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Introduction: Cilta-cel is approved in the US and EU for the treatment (tx) of patients (pts) with len-refractory MM after ≥1 line based on the randomized, phase 3 CARTITUDE-4 trial (NCT04181827). At the first interim analysis (15.9-month [mo] median follow-up), cilta-cel significantly improved progression-free survival (PFS) vs SoC (hazard ratio [HR], 0.26 [protocol-specified weighted analysis]; P<0.0001). At the second interim analysis, overall survival (OS) was significantly improved with cilta-cel vs SoC (HR, 0.55; P=0.0009). MRD negativity is a prognostic marker of prolonged survival outcomes for pts with MM. We report MRD negativity, including overall and sustained MRD negativity, overall MRD-negative complete response or better (≥CR), and MRD-negative ≥CR at mo 12, from the prespecified second interim analysis of CARTITUDE-4. Methods: Eligibility criteria were previously described. Pts were assigned 1:1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). Pts in the cilta-cel arm underwent apheresis, received bridging therapy (PVd/DPd), and then a single cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5-7 days (d) after the start of lymphodepletion. PFS was the primary endpoint; ≥CR rate, overall response rate, overall MRD-negativity rate, and OS were key secondary endpoints. MRD was assessed centrally via next-generation sequencing (clonoSEQ v2.0; Adaptive Biotechnologies). MRD was evaluated at d 56 post infusion in the cilta-cel arm; and in both arms at suspected ≥CR and at 6, 12, 18, and 24 mo post infusion (cilta-cel arm) or cycle 1 d 1 (SoC arm), as well as yearly until progression/start of subsequent therapy in pts in ≥CR. Sustained MRD negativity (10−5) was defined as confirmed MRD negativity ≥12 mo apart and without MRD positivity in between. Pts were evaluable for sustained MRD negativity if they achieved MRD negativity and had ≥1 evaluable MRD sample ≥12 mo after the first negative result or progressed/died/started subsequent tx <12 mo after the first negative result. Results: 419 pts were randomized (intent-to-treat [ITT] set; cilta-cel, n=208; SoC, n=211); 176 pts in the cilta-cel arm received cilta-cel as study tx. As of May 1, 2024, median follow-up for the study was 33.6 mo. At the 10−5 threshold, 145 pts in the cilta-cel arm and 103 in the SoC arm were evaluable for MRD. MRD-negativity rates (10−5) in the ITT set and the MRD-evaluable subset were higher with cilta-cel vs SoC (ITT, 62% vs 18%; MRD evaluable, 89% vs 38%; both P<0.0001). Across subgroups, cilta-cel vs SoC consistently increased overall MRD-negativity rates (10−5). In the ITT set, 48% of the cilta-cel arm achieved MRD negativity (10−5) by d 56, with the MRD-negative rate rising to 60% by 6 mo post cilta-cel infusion. Overall MRD-negativity rates at the 10−6 threshold in the ITT set were higher with cilta-cel vs SoC (57% vs 9%; P<0.0001). In the cilta-cel arm, 119 (57%) pts vs 26 (12%) in the SoC arm achieved overall MRD-negative (10−5) ≥CR (P<0.0001). At the 12-mo MRD assessment, 92 (44%) pts in the cilta-cel arm vs 17 (8%) in the SoC arm (P<0.0001) had MRD-negative (10−5) ≥CR. In pts with MRD-negative (10−5) ≥CR at mo 12, median PFS was not reached (NR; 95% CI, not estimable [NE]-NE) with cilta-cel and 37.8 mo (95% CI, 25.0-NE) with SoC; median OS was NR (95% CI, NE-NE) and NR (95% CI, 37.8 mo-NE), respectively. Sustained MRD-negativity rates (10−5) in the ITT set were 40% in the cilta-cel arm vs 6% in the SoC arm (P<0.0001); among 110 and 26 evaluable pts for sustained MRD, sustained MRD-negativity rates were 75% vs 50% (P=0.0159). Among the 176 pts who received cilta-cel as study tx, overall MRD negativity at 10−5 was achieved by 129 (73%) pts (89% of 145 evaluable pts). Conclusions: At 33.6-mo median follow-up in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates >3-fold in the ITT set, with pts achieving MRD negativity rapidly post cilta-cel. The prognostic value of MRD-negative ≥CR at mo 12 was shown, as median PFS was >3 years in pts with MRD-negative ≥CR at mo 12, regardless of tx. These data further underscore the benefit of cilta-cel, which led to significant >3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity. Our MRD data demonstrate higher rates of deep and sustained MRD negativity achieved with cilta-cel vs SoC in tx of len-refractory MM as early as first relapse.

