ALBERT

Description: P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (TSCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 106 P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 106 cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study. A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be 〉=18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 106 P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials. Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM). Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Ali:Celgene: Research Funding; Poseida: Research Funding. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Patel:Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding; Poseida Therapeutics, Cellectis, Abbvie: Research Funding. Shah:University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Ghoddusi:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding.

Description: Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after myeloablative AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report updated results of the primary (PFS) and secondary (overall survival [OS] and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=57 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity 〉 grade 1 and significant cytopenias (ANC 〈 1000/mL, platelet count 〈 100,000/ml). For the 1st 8 weeks, pts

Description: Background: IL-15-mediated responses have been shown to have a crucial role in the development, function, and survival of CD8+ T cells, natural killer (NK) cells, and NK T cells. However, exploiting native IL-15 is challenging due to its unfavorable pharmacokinetics and tolerability. NKTR-255 is a polymer-conjugated IL-15 that retains binding affinity to IL-15Ra, maintaining full spectrum of IL-15 biology. NKTR-255 also exhibits improved pharmacokinetics, thereby providing sustained pharmacodynamic responses without the need for daily dosing. Studies have indicated that NK cells from patients with multiple myeloma (MM) appear to be dysfunctional, and successful activity against MM cells requires highly active NK cells ideally activated from immunomodulatory agents or cytokine support. In recent years, several new agents have been introduced in the MM landscape to engage NK-mediated myeloma cell elimination, including the CD38-targeting monoclonal antibody daratumumab, and elotuzumab, further supporting the anti‐MM effect of NK cells in the post-autologous transplant setting. In non-Hodgkin lymphoma (NHL), studies have shown low peripheral blood NK cell counts are associated with poor clinical outcomes in diffuse large B-cell lymphoma patients receiving R-CHOP chemotherapy regimens. Recently published data indicate that NKTR-255 in combination with CAR T cells decreases tumor burden and increases survival compared to CAR T cells alone. NKTR-255 may address the need to boost NK cell quality and numbers in these patients with the purpose of aiding current approved therapies. Methods: In this phase 1, open-label, multi-center, dose escalation and dose expansion study of NKTR-255, patients with relapsed or refractory (r/r) MM or NHL with no available therapies will be eligible. In the dose escalation portion, approximately 46 patients will be enrolled. Successive cohorts of 3 patients each will receive single increasing doses of NKTR-255 until the maximum tolerated dose (MTD) is determined. All patients will receive NKTR-255 once every three weeks. Patients will be observed for a dose-limiting toxicity (DLT) window of three weeks following the first NKTR-255 dose. A two-parameter Bayesian logistic regression model (BLRM) will be used during the escalation part of the study for dose level selection and for determination of MTDs. The selected recommended phase 2 dose (RP2D) of NKTR-255 will be evaluated in two dose expansion cohorts. Cohort A will expand NKTR-255 in patients with r/r MM or NHL as a salvage regimen to further characterize safety and tolerability. Cohort B will combine NKTR-255 with daratumumab in patients with MM with progressive disease who have had at least 3 prior lines of therapy with no other regimens that would confer clinical benefit. Daratumumab will be administered IV at the standard approved regimen. The primary objectives of the study are to evaluate: safety, tolerability, MTD, and RP2D of NKTR-255 as a single agent, as well as safety and tolerability of NKTR-255 in combination with daratumumab in patients with r/r MM. Secondary objectives include measures biomarker and pharmacokinetic analyses. Figure Disclosures Shah: University of California, San Francisco: Employment; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member. Cowan:Cellectar: Consultancy; Juno: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding. Chavez:Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Marcondes:Nektar Therapeutics: Employment, Equity Ownership. Lee:Nektar Therapeutics: Employment. Lin:Nektar Therapeutics: Employment, Equity Ownership. Zalevsky:Nektar Therapeutics: Employment, Equity Ownership. Tagliaferri:Nektar Therapeutics: Employment, Equity Ownership. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding.

