH) is an aggressive life-threatening activation of the immune system triggered by an underlying condition. Use of chimeric antigen receptor therapy (CAR-T) to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and development of secondary HLH. Application of HLH scoring systems such as the H-score or HLH-2004 criteria to identify CAR-T triggered HLH is not validated in this setting. Inability to promptly recognize the development of secondary HLH in CAR-T patients and to distinguish it from CRS may lead to delay in HLH specific therapy and increased mortality. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify possible patients with HLH post-CAR-T for R/R DLBCL. Methods: A single center retrospective analysis of 75 patients with R/R DLBCL following CAR-T was performed. Using a peak ferritin of 500 mcg/L or higher within 30 days of CAR-T administration, 43 out of 75 patients were identified at risk for HLH. The H-score and HLH-2004 criteria were applied retrospectively. Measurement of NK activity was not available for any patients and soluble IL2 was collected intermittently. The mean H-score was calculated, and two sample t-test performed to evaluate for a difference in the mean H-score between low versus high grade CRS, low versus high grade ICANS, as well as presence versus absence of cytopenias at days 30, 90 and 180. Low grade CRS/ICANS was defined as 1, and high grade as 2 or higher. CRS was graded per Lee 2014 criteria and ICANS per CTCAEv.4. The 43 patients were then subdivided by H-score threshold of 169 into H-score Low (< 169) and H-score High (≥ 169). The threshold of 169 was used given a prior validation study showing optimal sensitivity and specificity for identifying acquired HLH in adult patients with an H-score equal to or higher than 169. Both Progression Free Survival (PFS) and Overall Survival (OS) were defined as time from CAR-T infusion until an event of last follow up. Kaplan-Meier curves were produced to describe the distribution of PFS and OS between two subpopulations of low and high H-Score. Results: Median peak ferritin was 1571.8 mcg/L (range: 375 mcg/L - >50,000 mcg/L, table 1). Median H-score was 135 (range 61 -250). Four patients were treated with HLH directed therapy receiving steroids with either tocilizumab, siltuximab and/or anakinra. Of these 4 patients, only 2 met five HLH-2004 criteria. All 4 patients had H-scores above 169 (209, 211, 228 and 250). Of these 4 patients, one died from complications thought secondary to HLH. Fourteen patients (14/43, 32%) had an H-score >169. Ten patients did not require any HLH directed therapy and had no clinical evidence of HLH. The mean H-score was not different between patients with low vs high grade CRS (148.2 vs 141.8, p=0.7) or low vs high grade ICANS (145.9 vs 142.6, p=0.8). No statistical correlation was seen between H-score and cytopenias at any time point. There was no significant difference in PFS or OS between the H-score low vs high subgroups (p=0.7, p=0.1 respectively, figure 1 and 2). Patients with higher H-score tended to have longer length of hospitalization for CAR-T (Pearson correlation coefficient 0.289). Conclusions: In patients with R/R DLBCL post CAR-T, the use of either the H-score or application of HLH-2004 criteria had low utility in identifying possible HLH in patients who screened in based on peak ferritin within 30 days of CAR-T administration. While apparent differences between the H-score high and low categories may not reach statistical significance due to the small number of patients, our exploratory analysis does not support the use of H-Score to evaluate for HLH post-CAR-T. The immediate post-CAR-T period is characterized by a high inflammatory state, which likely results in high H-scores. Results from our study suggest a need for further characterization of HLH following CAR-T and the role for a CAR-T specific HLH scoring system to distinguish secondary HLH from CAR-T related inflammation in this specific patient population. Disclosures Hardy: American Gene Technologies: Other: DSMB Member; Kite/Gilead: Other: Advisory Board Member; Incyte Corporation: Other: Advisory Board Member.

