Abstract: B-cell maturation antigen (BCMA)–targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI] ) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9—not estimable) and 9.1 (1.5—not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.

Abstract: Introduction: There are several treatment options for patients (pts) with progressive multiple myeloma (MM) who are refractory to lenalidomide but most pts relapse shortly after receiving salvage treatment. Cilta-cel is a CAR-T therapy expressing 2 BCMA-targeting, single-domain antibodies that demonstrated early, deep, and durable responses in pts with MM who had received ≥3 prior lines of therapy (LOT) in the phase 1b/2 CARTITUDE-1 study (Berdeja, Lancet, 2021). The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating cilta-cel safety and efficacy in various clinical settings for pts with MM and exploring suitability of outpatient administration. Initial analysis (median follow-up 5.8 mo) of pts in CARTITUDE-2 cohort A (lenalidomide-refractory with 1-3 prior LOT) demonstrated an overall response rate (ORR) of 95%, with 75% of pts achieving complete response or better (≥CR) and 85% achieving very good partial response or better (≥VGPR). Here, we present updated results for this population. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and immunomodulatory drug (IMiD), were lenalidomide-refractory, and had no prior exposure to BCMA-targeting agents. Bridging therapy was allowed after apheresis. A single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) was given 5-7 d after start of lymphodepletion (daily cyclophosphamide [300 mg/m 2] and fludarabine [30 mg/m 2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10 -5. Secondary endpoints were ORR, duration of response (DOR), time and duration of MRD negativity, and incidence and severity of AEs. MRD was assessed by next-generation sequencing, response was assessed per IMWG criteria, and adverse events (AEs) were graded using CTCAEv5.0 (CRS and ICANS by ASTCT). Results: Initial results from this cohort were published at ASCO 2021 . Here we report data as of the April 15, 2021, data cutoff (median follow-up 9.7 mo: range 3.3-13.4) . 20 pts (65% male; median age 60 years [range 38-75]) received cilta-cel; 1 pt was treated in an outpatient setting. Pts received a median of 2 prior LOT (range 1-3); 60% received 1 or 2 prior LOT and 40% received 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. In all, 95% of pts were refractory to the last LOT; 40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9); 85% (95% CI 62.1-96.8) of pts had ≥CR, and 95% (95% CI 75.1-99.9) had ≥VGPR (Figure). Median time to first response was 1.0 mo (range 0.7-3.3); median time to best response was 3.3 mo (range 0.9-7.9); median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached; 6-mo PFS rate was 90% (95% CI 65.6-97.4). Of MRD-evaluable pts (n=13), 92.3% (95% CI 64.0-99.8) were MRD-negative at 10 -5. Hematologic AEs in ≥20% of pts were neutropenia (95%; grade [gr] 3/4: 95%), thrombocytopenia (80%; gr 3/4: 35%), anemia (75%; gr 3/4: 45%), lymphopenia (65%; gr 3/4: 60%) and leukopenia (55%; gr 3/4: 55%). CRS occurred in 95% of pts (gr 3/4: 10%). Median time to CRS onset was 7 d (range 5-9), with a median duration of 4 d (range 2-11). CRS resolved within 7 d in 90% of pts. CAR T-cell neurotoxicity occurred in 4 pts (20%; all gr 1/2). Three pts (15%) had ICANS (all gr 1/2); median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had other neurotoxicities (gr 2 facial paralysis); time to onset was 29 d with a duration of 51 d. No movement and neurocognitive TEAEs were observed. One death occurred due to COVID-19 (assessed as treatment-related by the investigator). Safety profile was manageable in the pt treated in an outpatient setting. Conclusions: At a longer median follow-up of 9.7 mo, a single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. ORR in this cohort was consistent with the CARTITUDE-1 study in heavily pretreated pts; responses deepened over time, with 92% of MRD-evaluable pts achieving MRD 10 -5 negativity. The safety profile was manageable; CRS was mostly gr 1/2, and no movement and neurocognitive TEAEs occurred, suggesting the efficacy of monitoring and pt management strategies that were implemented across phase 2/3 studies in the CARTITUDE program. Follow-up is ongoing, including additional enrollment in this cohort; this pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827). Figure 1 Figure 1. Disclosures Cohen: Amgen: Honoraria, 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; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Research Funding; neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cohen: Janssen: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Research Funding; Oncopeptides: Consultancy; Genentech/Roche: Consultancy. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Hillengass: Adaptive: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau; Curio Science: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees. Goldschmidt: GSK: Honoraria; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: 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; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raab: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. De Braganca: Janssen: Current Employment. Varsos: Janssen: Current Employment. Yeh: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Corsale: Janssen: Current Employment. Akram: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. 