Description: Background: TAK-079 is a subcutaneously (SC) administered, mAb which exhibits more selective binding to human CD38 protein expressed by myeloma cells and less cross reactivity with the CD38 antigen present on red blood cells and platelets. It depletes myeloma cells via apoptosis antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). TAK-079 was safe and well-tolerated in a first in human study in healthy subjects with potent pharmacodynamic activity when administered as a SC injection (Fedyk et al ASH 2018; abstract 3249). Methods: A multicenter phase 1 study (NCT03439280) evaluating safety, pharmacokinetic (PK), pharmacodynamics, and efficacy of TAK-079 in patients with heavily pretreated RRMM was initiated. Pt with RRMM were eligible after at least 3 lines of therapy and previous exposure to immunomodulatory drug (IMiD), proteasome inhibitor (PI), alkylating agent, and corticosteroid with or without an anti-CD38 or SLAMF7 antibody. Patients were refractory or intolerant to at least 1 PI and 1 IMiD. Ph 1 dose escalation proceeded using a 3+3 design. The TAK-079 dose was given as a SC injection weekly for 8 doses, every other week for 8 doses, then monthly until disease progression (PD) or unacceptable toxicity. Results: 31 patients have been enrolled across 4 dose cohorts (TAK-079 45-135-300-600 mg fixed dose SC); data is available on 28 patients as of the 14 June 2019 data cutoff. Median age was 65 (53-81) years. ISS stage at study entry was I/II/III/missing in 42%, 32%, 19%, 6% of patients respectively, 94% of patients were refractory to either a PI or IMiD and 61% were refractory to both, 23% of patients were previously exposed to at least 1 anti-CD38 monoclonal antibody; 84% had a prior stem cell transplant. The maximum volume of a SC injection was 2 mL, resulting in an administration duration of ≤ 1 minute. No ≥ Grade 1 early or late systemic infusion reactions have been reported. One (

Description: Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab). Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily on days -5 to -3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant. Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin 〉3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR). Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P 50 years (79% vs 50%), β2-microglobulin 〉3 mg/L (73% vs 45%), 〉3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR. Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT. Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen. Disclosures No relevant conflicts of interest to declare.

Description: Background: The addition of R has been shown to improve results for pts with relapsed DLBCL who undergo BEAM (carmustine, etoposide, cytarabine, melphalan) high-dose chemotherapy followed by an autologous stem cell transplantation (ASCT) (Khouri IF, J Clin Oncol 2005;23;2240). The incorporation of radiolabeled antibodies such as yttrium-90 ibritumomab tiuxetan to conditioning regimens has also been evaluated without additional toxicity (Khouri IF, ASH 2007, abstract 620). Subsequently, a randomized trial which was undertaken at our center to compare these 2 regimens was closed early because of slow accrual. Herein, we compare the long-term outcome in pts treated in these trials. Methods: A combined analysis was carried out from 113 pts. Between 1999 and 2003, 57 pts with relapsed DLBCL were enrolled on a protocol with BEAM conditioning plus R at 1000 mg/m2 on days +1 and +8 after ASCT (Group A). Between 2004 and 2006, a similar group of 26 patients