Berdeja, Jesús G.

8028 Background: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, led to early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study (NCT03548207) in heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM). At ̃1-year (y) median follow-up (MFU), overall response rate (ORR) was 97%; 67% of pts achieved stringent complete response (sCR). 1-y progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively (Berdeja 2021). Updated results 2-y post last patient in (LPI) will be presented (̃30-month total MFU). Here, we report CARTITUDE-1 results at 21.7-month MFU. Methods: Eligible pts with RRMM received ≥3 prior lines of therapy (LOT) or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Bridging therapy was permitted after apheresis. Pts received a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5–7 days after lymphodepletion. Primary objectives were to evaluate cilta-cel safety and efficacy. Response was assessed per International Myeloma Working Group criteria by independent review committee and minimal residual disease (MRD) negativity at 10-5 by next-generation sequencing. Results: As of July 22, 2021, 97 pts (59% male; median age 61 y) received cilta-cel. Pts had a median of 6 (range 3–18) prior LOT; 84% were penta-drug exposed, 88% were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to last LOT. ORR was 97.9% (95% CI 92.7–99.7), 94.9% achieved very good partial response, and 82.5% achieved sCR. Median times to first response, best response, and ≥CR were 1.0, 2.6, and 2.9 months (m), respectively; median duration of response was not reached (NR). Of 61 pts evaluable for MRD, 92% were MRD negative (10-5), sustained for ≥6 m in 44% (27/61) and ≥12 m in 18% (11/61). 2-y PFS was 60.5% (95% CI 48.5–70.4). Median PFS and OS were NR. 2-y PFS rates in pts with sustained MRD negativity for ≥6 m and ≥12 m were 91% and 100%, respectively. There were no new safety signals or new events of CAR-T cell neurotoxicity, movement and neurocognitive treatment-emergent adverse events, or treatment-related deaths since 1-y MFU. 15 second primary malignancies were reported in 11 pts over ̃2-y MFU. Conclusions: At ̃2-y MFU, a single cilta-cel infusion led to deepening and durable responses in heavily pretreated pts with RRMM with a manageable safety profile. Follow-up is ongoing, and landmark 2-y post LPI data (̃8 m additional follow-up; ̃30 m total MFU) will be presented. Further investigations of cilta-cel are ongoing in earlier LOT and outpatient settings across the CARTITUDE program (NCT04133636, NCT04181827, NCT04923893). Clinical trial information: NCT03548207.

e20021 Background: CAR T cell therapies are FDA approved for patients with triple refractory multiple myeloma (MM) and >4 lines of therapy. The median survival of this is group is less than 12 months so salvage therapies need to be implemented quickly. Real-world access to CAR T remains challenging due to supply chain limitations impacting manufacturing. The goal of this study was to evaluate how centers are handling the challenges of CAR T slot allocation. Methods: MM CAR T physician leaders at each CAR T treatment center certified for idecabtagene vicleucel across the US were surveyed. Results: We received responses from 15/20 centers. Summary of CAR T volumes and outcomes of patient on waitlists are shown in the table. The median time on the waiting list was 6 months with only 25% of patients receiving CAR T eventually. For patient selection, all centers reported using a committee of experienced CART physicians to ensure consistency. Selection committee included: primary MD (n=9), CAR T MD (n=12), social workers (n=3), CAR T RN (n=10), APP (n=2), pharmacists (n=2) and ethicists (n=1). To ensure transparency, centers have clear selection criteria (n=10), priority score (n=8) and selection timeline (n=11) . To ensure accountability, centers document priority scores (n=5) and have pre-specified criteria (n=9) for selection. Centers also reported using ethical principles for selection: a) equal treatment: time spent on waiting list (n=8); b) priority to the worst-off: limited therapeutic options (n=10), MM burden (n=7), ineligible for trials (n=2); c) maximize benefit: most likely to complete apheresis (n=8) or infusion (n=8) or achieve response (n=6) and d) social value: younger pts (n=2). Maximizing benefit was considered the most important criterion by 7 centers. Conclusions: More stringent GMP manufacturing requirements with FDA approved CAR T and real-world practice with broader patient demographics can present challenges to implementation of CAR T in standard of practice. Our study is the first attempt to evaluate and highlight existing issues with MM CAR T access and the variability and challenges in patient selection. Learning from other models of resource allocation (ex: UNOS) and sharing experience across centers can help providers optimize slot allocation to improve accrual. Increasing supplies of key reagents and novel manufacturing methods(eg: non-viral vectors and allogeneic CAR) could help overcome these limitations. [Table: see text]