Introduction The "POEMS" Syndrome, defined by its hallmark features of polyneuropathy, organomagaly, endocrinopathy, monoclonal plasma cell proliferative disorder, and skin changes has long been an enigma in terms of diagnosis and treatment. In recent years, clinicians and researchers have attempted to clarify diagnostic criteria. It is known that "VEGF," vascular endothelial growth factor, plays a large role in the pathophysiology of this disease.1Most recently, Angela Dispenzieri proposed a set of diagnostic criteria, which were published in the American Journal of Hematology.2We applied this suggested diagnostic criteria retrospectively to patients in our institution who carried a diagnosis of POEMS Syndrome. Additionally, we recorded the VEGF of these patients and their outcomes. Methods The.medical record was queried for patients with POEMS diagnosed in the last 5 years. A total of 16 patients met criteria. The primary outcome was to determine the percentage of patients who met the criteria proposed by Dispenzieri. A secondary outcome was to determine, in those patients who did not meet the criteria, the reason that they were not met. Another secondary outcome was to determine the percentage of patients who were alive or deceased. The criteria proposed by Dispenzieri (Table 1) were applied to each patient to assess whether they were met. If the diagnostic criteria were not met, the reason as to why they were not was recorded. Each patient outcome of "alive," "deceased," or "unknown" was recorded. Results Of the 16 patients analyzed, 14 (88%) had enough information to be included. Of these 14 patients, nine (64%) met the criteria proposed by Dispenzieri. Of the five patients that did not meet the criteria, four (80%) did not meet them due to the lack of a presence of a major criteria. One patient of the five (20%) that did not meet the criteria did not have the mandatory finding of polyneuropathy. VEGF levels ranged from 26-9504pg/mL, with an average of 1190pg/mL. The range for the patients who met the diagnostic criteria proposed by Dispenzieri was 1755pg/mL. Of our total patient population analyzed, 10 out of 14 patients (72%) were alive at time of retrospective review, including six out of nine (66%) that met the diagnostic criteria. Two out of 14 patients (14%) were found on review to be deceased, including one out of the nine (11%) that met the diagnostic criteria. Two out of 14 patients (14%) were determined to be "unknown" if alive or deceased, both of whom met the diagnostic criteria. Discussion Patients with POEMS syndrome often experience a delay in diagnosis due to the rarity of the disease as well as a lack of high index of suspicion for the condition in many cases. Additionally, POEMS syndrome is often mislabeled as another neuropathic condition. Efforts have been made to establish a standard criteria for diagnosis. We applied the criteria proposed by Dispenzieri this year in the American Journal of Hematology. In our retrospective study, we found that that 64% of our patients who carried a diagnosis of POEMS syndrome met the criteria for POEMS diagnosis using these proposed criteria. We found that the most common reason for not meeting the criteria in our patient population was the lack of a major criterion. Major criteria (Table 1) include Castleman Disease, sclerotic bone lesions and VEGF elevation, one of which must be met to receive a diagnosis of POEMS syndrome. Additionally, one of our patients did not meet the criteria due to the lack of the mandatory finding of polyneuropathy. The average VEGF levels in our patients were 1190pg/mL, but were higher at 1755pg/mL in the cohort who met the diagnostic criteria. 72% of our total patients were alive at time of review, including 66% of the patients who met the diagnostic criteria. We conclude that the criteria proposed by Dispenzieri provide a concise guideline to identify patients with POEMS syndrome. These criteria are simple to apply, and would potentially help to increase the index of suspicion and earlier diagnosis of patients with POEMS syndrome. This would be expected to lead to earlier initiation of therapy. Additionally, this analysis supports previous studies that show that VEGF levels are correlated with disease activity and that overall prognosis for patients with POEMS syndrome is favorable. Disclosures No relevant conflicts of interest to declare.

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known complications of chimeric antigen receptor T-cell (CAR-T) therapy. These clinical syndromes develop as a result of CAR-T activation, proliferation, and tumor lysis with resultant cytokine secretion. In prior reports of CD19 CAR-T therapy patients, those who developed ICANS showed evidence of endothelial activation and disruption of the blood-brain barrier as a result of cytokine release while only approximately one-third demonstrated changes on Brain MRI (Gust et al. Cancer Discov 2017). As such, further predictive markers and studies are needed to identify patients at risk for ICANS to allow for expedited management and improved outcomes. Herein we report a single-center analysis exploring glycolytic activity on PET/CT and the association with clinical outcomes for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) after CAR-T therapy. Methods: An organ-based evaluation of uninvolved sites was conducted in R/R DLBCL patients (n=32) who underwent CD19 CAR-T therapy with evaluable PET/CT imaging at baseline immediately prior to CAR-T therapy and at 30 days post-infusion (D+30). All patients in this analysis were treated with axicabtagene ciloleucel as standard of care therapy after 2 or more lines of therapy. Tumor metabolic volume (TMV) and mean standard uptake value (SUVmean) of various organs were quantified using ROVER [Region of interest (ROI) visualization, evolution, and image registration] software (ABX advanced biochemical compounds GmbH, Radeberg, Germany). Statistical analysis was completed using STATA 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). All tests were performed after testing the normality distribution assumption. Temporal changes were assessed using paired t-tests, and between-group analyses were completed with two-sample t-tests. Results: SUVmean increased significantly after CAR-T therapy in the following organs (D+30 v baseline pre-CAR-T PET/CT): cerebral cortex (8.23 v 7.09, p=0.036), cerebellum (6.26 v 5.56, p=0.024), basal ganglia (9.22 v 7.61, p=0.005), parotid gland (1.61 v 1.42, p=0.004), liver (2.47 v 2.17, p=0.002), spleen (2.08 v 1.84, p=0.043), and pancreas (1.76 v 1.48, p Conclusion: For patients with R/R DLBCL undergoing CD19 CAR-T therapy, significantly increased CNS glycolytic activity is seen on PET/CT at D+30 post-infusion when compared to baseline. Interestingly, these changes do not correlate with development of ICANS or lymphoma response; however, changes in cortical activity were associated with CRS grade ≥2. Overall, our findings illustrate a functional and radiographic link between cytokine release and subsequent disruption of the blood-brain barrier as quantified by increased cortical glycolysis 30 days post-CAR-T therapy. While findings are limited by small sample size, further validation in a larger data set is warranted. Disclosures Hutnick: Kite/Gilead: Other: Yescarta Speakers Bureau, Speakers Bureau. Badros:Celgene Corporation: Consultancy; Amgen: Consultancy.