Abstract Background: Ciltacabtagene autoleucel (cilta-cel) is a novel chimeric antigen receptor T-cell therapy that is being evaluated in the CARTITUDE-1 trial (NCT03548207) in patients with relapsed or refractory multiple myeloma (RRMM) who are triple-class exposed (to immunomodulatory drugs, proteasome inhibitors, and an anti-CD38 monoclonal antibody). As there is no clear standard of care for this patient population, and due to an absence of direct head-to-head trials evaluating cilta-cel and other relevant treatments, indirect treatment comparisons (ITCs) between cilta-cel and treatments used in current clinical practice, ie, physician's choice of treatment (PCT), have been previously conducted. Meta-analyses were performed to derive single summary effect estimates for overall survival (OS) and progression-free survival (PFS) by pooling ITCs evaluating cilta-cel versus PCT in patients with triple-class exposed RRMM. Methods: ITCs examining the comparative effectiveness of cilta-cel versus PCT on OS and PFS were included. Data on cilta-cel corresponded to the February 2021 data-cut for CARTITUDE-1. Data on PCT was leveraged from the following sources: (i) the Flatiron database, a primarily US community-based multiple myeloma registry, (ii) the long-term follow-up results of three global RRMM daratumumab randomized clinical trials (POLLUX [NCT02076009], CASTOR [NCT02136134], and EQUULEUS [NCT01998971]), (iii) the US-based retrospective MAMMOTH study, and (iv) a representative German patient registry maintained by OncologyInformationService (OIs). In each ITC, the PCT group was comprised of patients who satisfied key eligibility criteria for CARTITUDE-1 and was made comparable to CARTITUDE-1 using inverse probability of treatment weighting. Hence, the ITCs were deemed appropriate to meta-analyze. The meta-analyses used a robust variance estimator to account for the use of CARTITUDE-1 in each pairwise ITC. The main meta-analyses considered all participants treated with cilta-cel in CARTITUDE-1 compared with PCT. Sensitivity analyses considered ITC effect estimates based on all enrolled participants in CARTITUDE-1. Pooled summary effect estimates were presented as hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs). Results: Based on availability of data, the main meta-analyses included four ITCs for OS and three ITCs for PFS. Cilta-cel was associated with a statistically significant improvement in OS (HR: 0.21, 95% CI: 0.13 to 0.34; Figure 1) and PFS (HR: 0.20, 95% CI: 0.07 to 0.63; Figure 2) compared to PCT. Sensitivity analyses including all enrolled participants confirmed the results of the main meta-analyses. Conclusions: In the meta-analyses, cilta-cel demonstrated a significant advantage over PCT in terms of OS and PFS, highlighting its potential as an effective therapy in patients with triple-class exposed RRMM. Figure 1 Figure 1. Disclosures Hari: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: 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; Amgen: Consultancy, 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; Takeda: Consultancy, Honoraria, 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; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding. Berdeja: EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Gay: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Takeda: 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; Celgene: 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: Consultancy, Honoraria. Hooper: Eversana: Current Employment; Janssen: Consultancy. Haltner: Eversana: Current Employment; Janssen: Consultancy. Kumar: Carsgen: Research Funding; Novartis: Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding. Martin: Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding; Oncopeptides: Consultancy. Mateos: AbbVie: Honoraria; Oncopeptides: 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; Amgen: 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; 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; Bluebird bio: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; 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; GSK: Honoraria; Sanofi: 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. Moreau: Sanofi: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Rosta: EVERSANA: Current Employment; Janssen Inc.: Consultancy. Samjoo: EVERSANA: Current Employment; Janssen Inc.: Consultancy. Usmani: GSK: Consultancy, Research Funding; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Weisel: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Karyopharm: 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; Roche: Honoraria; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Olyslager: Janssen: Current Employment. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. 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. Garrett: Legend Biotech USA: Current Employment. Lee: Legend Biotech: Current Employment, Current equity holder in publicly-traded company. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Valluri: Janssen: Current Employment, Current equity holder in publicly-traded company. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Lin: Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Takeda: Research Funding; Legend: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding.