PURPOSE CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel–related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Abstract Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on myeloma cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody (BsAb) that facilitates T cell-directed killing of myeloma cells. Initial data from the dose-escalation phase of the ongoing Phase I study (NCT03275103) of cevostamab monotherapy in patients (pts) with heavily pre-treated RRMM demonstrated promising activity and manageable safety, along with near ubiquitous FcRH5 expression on myeloma cells (Cohen et al. ASH 2020; Sumiyoshi et al. EHA 2021). We present updated safety and efficacy data from a larger cohort of pts, including results comparing Cycle (C) 1 single step-up (SS) and double step-up (DS) dosing for the mitigation of cytokine release syndrome (CRS). Methods: Participants have RRMM for which no established therapy is available or appropriate. Cevostamab (intravenous infusion) is administered in 21-day cycles. In the SS cohorts, the step dose (0.05-3.6mg) is given on C1 Day (D) 1 and the target dose (0.15-198mg) on C1D8. In the DS cohorts, the step doses are given on C1D1 (0.3-1.2mg) and C1D8 (3.6mg), and the target dose (60-160mg) on C1D15. In both regimens, the target dose is given on D1 of subsequent cycles. Cevostamab is continued for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurs. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (18 May 2021), 160 pts had been enrolled (median age: 64 years, range: 33-82 years; male: 58.1%); 21.3% of pts had extramedullary disease. Median number of prior lines of therapy was 6 (range: 2-18). Most pts (85.0%) were triple-class refractory (PI, IMiD, anti-CD38 antibody). 28 pts (17.5%) had received ≥1 prior CAR-T, 13 pts (8.1%) ≥1 prior BsAb, 27 pts (16.9%) ≥1 prior antibody-drug conjugate (ADC), and 54 pts (33.8%) ≥1 prior anti-BCMA targeting agent. Median follow-up in exposed pts was 6.1 months. Almost all had ≥1 adverse event (Table). The most common was CRS (128/160 pts [80.0%]; Grade [Gr] 1: 42.5%; Gr 2: 36.3%; Gr 3: 1.3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CRS was observed in 21 pts (13.1%) and in 34/211 (16.1%) CRS events (Gr 1: 8.5%; Gr 2: 6.2%; Gr 3: 1.4%). Most CRS events occurred in C1 (87.2%), arose within 24 hours of cevostamab administration (70.5%), and resolved within 48 hours of onset (83.4%). In the pts with CRS, tocilizumab was used for CRS management in 43.8% and steroids in 25.8% (both agents: 18.0%). In SS dose-escalation (68 pts), 3.6mg was chosen as the most effective C1D1 SS dose for limiting CRS in C1, with no target dose-dependent increase in the rate or severity of CRS observed after the C1D8 administration. Likewise, in DS dose-escalation (30 pts), 0.3/3.6mg was identified as the preferred C1D1/C1D8 DS dose for limiting CRS in C1. Notably, the overall rate of CRS was lower in the pts who received the 0.3/3.6mg/target DS regimen than in those who received the 3.6mg/target SS regimen (77.3% [34/44] vs 88.2% [75/85], respectively). The rate of ICANS associated with CRS was also lower in the 0.3/3.6mg/target DS cohort than in the 3.6mg/target SS cohort (4.5% [2/44] vs 21.2% [18/85], respectively). At data cut-off, 158/160 pts were efficacy evaluable. In dose-escalation, responses were observed at the 20-198mg target dose levels, and data suggested a target dose-dependent increase in clinical efficacy. Median time to response was 29 days (range: 20-179 days). Two dose-expansion cohorts were opened: ORR was higher at the 160mg dose level (54.5%, 24/44 pts) than at the 90mg dose level (36.7%, 22/60). At target dose levels >90mg, ORRs in pts with prior exposure to CAR-Ts, BsAbs, ADCs, and anti-BCMA targeting agents were 44.4% (4/9 pts), 33.3% (3/9), 50.0% (7/14), and 36.4% (8/22) respectively. Median follow-up among all responders (n=61) was 8.1 months; estimated median duration of response was 15.6 months (95% CI: 6.4, 21.6). Conclusions: Cevostamab monotherapy continues to show clinically meaningful activity in a large cohort of pts with heavily pre-treated RRMM, with a target dose-dependent increase in ORR, but no increase in CRS rate. Responses appear durable, and are observed in pts with