were entered onto a trial consisting of ibritumomab tiuxetan plus BEAM (Z/BEAM). Ibritumomab tiuxetan was given at the fixed doseof 0.4 mCi/Kg on day -21 followed by BEAM(days -7 to -1) (Group B). In 2007-2010, a randomized trial was undertaken comparing BEAM/R (Group C, n=16) and Z/BEAM (Group D, n=14). All pts received R during stem cell collection, administered at 375 mg/m2 on the day before initiating chemotherapy for stem cell mobilization, and again at 1000 mg/m2, 7 days later. The same eligibility criteria were used for all groups. In addition, pts who were enrolled on the randomized trial (Groups C and D) underwent FISH analysis for -5 and -7 and cytogenetic analysis by G-banding pre-enrollment; those who had a clonal abnormality were excluded. We also retrospectively evaluated the histologic subtypes of mediastinal, transformed and de novo DLBCL. We determined the cell-of-origin of the latter using the Visco/Young and Choi W, et al. immunohistochemical algorithms. A univariate analysis was conducted for factors of interest: this included the group conditioning, age, sex, number of prior treatments, disease status at transplantation (CR/PR), IPI (0 vs 〉0), LDH, β2-microglobulin, PET status, and histology subtype. Multivariate survival analysis was then conducted using backward elimination on the basis of the likelihood ratio test and including the conditioning regimens and all the factors with P 〈 0.05 in the univariate analyses. Patients: There was no significant difference in the prognostic factors described above between the 4 groups with the exception of prior treatments. More pts in the BEAM/R groups received 〉 2 prior chemotherapies than the Z/BEAM groups (32%, 11.5%, 69% and 50% in Groups A, B, C and D, respectively; P 〈 0.001). Non-GCB histology within the 4 groups was present in 39%, 26%, 31% and 21%, respectively (P=0.31). Results: The median follow-ups times for Groups A, B, C and D were 11.8, 8.1, 4.2 and 4.9 years, respectively. The 5-year overall survival (OS) rates for these groups were 74%, 73%, 69% and 86%, respectively (P = 0.46) and the disease-free survival (DFS) rates were 62%, 65%, 63%, and 63%, respectively (P = 0.99) (Figure 1). Multivariate analysis at 5-year showed that previous exposure to 〉3 prior chemotherapies and IPI were predictors for OS (P= 0.003 and 0.005, respectively), and DFS (P = 0.003 and 0.006, respectively). There was no significant difference in OS or DFS rates between GCB, non-GCB, mediastinal and transformed DLBCL (Figure 2). The 5-year non-relapse mortality for all pts was 4.7% and the 5-year relapse rate was 32.5% (34.0%, 30.8%. 25% and 37.5% for Groups A, B, C and D, respectively). The 5-year risk of secondary myelodysplasia (MDS) for all pts was 6.2%. None of the pts in Groups C and D who had pre-transplant cytogenetic testing developed MDS at 5-year. Conclusions: Long-term follow-up results show no difference in OS, DFS, relapse rate, or risk of MDS between Z/BEAM and BEAM/R after in-vivo purging with R during stem cell collection. Our results were reproducible in 3 trials and appear to be superior to published reports in the literature of similar trials without in-vivo purging. This highlights the importance of this procedure for ASCT in DLBCL. Figure 1. Figure 1. Disclosures Off Label Use: The use of Zevalin and rituximab in transplantation. Alousi:Therakos, Inc: Research Funding. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Nastoupil:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding; Genentech: Honoraria. Westin:Spectrum: Research Funding.

