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What is this summary about? This is a summary of a phase 3 clinical trial called CARTITUDE-4. This trial compared the anti-cancer therapy ciltacabtagene autoleucel (or cilta-cel) with standard therapies in people who have multiple myeloma, a cancer that affects specific kinds of blood cells called plasma cells. The people in the study had been treated with 1 to 3 previous treatments for multiple myeloma, including a common anti-myeloma treatment called lenalidomide, but their multiple myeloma did not get better. How was the study in this summary conducted? About half of the 419 participants in this study received cilta-cel, while the other half received standard therapies, or therapies that are commonly used to treat multiple myeloma. Participants who received cilta-cel had a type of immune cell called T cells collected from their blood and genetically modified to recognize a specific protein found on myeloma cells. These modified T cells, which comprise cilta-cel, were then infused back into the bloodstream. What were the results of the study? After approximately 1 year in the study, more participants were alive without their cancer getting worse in the cilta-cel group (76%) than in the standard therapies group (49%). The most common side effects in both groups were infections and low blood cell counts. Cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system) was common but mostly mild. Neurotoxicities (including immune effector cell–associated neurotoxicity syndrome, which can cause symptoms such as headaches, changes in consciousness, and difficulty with memory, attention, speaking, or understanding others) were less common and were reported in 20.5% of participants treated with cilta-cel. What were the main conclusions reported by the researchers? In CARTITUDE-4, more participants treated with cilta-cel showed improvements and were alive with control of their disease 12 months after receiving cilta-cel compared with participants who received standard therapies. Clinical Trial Registration:NCT04181827 (CARTITUDE-4) (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to unprecedented treatment outcomes. Among CAR T therapies available, ciltacabtagene autoleucel (cilta-cel) is a good candidate for outpatient administration due to its generally predictable safety profile. There are multiple advantages of outpatient administration of cilta-cel, including reduced healthcare burden, expanded access, and patient autonomy. This mixed methods qualitative study aimed to identify key factors for outpatient administration of CAR T and best practice recommendations by combining a targeted literature review with expert interviews and panels. Methods: The targeted review (Phase 1) aimed to identify factors for outpatient CAR T administration in the US and determine key topics for the exploratory interviews (Phase 2) and expert panels (Phase 3), which aimed to inform on best practices and challenges of outpatient CAR T administration (focusing on ciltacel). Participants in clinical and administrative positions based in treatment centers that had experience with real-world outpatient administration of ciltacel were recruited. Results: Seventeen studies were identified in Phase 1. Key factors for outpatient administration included the development of protocols for CAR T complications, education for caregivers, outpatient specialists, hospital staff, and emergency services staff for identification and referral after possible adverse events, the creation of multidisciplinary teams for effective communication and management, straightforward patient intake processes encompassing financial eligibility review and provision of patient education materials, and close patient monitoring throughout the treatment journey. In Phase 2, 5 participants from 2 centers were interviewed. In Phase 3, 14 participants across 6 treatment centers were interviewed. Two 90-minute virtual panel discussions took place. All participants agreed that cilta-cel can be safely and effectively administered in an outpatient setting. Key recommendations included the creation of educational resources for patients and caregivers, the development of standard operating procedures, dedicated outpatient infrastructure and establishment of interdisciplinary teams, outpatient monitoring for toxicity management, and monitoring of the reimbursement landscape. Discussion: This study offers a comprehensive understanding of the feasibility of outpatient cilta-cel administration in participating CAR T centers and provides actionable recommendations while acknowledging existing challenges. [ABSTRACT FROM AUTHOR]

Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy. [ABSTRACT FROM AUTHOR]

IntroductionChimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to unprecedented treatment outcomes. Among CAR T therapies available, ciltacabtagene autoleucel (cilta-cel) is a good candidate for outpatient administration due to its generally predictable safety profile. There are multiple advantages of outpatient administration of cilta-cel, including reduced healthcare burden, expanded access, and patient autonomy. This mixed methods qualitative study aimed to identify key factors for outpatient administration of CAR T and best practice recommendations by combining a targeted literature review with expert interviews and panels.MethodsThe targeted review (Phase 1) aimed to identify factors for outpatient CAR T administration in the US and determine key topics for the exploratory interviews (Phase 2) and expert panels (Phase 3), which aimed to inform on best practices and challenges of outpatient CAR T administration (focusing on cilta-cel). Participants in clinical and administrative positions based in treatment centers that had