prior exposure to CAR-Ts, BsAbs, and ADCs. Compared with SS dosing, DS dosing at the 0.3/3.6mg level appears to be associated with a trend for an improved C1 safety profile. Figure 1 Figure 1. Disclosures Trudel: Amgen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria. Cohen: BMS/Celgene: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Oncopeptides: Consultancy; Novartis: Research Funding; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Krishnan: MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Fonseca: Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; GSK: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Amgen: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Spencer: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Lesokhin: Serametrix, Inc: Patents & Royalties; Behringer Ingelheim: Honoraria; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy. Forsberg: University of Colorado: Current Employment; Karyopharm, Sanofi, Genentech: Research Funding. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Kaedbey: Takeda, Sanofi: Honoraria; Celgene/BMS, Janssen: Honoraria; Royal Victoria Hospital Lakeshore Hospital: Ended employment in the past 24 months; Jewish General Hospital - McGill University: Current Employment. Richter: Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. Thomas: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta Pharma: Research Funding; X4 Pharma: Research Funding; Ascentage Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Wong: Genentech: Current Employment; CTMX, UBX, BMRN: Current equity holder in publicly-traded company. Li: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Choeurng: Genentech: Current Employment, Current equity holder in publicly-traded company. Vaze: Roche/Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Samineni: Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Genentech: Current Employment; Roche: Current holder of individual stocks in a privately-held company. Harrison: Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria. OffLabel Disclosure: Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-directed killing of myeloma cells. Cevostamab is an investigational agent.

Abstract Background: Patients with relapsed and refractory multiple myeloma (RRMM) who have triple class exposure to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (MoABs) have a poor prognosis and high unmet medical need. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy which may offer long-term disease control for these patients. CARTITUDE-1 is an open-label, single arm phase 1b/2 clinical trial conducted to characterize the safety and efficacy of cilta-cel in adult patients with triple-class exposed RRMM. Since CARTITUDE-1 is a single-arm study, adjusted comparisons to other currently available therapies can provide valuable information on relative efficacy and safety benefits of cilta-cel over current real-world clinical practice (RWCP). LocoMMotion is the first prospective study of RWCP efficacy and safety outcomes in triple-class exposed patients with RRMM. It was designed a priori to serve as an external control cohort for CARTITUDE-1, using aligned inclusion criteria and endpoint definitions, to enable robust, high quality indirect comparisons vs. cilta-cel. Objective: To compare patient outcomes of cilta-cel vs. RWCP, including overall response rate (ORR), complete response or better rate (≥CR rate), progression-free survival (PFS) as assessed by a review committee and overall survival (OS) in patients with triple-class exposed RRMM. Methods: Individual patient level data available from both CARTITUDE-1 (clinical cut-off February 2021) and LocoMMotion (clinical cut-off March 2021) were pooled to conduct the comparative analyses. Imbalances between both cohorts on key prognostic baseline characteristics, including refractory status, ISS stage, time to progression on prior line, number of prior lines, average duration of prior lines, age, creatinine clearance, ECOG PS and MM type were adjusted for using inverse probability weighting. Average treatment effect on the treated (ATT) weights derived from propensity scores estimated using multivariable logistic regression modeling were applied to the LocoMMotion patients to have the weighted RWCP cohort reflecting the CARTITUDE-1 patient population. Balance between the ATT weighted RWCP cohort versus the CARTITUDE-1 population was evaluated based on reduction of standardized mean differences and overlap of propensity score distributions. Weighted logistic and Cox proportional hazards regression were used to estimate the relative treatment effects for cilta-cel vs. RWCP on binary