Abstract Introduction: Cytokine release syndrome (CRS) is a common toxicity associated with chimeric antigen receptor (CAR) T-cell therapies. Corticosteroids and steroid-sparing therapies such as tocilizumab, an interleukin-6 receptor antagonist, and anakinra, an interleukin-1 receptor antagonist, have been used to reduce the incidence and severity of these toxicities. Preclinical and clinical case studies of anakinra, administered subcutaneously or intravenously at various doses, have shown promising results in the management of CRS and systemic inflammatory responses resembling hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). In CARTITUDE-1, CRS occurred in 95% of heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) receiving ciltacabtagene autoleucel (cilta-cel), a CAR T-cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies (Berdeja et al. Lancet 2021). Per protocol, tocilizumab was required to manage CRS with option to give steroids and/or anakinra per investigator discretion. Here, we report the institutional experiences of anakinra use in the management of CRS in patients who have received cilta-cel as part of the CARTITUDE-1 study. Methods: Eligible patients had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody (Berdeja et al. Lancet 2021). After apheresis, bridging therapy was permitted. Patients 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 after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 days). Lee et al (Blood 2014) grading criteria for CRS were mapped to the ASTCT criteria for CRS. Post-hoc analysis of data revealed use of anakinra at some sites in patients who failed to respond to the initial management of CRS with tocilizumab +/- dexamethasone or in clinical settings where rise of ferritin and/or liver function tests were indicative for continued HLH/MAS-like manifestations (Kennedy et al. ASH 2020). Results: Of 97 patients in CARTITUDE-1, CRS occurred in 92 (95%) patients; 4% were grade 3/4. The median time to onset was 7 days (range 1-12) and median duration was 4 days (range 1-14). Supportive measures to treat CRS were administered to 91% of patients, most commonly tocilizumab (69%; 4 patients received ≥3 doses), corticosteroids (22%), and anakinra (18 patients, 19%). CRS resolved in 99% of patients. Anakinra was administered after initial tocilizumab and within the first 48 hours (range 0-6 days) of CRS onset for the majority of patients as part of effective management of CRS. Anakinra was administered at a dose of 100-200 mg every 8-12 hours over a median of 2.5 days (range 1-15 days). CRS uniformly resolved following anakinra use in CARTITUDE-1, apart from one patient who died from sepsis (grade 5 outcome) due to HLH/MAS considered related to treatment (Table). Conclusions: CRS events in cilta-cel-treated patients in CARTITUDE-1 were common, generally low-grade, and successfully managed with standard tocilizumab +/- dexamethasone. The use of anakinra should be considered in patients with persistent CRS/inflammatory symptoms despite tocilizumab use, and in particular in patients with HLH/MAS-like symptoms/phenotype occurring following CRS or in the absence of prior CRS. Figure 1 Figure 1. Disclosures Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Richard: Karyopharm, Janssen: Honoraria. Lin: Juno: Consultancy; Legend: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy. Madduri: Janssen: Current Employment. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Zudaire: Janssen: Current Employment. Romanov: Janssen: Current Employment. Trigg: 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. Garrett: Legend Biotech USA: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Martin: Oncopeptides: Consultancy; Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: 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