experience with real-world outpatient administration of cilta-cel were recruited.ResultsSeventeen studies were identified in Phase 1. Key factors for outpatient administration included the development of protocols for CAR T complications, education for caregivers, outpatient specialists, hospital staff, and emergency services staff for identification and referral after possible adverse events, the creation of multidisciplinary teams for effective communication and management, straightforward patient intake processes encompassing financial eligibility review and provision of patient education materials, and close patient monitoring throughout the treatment journey. In Phase 2, 5 participants from 2 centers were interviewed. In Phase 3, 14 participants across 6 treatment centers were interviewed. Two 90-minute virtual panel discussions took place. All participants agreed that cilta-cel can be safely and effectively administered in an outpatient setting. Key recommendations included the creation of educational resources for patients and caregivers, the development of standard operating procedures, dedicated outpatient infrastructure and establishment of interdisciplinary teams, outpatient monitoring for toxicity management, and monitoring of the reimbursement landscape.DiscussionThis study offers a comprehensive understanding of the feasibility of outpatient cilta-cel administration in participating CAR T centers and provides actionable recommendations while acknowledging existing challenges.

Ciltacabtagene autoleucel (also known as cilta-cel) is a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) on the surface of cancer cells in B cell malignancies, such as multiple myeloma (MM). It is a second-generation CAR that is outfitted with an ectodomain comprising two BCMA-binding single chain variable fragment (ScFv) domains, a transmembrane domain, and an endodomain possessing CD3z and 4-1BB. Cilta-cel is an autologous, gene-edited CAR T-cell that is prepared by collecting and modifying the recipient's T-cells to create a patient personalized treatment in the laboratory to be infused back. This CAR T-cell product exceptionally entails CARs with two BCMA-targeting single-domain antibodies that detect two epitopes of BCMA expressed on the malignant cells of MM. Cilta-cel is the current addition to the treatment armamentarium of relapsed or refractory (r/r) MM after its approval by the FDA on February 28, 2022, based on the results of the Phase 1b/2 CARTITUDE-1 study. It was the second approved anti-BCMA CAR T-cell product after idecabtagene vicleucel (ide-cel) to treat myeloma patients. It induces early, deep, and long-lasting responses with a tolerable safety profile in r/r MM. Cilta-cel-treated myeloma patients may potentially experience adverse effects ranging from mild to lifethreatening, but they are mostly manageable toxicities. Besides, it has a consistent safety profile upon a longer follow-up of patients. Cilta-cel generally outperforms ide cel in terms of efficacy in MM, but shows comparable adverse events. This review highlights the current updates on cilta-cel efficacy, adverse events, comparison with ide-cel, and its future direction in the treatment of MM. [ABSTRACT FROM AUTHOR]

Summary: In this review we highlight the current developments in Chimeric antigen receptor (CAR) T cell therapy for myeloma. Two advanced products (idecabtagene vicleucel and ciltacabtagene autoleucel) targeting B‑cell maturation antigen have already been approved by the US Food and Drug Administration (FDA). In heavily pretreated myeloma patients, response rates between 82 and 98% and a median progression-free survival between 12 and > 24 months have been achieved. Currently these two products are being investigated in earlier lines of therapy. Beside BCMA, other targets have been selected for CAR T cell therapy in myeloma, with advanced constructs targeting two antigens. We highlight current strategies to improve CAR T cell effectiveness and safety and give a personal outlook where cellular immunotherapy in myeloma might be heading. [ABSTRACT FROM AUTHOR]

Ciltacabtagene autoleucel (also known as cilta-cel) is a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) on the surface of cancer cells in B cell malignancies, such as multiple myeloma (MM). It is a second-generation CAR that is outfitted with an ectodomain comprising two BCMA-binding single chain variable fragment (ScFv) domains, a transmembrane domain, and an endodomain possessing CD3ζ and 4-1BB. Cilta-cel is an autologous, gene-edited CAR T-cell that is prepared by collecting and modifying the recipient’s T-cells to create a patient personalized treatment in the laboratory to be infused back. This CAR T-cell product exceptionally entails CARs with two BCMA-targeting single-domain antibodies that detect two epitopes of BCMA expressed on the malignant cells of MM. Cilta-cel is the current addition to the treatment armamentarium of relapsed or refractory (r/r) MM after its approval by the FDA on February 28, 2022, based on the results of the Phase 1b/2 CARTITUDE-1 study. It was the second approved anti-BCMA CAR T-cell product after idecabtagene vicleucel (ide-cel) to treat myeloma patients. It induces early, deep, and long-lasting responses with a tolerable safety profile in r/r MM. Cilta-cel-treated myeloma patients may potentially experience adverse effects ranging from mild to life-threatening, but they are mostly manageable toxicities. Besides, it has a consistent safety profile upon a longer follow-up of patients. Cilta-cel generally outperforms ide cel in terms of efficacy in MM, but shows comparable adverse events. This review highlights the current updates on cilta-cel efficacy, adverse events, comparison with ide-cel, and its future direction in the treatment of MM.