endpoints (Odds ratios (OR), transformed into Response-rate Ratios (RR) and time to event endpoints (Hazard ratios (HR)), respectively. The base case analyses included all enrolled (apheresed) patients from CARTITUDE-1, reflecting an intention to treat approach. Additional analyses were conducted including only patients who received cilta-cel infusion compared to an aligned population of LocoMMotion where patients that progressed or died within 52 days were excluded from the LocoMMotion cohort. Results: 113 patients were enrolled in CARTITUDE-1, of which 97 were infused with cilta-cel. 246 patients were enrolled in LocoMMotion receiving RWCP in Italy (24%), Germany (15%), France (14%), UK (11%), Spain (10%), USA (9%), Belgium (5%), Poland (5%), Netherlands (4%) and Russia (3%). Therapies within the RWCP cohort were diverse and >90 unique treatment regimens were used. The most frequent regimens were Kd (13.8%), PCd (12.6%) and Pd (11.0%). The weighted LocoMMotion population was well balanced with the CARTITUDE-1 cohort. Adjusted comparisons (Table 1) showed statistically significant improvements for cilta-cel vs. RWCP for ORR (RR=4.43), ≥CR (RR=568.92), PFS (HR=0.15) and OS (HR=0.38), all comparisons with p<0.001. All additional analyses were consistent with these findings (Table 1). Conclusions: Outcomes for patients with triple-class exposed RRMM treated with RWPC observed in LocoMMotion are poor, illustrating the high unmet medical need. Adjusted comparisons vs. CARTITUDE-1 demonstrate significantly improved ORR, ≥CR, PFS and OS for cilta-cel compared to a diverse set of RWCP. These findings highlight cilta-cel's potential as a highly effective treatment option for patients with triple-class exposed RRMM. Figure 1 Figure 1. Disclosures Mateos: Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel: GSK: 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, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Martin: Sanofi: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Berdeja: Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Jakubowiak: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stewart: Oncopeptides: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Skyline diagnostics: Consultancy; Genomcs England: Membership on an entity's Board of Directors or advisory committees; Tempus Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; PikSci Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Sanofi Aventis: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Lin: Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Juno: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Diels: Janssen: Current Employment. Ghilotti: Janssen-Cilag SpA, Cologno Monzese, Italy: Current Employment. Perualila: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Haefliger: Janssen-Cilag AG: Ended employment in the past 24 months; Cilag GmbH International: Current Employment. Erler-Yates: Janssen: Current Employment. Hague: Janssen: Current Employment, Current equity holder in publicly-traded company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Strulev: Janssen Pharmaceutica NV: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Moreau: Janssen: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA) targeting single-domain antibodies, demonstrated early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who had been heavily pretreated (Berdeja, Lancet, 2021). After a median follow-up of 12.4 months, the overall response rate (ORR; as assessed by independent review committee) was 97%, with 67% of pts achieving stringent complete response (sCR). The 12-month progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively. Here, we report updated results from CARTITUDE-1 with longer duration of follow-up (median 18 months). Methods: Eligible pts had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and had received a PI, IMiD, and an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Pts received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days (d) after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 d). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate cilta-cel efficacy (phase 2). Response was assessed per IMWG criteria by an independent review committee and minimal residual disease (MRD) negativity at 10 -5 by next-generation sequencing. In this combined phase 1b and phase 2 analysis, cytokine release syndrome (CRS; per Lee et al Blood 2014 grading criteria) and neurotoxicity (by CTCAE v5.0) were mapped to the ASTCT criteria for CRS and immune effector cell-associated neurotoxicity (ICANS), respectively. Results: As of Feb 11, 2021, 97 pts (58.8% male; median age 61.0 years [range 43-78]) received cilta-cel. Pts had received a median of 6 (range 3-18) prior lines of therapy; 83.5% were penta-drug exposed, 87.6% were triple-class refractory, 42.3% were penta-drug refractory, and 99.0% were refractory to last line of therapy. ORR was 97.9% (95% CI: 92.7-99.7); 80.4% of pts achieved sCR, and 94.8% achieved very good partial response or better (Figure). The median time to first response was 1 month (range 0.9-10.7), median time to best response was 2.6 months (range 0.9-15.2), and median time to complete response or better was 2.6 months (range 0.9-15.2). The median duration of response was 21.8 months (95% CI: 21.8-not estimable). Of 61 pts evaluable for MRD, 91.8% were MRD negative at the 10 -5 threshold; MRD 10 -5 negativity was sustained for ≥6 months in 44.3% (27/61) of pts and ≥12 months in 18% (11/61) of pts. The 18-month PFS and OS rates were 66.0% (95% CI: 54.9-75.0) and 80.9% (95% CI: 71.4-87.6), respectively. 18-month PFS rates in pts who achieved sustained MRD for ≥6 months and ≥12 months were 96.3% (95% CI: 76.5-99.5) and 100%, respectively. The most common grade 3/4 hematologic AEs in ≥25% of pts were neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), thrombocytopenia (59.8%), and lymphopenia (49.5%). There were no fatalities related to cytopenias, and no new safety signals with longer follow-up. CRS occurred in 94.8% of pts (mostly grade 1/2); median time to onset was 7 d (range 1-12), and CRS resolved within 14 d in 98.9% of pts. There was no new CAR T-cell neurotoxicity since the previous report. Post cilta-cel infusion, 21 deaths occurred during the study: 0 within first 30 d, 2 within 100 d, and 19 more than 100 d post infusion. Ten deaths were due to disease progression, 6 were treatment-related (as assessed by the investigator), and 5 were due to AEs unrelated to treatment. One patient was retreated with cilta-cel (for progressive disease) and had stable disease (per computerized algorithm) post-retreatment with no incidence of CAR T-cell neurotoxicity. Conclusions: At a longer median follow-up of 18 months, a single cilta-cel infusion led to early, deep, and durable responses in heavily pre-treated pts with MM. Follow-up is ongoing and updated data will be presented. Cilta-cel demonstrated a manageable safety profile with no new safety signals observed with longer follow-up. Further investigations of cilta-cel are ongoing in earlier lines of therapy (CARTITUDE-2 [NCT04133636], CARTITUDE-4 [NCT04181827], and CARTITUDE-5 [NCT04923893]) and in outpatient settings. Figure 1 Figure 1. Disclosures Martin: GlaxoSmithKline: Consultancy; Janssen: Research Funding; Sanofi: Research Funding; Amgen: Research Funding. Usmani: Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; EdoPharma: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. Berdeja: Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding. Jakubowiak: Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cohen: Novartis: Research Funding; BMS/Celgene: Consultancy; Takeda: Consultancy; Genentech/Roche: Consultancy; Oncopeptides: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Hari: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Deol: Kite, a Gilead Company: Consultancy. Lesokhin: bristol myers squibb: Research Funding; Iteos: Consultancy; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Janssen: Honoraria, Research Funding. Munshi: Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Legend: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. O'Donnell: Onocopeptide: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy. Stewart: Oncopeptides: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Skyline diagnostics: Consultancy; Genomcs England: Membership on an entity's Board of Directors or advisory committees; Tempus Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; PikSci Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Sanofi Aventis: Honoraria. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Yeh: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Allred: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zudaire: Janssen: Current Employment. Deraedt: Janssen: Current Employment. Olyslager: Janssen: Current Employment. Pacaud: Legend Biotech: Current Employment. Lin: Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Sorrento: Consultancy; Legend: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Jagannath: Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