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

Description: Background High-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is considered the standard of care for newly diagnosed, transplant-eligible multiple myeloma (MM) patients. Due to improvements in induction, stem cell mobilization, and dose adjustment of the conditioning regimen, auto-HCT is increasingly used in older MM patients, with several retrospective analyses showing similar clinical outcomes compared to younger patients. Methods To further confirm these results, we performed a single-center retrospective analysis of MM patients undergoing auto-HCT between January 2006 and December 2016. Patients were divided into two groups: older (〉 70 years) and younger (≤ 70 years). Results 1128 patients (182 older, 946 younger) were included in this analysis. Patient characteristics are summarized in the attached Table. More patients (59% vs. 45%, p = 0.01) in the older cohort had ISS stage II or III disease. Older cohort was more likely to receive reduced-dose melphalan (140 mg/m²) as conditioning regimen (32% vs 3%, p = 2 mg/dl and ISS stage III were associated with worse PFS and OS. In contrast, melphalan 200 mg/m² for conditioning and achievement of CR after induction therapy were associated with better PFS and OS. These 6 factors were studied in multivariate analyses using a classification and regression tree (CART) method. In CART analysis for PFS, ISS stage II or III, and high-risk cytogenetics were associated with shorter PFS. Similarly, in CART analysis for OS, older age (〉 69 years), ISS stage II or III, and high-risk cytogenetics were associated with a shorter OS. Conclusion In this large single-center analysis, there was no difference in 100-day NRM, CR rates and the risk of progression after auto-HCT between the older and the younger patients. However, older age was associated with a shorter PFS and OS due to increased NRM. On multivariate CART analysis, ISS stage II or III and high-risk cytogenetics were associated with a worse PFS and OS, while age 〉 69 years was associated with a worse OS only. The impact of comorbidities on NRM is being evaluated in ongoing analyses. Disclosures Lee: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Thomas:Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Array Pharma: Research Funding. Orlowski:BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Millenium Pharmaceuticals: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Description: P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell therapeutic targeting BCMA, which is highly expressed on MM cells. It is designed to increase efficacy while minimizing toxicity through reduced immunogenicity, lack of tonic signaling, a safety switch, and a product comprised predominantly of early memory T cells that are effectively all CAR-positive. Rather than using a traditional antibody-based binder, P-BCMA-101 utilizes an anti-BCMA Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic. P-BCMA-101 is produced using the piggyBac™ (PB) DNA Modification System instead of a viral vector, and requires only plasmid DNA and mRNA. This eliminates the need for virus, is less costly, and produces a purified population of CAR+ cells with a preponderance of the favorable stem cell memory T phenotype (TSCM). The higher cargo capacity permits the incorporation of other genes, a safety switch that allows for rapid depletion of product in vivo if indicated by adverse events, and a selection gene that allows for enrichment of CAR+ cells. These features are predicted to result in a greater therapeutic index. Efficacy of P-BCMA-101 in NSG mice bearing aggressive human MM.1S and p53 -/- MM.1S MM was reported (Hermanson, AACR 2016). Whereas control animals died early, tumor burden was reduced to the limit of detection after P-BCMA-101 treatment, and recurrences were spontaneously re-controlled without re-administration of product. A Phase 1, 3+3 dose escalation 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 as a single intravenous (IV) dose after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. As of 31Jul18, 12 patients have been treated with 48, 50, 55, 118, 122, 124, 143, 155, 164, 238, 324 and 430 x 106 P-BCMA-101 CAR-T cells in 3 weight-based cohorts. Patients were heavily pre-treated (3-9 prior therapies), 100% had failed IMiDs, proteasome inhibitors and daratumumab, and 64% had high-risk cytogenetics. Nine patients have yet reached their first 2-week response assessment. All patients have shown some improvement in myeloma assessments on study, yet only 1 patient (8%) has developed any cytokine release syndrome (CRS) (limited Grade 2). Of 3 patients in the first cohort 1 attained a PR and 1 with non-secretory disease near CR of her plasmacytomas on PET/CT. Of the subsequent 6 patients, 3 patients have thus far reached a PR, 1 a VGPR, and 1 a sCR. Thus of the yet evaluable patients treated above Cohort 1, the overall response rate (ORR) is 83% (5/6), in spite of only one experiencing CRS. This CRS was scored as Grade 2, based on short-lived fever and hypotension managed with IV fluids and antibiotics, with minimal CRS marker