Chimeric antigen receptor T-cell (CAR-T) therapies offer substantial advancement in the treatment of multiple myeloma (MM). However, the CAR-T therapy process involves complex decision-making that is informed by many variables. This review aims to provide an overview of the patient selection and administration process for CAR-T therapy for MM from the perspective of experienced healthcare providers (HCPs), including considerations for each step in the CAR-T therapy process. Referring HCPs should initiate conversations with HCPs at CAR-T capable centers earlier in the treatment journey, even before patients are eligible for CAR-T therapy, particularly for patients from underserved populations and patients with high-risk disease, to ensure adequate time for logistical planning and patient education. Patient selection for CAR-T therapy may be guided by factors such as performance status, rate of disease progression, and logistical considerations. Some anticancer therapies may affect T-cell fitness and therefore impact CAR-T manufacturing and patient outcomes; however, additional research is needed to confirm this in MM. Bridging therapies should be tailored to the needs of the patient and ideally halted 1 week or longer before CAR-T infusion, contingent upon the agent(s) used. Lymphodepletion regimens may need to be modified for patients with renal insufficiency. Collaboration with HCPs at both the treating and referring centers is important to optimize coordinated care of patients. Collaboration with and guidance from experienced HCPs throughout patient selection, referral, and CAR-T administration is instrumental in optimizing patient outcomes as access to CAR-T therapies expands., Competing Interests: Declaration of competing interest All authors received compensation from Janssen Pharmaceuticals, Inc, and Legend Biotech USA, Inc, for participation in an advisory board to discuss the topics described in this review article prior to initiation of manuscript development; however, authors received no compensation for their involvement as authors of this article. Additional disclosures include the following: SA reports consulting for Amgen, Beigene, BMS, GSK, Janssen Astra Zeneca, Pharmacyclics, Regeneron, Sanofi, and Takeda and receiving research funding from AbbVie, Amgen, Ascentage, BMS, Cellectar, GSK, Janssen, Medimmune, Pharmacyclics, and Xencor. SJ reports consulting for Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech, Merck, Sanofi, and Takeda Pharmaceuticals and is the Senior Editor-in-Chief of Clinical Lymphoma, Myeloma & Leukemia. YL reports consulting for bluebird bio, Celgene/BMS, Fosun Kite, Gamida Cell, Iovance, Janssen, Juno/BMS, Kite/Gilead, Legend BioTech, Novartis, Pfizer, and Takeda; receiving grant/research support from bluebird bio, Boston Scientific, Celgene/BMS, Janssen, Kite/Gilead, Legend Biotech, Merck, and Takeda; and serving on a data safety and monitoring board for Sorrento, a data review committee for Pfizer, and a scientific advisory committee for NexImmune. KP reports consulting for Arcellx, BMS, Celgene, Janssen, Karyopharm Therapeutics, and Pfizer; research funding from AbbVie/Genentech, Allogene Therapeutics, Celgene/GMS, Cellectis, Janssen, Nektar, Poseida, Precision Biosciences, and Takeda; and travel funds from BMS. LS reports consulting for Janssen. SWW reports consulting for Amgen and Sanofi and research funding from BMS, Caelum, Fortis, Genentech, GSK, and Janssen., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with prior allogeneic stem cell transplant (alloSCT) are typically excluded from trials of chimeric antigen receptor (CAR) T cell therapies, because their engineered cells may include allogeneic T cells. Ciltacabtagene autoleucel (cilta-cel) demonstrated early, deep, durable responses and manageable safety in heavily pretreated relapsed/refractory multiple myeloma patients. We retrospectively analyzed patients who received alloSCT prior to cilta-cel in CARTITUDE-1., Patients and Methods: Patients eligible for CARTITUDE-1 were ≥18 years, had ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Patients with active graft-versus-host disease (GVHD) or had alloSCT within 6 months before apheresis were excluded. Patients received cilta-cel 5 to 7 days after lymphodepletion., Results: Patients (N = 7) received median 9 prior LOTs (range, 6-14); median time since alloSCT was 5.1 years (range, 2.7-6.2). At median follow-up 27.7 months after cilta-cel infusion, overall response rate was 85.7% (n = 6). The safety profile was generally consistent with patients without alloSCT as prior therapy (cytokine release syndrome, 85.7% vs. 95.6%, respectively; immune effector cell-associated neurotoxicity syndrome, 14.3% vs. 16.7%). One patient with prior alloSCT had grade 3 movement and neurocognitive treatment-emergent adverse events/parkinsonism. No GVHD cases were reported. Two patients died due to adverse events (treatment-related lung abscess; unrelated liver failure)., Conclusion: Cilta-cel efficacy and safety were comparable between CARTITUDE-1 patients with and without prior alloSCT. Additional studies are needed to fully elucidate the suitability of CAR-T cell therapy in the post-alloSCT setting., Competing Interests: Disclosure M. Htut consulted and served on advisory committees for and received travel funding from Millennium; and received research funding from Judy and Bernard Briskin Center for Multiple Myeloma Research (Inst) and BMS (Inst). B. Dhakal consulted and served on advisory committees for Amgen, Takeda, Janssen, GlaxoSmithKline, Natera, and Sanofi; received honoraria from Celgene, Karyopharm Therapeutics, Sanofi, and GlaxoSmithKline; and received research funding from Amgen, Janssen, and GlaxoSmithKline. A.D. Cohen consulted and served on advisory committees for Celgene, Janssen Oncology, Oncopeptides, Takeda, Seattle Genetics, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, AstraZeneca, and Roche/Genentech; received research funding from Novartis (Inst) and GlaxoSmithKline (Inst); has patents related to CAR-T cells and biomarkers of cytokine release syndrome; has given expert testimony for Janssen Oncology; and received travel funding from GlaxoSmithKline, Takeda, Celgene, and Janssen Oncology. T. Martin consulted and served on advisory committees for GlaxoSmithKline and Legend Biotech USA Inc. and received research funding from Sanofi (Inst), Amgen (Inst), and Janssen Oncology (Inst). J.G. Berdeja consulted and served on advisory committees for Takeda (Inst), Bristol-Myers Squibb (Inst), CRISPR Therapeutics (Inst), Celgene (Inst), Kite, a Gilead company (Inst), Janssen (Inst), Legend Biotech (Inst), Secura Bio (Inst), and Bluebird Bio (Inst); and received research funding from Celgene (Inst), Takeda (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Janssen (Inst), Novartis (Inst), AbbVie (Inst), Bluebird Bio (Inst), Teva (Inst), Genentech/Roche (Inst), Poseida Therapeutics (Inst), Sanofi (Inst), Acetylon Pharmaceuticals (Inst), Lilly (Inst), Celularity (Inst), CRISPR Therapeutics (Inst), EMD Serono (Inst), Ichnos Sciences (Inst), GlaxoSmithKline (Inst), and Incyte (Inst). S.Z. Usmani consulted and served on advisory committees for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GlaxoSmithKline, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol-Myers Squibb/Celgene; served on speakers’ bureaus for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol-Myers Squibb/Celgene; and received research funding from Celgene, Array BioPharma, Janssen Oncology, Pharmacyclics, Sanofi, Bristol-Myers Squibb, Amgen, Seattle Genetics, Merck, SkylineDx, and GlaxoSmithKline. M. Agha owns stock in GenCART, Inc. D. Madduri is employed by Janssen Oncology; owns stock in Roivant; and consulted and served on advisory committees for Takeda, Janssen Oncology, Celgene, Legend Biotech USA Inc., GlaxoSmithKline, and Foundation Medicine. C.C. Jackson is employed by Janssen and owns stock in Janssen; and served as a consultant physician for Memorial Sloan Kettering Cancer Center. W. Deraedt, T.-m. Yeh, and X. Xu are employed by and own stock in Janssen. E. Zudaire is employed by, owns stock in, received travel funding from, and has patents pending with Janssen. L. Pacaud is employed by and owns stock in Legend Biotech USA Inc. M. Akram is employed by Legend Biotech USA, Inc. S. Jagannath consulted and served on advisory committees for Bristol-Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech USA Inc., Takeda, and Sanofi; and received travel funding from Bristol-Myers Squibb and Janssen., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This is a summary of a clinical study called CARTITUDE-1. This study tested the anti-cancer chimeric antigen