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: Patients (pts) with multiple myeloma (MM) who experience early clinical relapse, defined as disease progression ≤12 mo after autologous stem cell transplantation (ASCT) or start of initial treatment (tx), have median overall survival rates & lt;2 y despite tx with novel agents such as proteasome inhibitors (PI), immunomodulatory drugs (IMiDs), and monoclonal antibodies. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor (CAR) T-cell therapy with 2 BCMA-targeting single-domain antibodies. In the phase 1b/2 CARTITUDE-1 study, cilta-cel demonstrated deep and durable responses in heavily pretreated pts with relapsed/refractory MM (Berdeja, Lancet , 2021). The phase 2, multicohort CARTITUDE-2 study (NCT4133636) is evaluating the safety and efficacy of cilta-cel in pts with MM in various disease settings. Here, we present the first results from cohort B of CARTITUDE-2, which enrolled pts following early relapse after initial therapy that included a PI and IMiD. Methods: Eligible pts had MM, received 1 prior line of therapy (PI and IMiD required), had disease progression per IMWG criteria (either ≤12 mo after ASCT or ≤12 mo after start of anti-myeloma therapy for pts who did not undergo ASCT), and were tx-naïve to CAR-T or anti-BCMA therapies. A single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) was given 5-7 d after start of lymphodepletion (300 mg/m 2 cyclophosphamide and 30 mg/m 2 fludarabine daily for 3 d). The primary objective was minimal residual disease (MRD) negativity at 10 -5, as assessed by next generation sequencing. Adverse events (AEs) were graded using CTCAE v5.0 (cytokine release syndrome [CRS]) and immune effector cell associated neurotoxicity syndrome (ICANS) by ASTCT criteria. To minimize risk of movement and neurocognitive tx-emergent AEs (TEAEs), pt management strategy was implemented, consisting of enhanced bridging therapy to reduce baseline tumor burden, early aggressive tx of CRS and ICANS, and handwriting assessment tools for early detection of neurotoxicity symptoms. Results: As of the April 15, 2021, data cutoff, 18 pts (median age 57.0 y [range 44-67]; 78% male) received cilta-cel, and 2 pts died before cilta-cel infusion (1 each due to progressive disease and worsening general status). Median follow-up was 4.7 mo (range 0.6-13.5); median time from diagnosis to enrollment was 1.1 y (range 0.5-1.9). Two (11.1%) pts had high cytogenetic risk and 5 (27.8%) had bone marrow plasma cells & gt;30%; 14 (77.8%) pts received prior ASCT, and 15 (83.3%) were refractory to their prior therapy. Overall response rate was 88.9% (95% CI: 65.3-98.6), 27.8% of pts (95% CI: 9.7-53.5) achieved ≥complete response (CR), and 66.7% (95% CI: 41.0-86.7) achieved ≥very good partial response (VGPR). Median time to first response was 0.9 mo (range 0.9-2.6), median time to best response was 1.4 mo (range 0.9-11.8), and median time to ≥CR was 1.8 mo (range 0.9-11.6). Of the 13 pts with ≥3 mo follow up, 5 (38%) achieved ≥CR. Of pts who were MRD-evaluable (n=9), all were MRD 10 -5 negative (100% [95% CI: 66.4-100]). At data cutoff, all but 1 pt remained in clinical response (Figure). Hematologic TEAEs in ≥20% of pts were neutropenia (88.9%), thrombocytopenia (61.1%), anemia (50.0%), leukopenia (27.8%), and lymphopenia (22.2%). CRS occurred in 15 (83.3%) pts (1 gr 4); median time to onset was 8 d (range 5-11), consistent with the heavily pretreated pts in the CARTITUDE-1 study. Median duration of CRS was 4 d (range 1-7). ICANS (gr 1) occurred in 1 pt. One pt experienced movement and neurocognitive TEAEs (gr 3) on Day 38 post cilta-cel infusion. This pt had high disease burden at baseline, progressive disease despite triplet bridging therapy, and gr 4 CRS which have been identified as risk factors for movement and neurocognitive TEAEs. The pt was treated with immune-directed measures and was reported to be stable with some improvements at data cutoff and achieved VGPR. No study deaths occurred post cilta-cel infusion. Conclusions: A single cilta-cel infusion led to early and deep responses in pts who experienced early clinical relapse/tx failure to initial therapy, with a manageable safety profile. MRD negativity was achieved early. Responses continue to deepen, and follow-up is ongoing, including MRD assessment. These findings support the continued exploration of cilta-cel in earlier lines of treatment and incorporation into potentially curative front-line regimens. Figure 1 Figure 1. Disclosures Van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Cohen: Takeda: Consultancy; Janssen: Consultancy; BMS/Celgene: Consultancy; Novartis: Research Funding; AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech/Roche: Consultancy; Oncopeptides: Consultancy. Cohen: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Research Funding; Neopharm / Promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hillengass: Curio Science: Speakers Bureau; Beijing Medical Award Foundation: Speakers Bureau; Beijing Life Oasis Public Service Center: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Kerre: BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Elyad: Membership on an entity's Board of Directors or advisory committees. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. De Braganca: Janssen: Current Employment. Varsos: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Zudaire: Janssen: Current Employment. Corsale: Janssen: Current Employment. Akram: Legend Biotech USA: Current Employment. Geng: Legend Biotech USA: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.