elevations. Likewise, CRS markers were minimally elevated in other patients. The maximal IL-6 level in any patient was 86 pg/mL, which is orders of magnitude lower than levels generally reported in patients experiencing meaningful CRS after treatment with CAR-T products. No patients required treatment with tocilizumab or safety switch activation. There have been no patient deaths, and no neurotoxicity, DLTs or unexpected/off-target toxicities related to treatment. Generally, infusions were well-tolerated, with cytopenias, including transfusion requiring cytopenias and febrile neutropenia, being the most common Grade 3+ adverse events. Consistent with the hypothesis of the early memory phenotype conveying durability, circulating P-BCMA-101 cells were detected in the blood by flow and PCR, peaking at 2-3 weeks, and remaining detectable at the last timepoint tested in all patients (3 patients thus far assessed at 3 months). In conclusion, current clinical trial data in patients with r/r MM support preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, comparing favorably with other anti-BCMA CAR-T products at similar doses, with notably less CRS and no neurotoxicity, consistent with the hypothesis of an improved therapeutic index. Funding by Poseida Therapeutics and CIRM. Disclosures Gregory: Poseida Therapeutics, Inc.: Research Funding. Cohen:Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Oncopeptides: Consultancy; Poseida Therapeutics, Inc.: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Research Funding. Costello:Celgene: Consultancy; Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy. Ali:Celgene Inc: Research Funding; Aduro Biotech: Consultancy, Research Funding; Amgen Inc: Consultancy; Juno: Consultancy; Takeda Oncology: Consultancy; Poseida Therapeutics: Research Funding. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Glenmark: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Teva: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Resler:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Millenium Pharmaceuticals: Consultancy, Research Funding; Poseida: Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Description: Abstract: Background: Upfront autologous hematopoietic stem cell transplantation (auto-HCT) combined with novel anti-myeloma drugs is considered the standard of care for transplant-eligible patients with multiple myeloma (MM). However, this treatment is generally avoided in older patients due to concerns about toxicity. MM is primarily a disease of the elderly, with 〉35% patients being older than 70 years of age at diagnosis. We have previously reported on the role of auto-HCT in MM patients 〉70 years1. In this study, we evaluate the safety and feasibility of auto-HCT in patients ≥80 years who received auto-HCT at our institution. Methods: We retrospectively reviewed the outcomes of MM patients with age ≥80 years who underwent auto-HCT between January, 2007, and June, 2018. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of auto-HCT to the last follow up or the censored date. Kaplan-Meier method was used to estimate PFS and OS. Results: Between January, 2013, and December, 2017, out of a total of 1465 MM patients referred for evaluation for auto-HCT at our institution, only 10(0.68%) were of age ≥80 years. Also, between January, 2016, and June, 2018, a total of 210 MM patients with age ≥80 years were treated at our institution, and only 3(0.14%) underwent auto-HCT. Overall among 1740 patients with MM who received an auto-HCT at our institution between the beginning of 2007 to June, 2018, 9(0.5%) patients were ≥ 80 years of age (range 80-83). Table 1 summarizes the patient characteristics of these nine patients. All patients had an ECOG performance status of either 0 or 1. The median hematopoietic stem cell transplant - comorbidity index for the cohort was 3 (range, 0-5). Eight (89%) patients were in first remission, and 1 (11%) patient had relapsed disease at auto-HCT. All patients received melphalan at a reduced dose of 140 mg/m2 as the conditioning regimen. Eight patients (89%) received maintenance therapy with lenalidomide. The median follow-up from auto-HCT was 18 months (range 0.5 - 50 months). No (0%) patient died within 100 days of auto-HCT. Out of 8 evaluable patients, 4 (50%) achieved a complete response, 2 (25%) very-good partial, and 2 (25%) achieved a partial response with an overall response rate of 100%. Eight (89%) patients were alive until the last follow-up. Median PFS was 31.5 months, while the median OS has not been reached (Fig1). 2-yr PFS and OS were 62.5% and 75% respectively. One patient died 22 months post-transplant due to non-transplant related cause. Conclusions: In selected MM patients ≥80 years old, auto-HCT was feasible, with 0% TRM, 100% response rate, and 2-year OS of 75%. Almost 90% of these patients went on to receive maintenance therapy. References: Qazilbash, M. H. et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplantation39, 279-283 (2007). Disclosures Shpall: Affirmed GmbH: Research Funding. Thomas:Celgene: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Orlowski:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.