receptor-T cell (CAR-T) therapy ciltacabtagene autoleucel, abbreviated as cilta-cel, in people with multiple myeloma, a cancer that affects a specific type of blood cell called plasma cells. The participants in this study had relapsed or refractory disease, which means that their cancer did not improve or returned after 3 or more previous anti-cancer treatments. Ninety-seven participants went through the treatment process, which included collecting participants' own T cells (a type of immune cell), genetically modifying those T cells to recognize a certain protein found on myeloma cancer cells, pretreating with chemotherapy to prepare the participant's immune system to accept the modified T cells (cilta-cel), and finally injecting cilta-cel. Ninety-eight percent of participants showed decreases in indicators of cancer after treatment with cilta-cel. Seventy percent of participants were still alive approximately 28 months after treatment, and 55% of participants were still living without their cancer getting worse. The most common side effects were low blood cell levels, infections, cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system), and side effects that involved the nervous system (called neurotoxicities). Some participants experienced late-onset symptoms of neurotoxicity like the signs and symptoms of parkinsonism, meaning that they affected people's movement. Improvements in recognition of factors that increase the risk of these late-onset neurotoxicities and strategies to help avoid them has reduced their occurrence, although long-term monitoring for side effects is still an important part of treatment. Overall, almost all participants treated with cilta-cel had long-term reductions in signs of myeloma, and the majority of participants were alive and had no detectable signs of cancer over 2 years after being injected with cilta-cel. Clinical Trial Registration:NCT03548207 (1b/2 CARTITUDE-1 study) NCT05201781 (Long-term Follow-up Study for Participants Previously Treated With Ciltacabtagene Autoleucel) [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized the treatment paradigm for heavily pretreated B-cell malignancies such as large B-cell lymphoma. There is a major unmet need for effective treatments for heavily pretreated relapsed/refractory multiple myeloma (RRMM), for which many CAR-T therapies are under active clinical investigation. Goal of the review: This review provides an overview of recently updated clinical trial data and indirect treatment comparison analyses regarding two clinically advanced CAR-T therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel)., Discussion: Recently presented data after prolonged follow-up periods for ide-cel (KarMMa) and cilta-cel (CARTITUDE-1) have demonstrated that both therapies have the potential to elicit responses in individuals with heavily pretreated RRMM. Indirect treatment comparisons between cilta-cel and ide-cel suggest cilta-cel is associated with deeper and more durable responses than ide-cel in triple class-exposed RRMM; however, these types of comparisons have limitations and direct head-to-head trials are needed to confirm these findings. Additional indirect treatment comparisons conducted separately for ide-cel and cilta-cel have demonstrated that these CAR-T therapies hold promise for substantial clinical benefit relative to currently available treatments for RRMM. Further considerations, including safety profiles and real-world treatment considerations, are also discussed., Conclusion: Data collected to date support CAR-T therapies holding substantial promise for patients with heavily pretreated RRMM relative to other currently available therapies. Additional real-world data will help provide further insights into the comparative efficacy and safety profiles of these treatments in RRMM as these treatments become more widely available., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation., Methods: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study., Results: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments., Conclusion: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Ciltacabtagene autoleucel (also known as cilta-cel) is a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) on the surface of cancer cells in B cell malignancies, such as multiple myeloma (MM). It is a second-generation CAR that is outfitted with an ectodomain comprising two BCMA-binding single chain variable fragment (ScFv) domains, a transmembrane domain, and an endodomain possessing CD3ζ and 4-1BB. Cilta-cel is an autologous, gene-edited CAR T-cell that is prepared by collecting and modifying the recipient's T-cells to create a patient personalized treatment in the laboratory to be infused back. This CAR T-cell product exceptionally entails CARs with two BCMA-targeting single-domain antibodies that detect two epitopes of BCMA expressed on the malignant cells of MM. Cilta-cel is the current addition to the treatment armamentarium of relapsed or refractory (r/r) MM after its approval by the FDA on February 28, 2022, based on the results of the Phase 1b/2 CARTITUDE-1 study. It was the second approved anti-BCMA CAR T-cell product after idecabtagene vicleucel (ide-cel) to treat myeloma patients. It induces early, deep, and long-lasting responses with a tolerable safety profile in r/r MM. Cilta-cel-treated myeloma patients may potentially experience adverse effects ranging from mild to life-threatening, but they are mostly manageable toxicities. Besides, it has a consistent safety profile upon a longer follow-up of patients. Cilta-cel generally outperforms ide cel in terms of efficacy in MM, but shows comparable adverse events. This review highlights the current updates on cilta-cel efficacy, adverse events, comparison with ide-cel, and its future direction in the treatment of MM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chekol Abebe, Yibeltal Shiferaw, Tadele Admasu and Asmamaw Dejenie.)

Introduction: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody., Patients and Methods: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival., Results: After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant., Conclusion: Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Simple Summary: There is an urgent need to develop new treatments for patients with relapsed/refractory multiple myeloma (RRMM) to address unmet medical needs. Chimeric antigen receptor T-cell (CAR-T) therapy is a novel approach with the potential for long-term disease control. Ciltacabtagene autoleucel (cilta-cel) is a CAR-T treatment studied in patients with RRMM in the CARTITUDE-1 clinical trial and has shown clinically important effects. However, CARTITUDE-1 was a single arm study. The current study compared outcomes for cilta-cel with an external cohort of German patients that are similar to the ones in CARTITUDE-1 to compare the effectiveness of cilta-cel versus established clinical practice. To overcome potential bias, individual patient data were used to adjust for the differences in patient characteristics between cohorts. The results showed substantially better outcomes for cilta-cel on both overall survival and the time to next treatment. These findings highlight cilta-cel's potential as a novel, effective treatment to address unmet treatment needs. Ciltacabtagene autoleucel (cilta-cel) is a Chimeric antigen receptor T-cell therapy with the potential for long-term disease control in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM). As cilta-cel was assessed in the single-arm CARTITUDE-1 clinical trial, we used an external cohort of patients from the Therapie Monitor registry fulfilling the CARTITUDE-1 inclusion criteria to evaluate the effectiveness of cilta-cel for overall survival (OS) and time to next treatment (TTNT) vs. real-world clinical practice. Individual patient data allowed us to adjust the comparisons between both cohorts, using the inverse probability of treatment weighting (IPW; average treatment effect in the treated population (ATT) and overlap population (ATO) weights) and multivariable Cox proportional hazards regression. Outcomes were compared in intention-to-treat (HR, IPW-ATT: TTNT: 0.13 (95% CI: 0.07, 0.24); OS: 0.14 (95% CI: 0.07, 0.25); IPW-ATO: TTNT: 0.24 (95% CI: 0.12, 0.49); OS: 0.26 (95% CI: 0.13, 0.54)) and modified intention-to-treat (HR, IPW-ATT: TTNT: 0.24 (95% CI: 0.09, 0.67); OS: 0.26 (95% CI: 0.08, 0.84); IPW-ATO: TTNT: 0.26 (95% CI: 0.11, 0.59); OS: 0.31 (95% CI: 0.12, 0.79)) populations. All the comparisons were statistically significant in favor of cilta-cel. These results highlight cilta-cel's potential as a novel, effective treatment to address unmet needs in patients with RRMM. [ABSTRACT FROM AUTHOR]