Abstract Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. bb21217 is a B-cell maturation antigen (BCMA) directed CAR T cell therapy which uses the same CAR molecule as ide-cel, with the addition of a PI3K inhibitor (bb007) during ex vivo culture to enrich the drug product (DP) for memory-like T cells and decrease the proportion of highly differentiated or senescent T cells. We hypothesize that DPs enriched for memory like CAR T cells will persist and function longer than non-enriched DPs and this increased persistence will positively influence duration of response (DOR). We previously demonstrated patients with sustained response are more likely to have drug product enriched for naïve gene signatures and depleted of effector gene signatures compared to patients without a sustained response. Methods: CRB-402 (NCT03274219) is a multi-center phase 1 trial of bb21217 in RRMM patients who received ≥3 prior lines of antimyeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory to both classes. In expansion, patients were required to have prior exposure to an anti-CD38 antibody and were required to be refractory to their last line of therapy. Patients underwent lymphodepletion with fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) daily for 3 days, then received a single infusion of bb21217 at 150, 300 or 450 x 10 6 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. Exploratory analyses include correlation of outcome with the molecular characteristics of materials collected temporally through the treatment course, including PBMCs at apheresis, CAR+ T cells from drug product and CAR+ T cells collected from patients around the time of peak expansion. Results: Asof Feb 16, 2021, 72 patients received bb21217, 12 at 150, 14 at 300 and 46 at 450 x 10 6 CAR+ T cells; median follow up for all patients is 9.0 (<1-36) months (M). Patients had a median of 6 (3-17) prior lines of therapy with 49/72 (68%) triple refractory. Cytokine release syndrome (CRS) developed in 54/72 (75%) patients and was predominately G1/2 (51 pts), with 1 G3 event and 2 deaths (previously reported). Median time to first onset of CRS was 2 days (1-20); tocilizumab (38 pts) + corticosteroids (12 pts) was used to manage CRS. Eleven (15%) patients developed neurotoxicity [8 G1/G2, 2 G3, 1 G4] with median time to first onset of 7 (2-24) days. Response was assessed per investigator for 72 patients treated with bb21217 (Table). CAR+ T cells remained detectable in 30/37 (81%) patients and 9/15 (60%) patients at 6 and 12 M respectively, post bb21217 infusion. Of the 15 patients evaluable for MRD with ≥CR, 14 (93%) were MRD negative at 10 -5 by NGS. Analysis of peripheral blood samples collected 15 days post bb21217 infusion demonstrated patients with higher than the median number of CD8+ CAR+ T cells expressing CD27 and CD28 had significantly longer DOR (p=0.0024), compared to patients with lower than the median values. This suggests less differentiated, more proliferative CAR+ T cells at peak expansion are associated with prolonged disease response (median DOR in high vs low: 27.2M (95% CI; 16.8, NE) vs 9.4M (95% CI; 5.1, NE). Conclusions: Adverse events are consistent with known toxicities of CAR T cell therapies. Efficacy results are encouraging with a median DOR estimate of 17M, CR rate continues to mature. Patients with higher levels of proliferative, less differentiated memory like CAR+ T cells at peak expansion are more likely to experience prolonged DOR, continuing to support the hypothesis that the memory like T cell phenotype associated with bb21217 results in prolonged DOR. Figure 1 Figure 1. Disclosures Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Shah: Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; Oncopeptides: Consultancy; Kite: Consultancy; Nektar: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CSL Behring: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Amgen: Consultancy; Teneobio: Research Funding. Kaufman: BMS: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Siegel: Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria, Speakers Bureau. Munshi: Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Legend: Consultancy; Adaptive Biotechnology: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Karyopharm: Consultancy; Pfizer: Consultancy. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Lin: Sorrento: Consultancy; Takeda: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Timm: bluebird bio: Current Employment. Yeri: bluebird bio: Current Employment. Martin: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Finney: bluebird bio: Current Employment, Current equity holder in publicly-traded company. Truppel-Hartmann: bluebird bio: Current Employment. Petrocca: blue bird bio: Ended employment in the past 24 months. Berdeja: Abbvie, Acetylon, Amgen: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding.