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Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T (n = 24) or BsAb (n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT. [ABSTRACT FROM AUTHOR]

Idecabtagene vicleucel (ide‐cel; bb2121) is a B‐cell maturation antigen–directed chimeric antigen receptor (CAR) T cell therapy approved for treatment of patients with heavily pretreated relapsed and refractory multiple myeloma. This analysis evaluated exposure–response (ER) relationships of ide‐cel with key efficacy end points and safety events. Ide‐cel exposure data were available from 127 patients treated at target doses of 150, 300, or 450 × 106 CAR+ T cells from the phase II KarMMa study (NCT03361748). Key exposure metrics, including area under the curve of the transgene level from 0 to 28 days and maximum transgene level, were calculated using noncompartmental methods. Logistic regression models, using both linear and maximum response function of exposure on the logit scale, were evaluated to quantify observed ER trends, and modified by including statistically significant individual covariates in a stepwise regression analysis. There was wide overlap of exposures across the target doses. ER relationships were observed for the overall and complete response rates, with higher response rates associated with higher exposures. Model‐based evaluations identified female sex and baseline serum monoclonal protein less than or equal to 10 g/L as predictive of a higher objective response rate and a higher complete response rate, respectively. ER relationships were observed for safety events of cytokine release syndrome requiring tocilizumab or corticosteroids. The established ER models were used to quantify the ide‐cel dose–response, which showed a positive benefit–risk assessment for the range of ide‐cel exposures associated with the target dose range of 150–450 × 106 CAR+ T cells. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the second-most common hematologic malignancy in adults worldwide. Despite ongoing advancement in therapeutic modalities, it remains an incurable disease with a 5-year survival rate of approximately 50%. The recent development and introduction of anti-BCMA immunotherapies into clinical practice, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, has radically shifted the treatment paradigm. However, despite the promising potential of these therapies for broader application, frequent and significant adverse effects have been reported, both in short- and in long-term settings, requiring increasing awareness and vigilance in the treating team, close monitoring, and prompt interventions with a multidisciplinary approach. In this review, we will discuss the toxicities associated with CAR-T cell and bispecific antibody therapies, focusing on results from major clinical studies and real-world observations. In addition, we will emphasize on effective strategies for prevention, monitoring and management, and provide expert recommendations. [ABSTRACT FROM AUTHOR]

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. Both groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group. Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients. Methods: We performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels. Results: We identified 16 consecutive RRMM patients treated with ide-cel between 06–10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3–12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders. Conclusions: We report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell‐based immunotherapy has been increasingly used in the clinic for cancer intervention over the past 5 years. CAR T‐cell therapy takes advantage of genetically‐modified T cells to express synthetic CAR molecules on the cell surface. To date, up to six CAR T cell therapy products have been approved by the Food and Drug Administration for the treatment of leukaemia, lymphoma, and multiple myeloma. In addition, hundreds of CAR‐T products are currently under clinical trials to treat solid tumours. In both the fundamental research and clinical applications, CAR T cell immunotherapy has achieved exciting progress with remarkable remission or suppression of cancers. However, CAR T cell‐based immunotherapy still faces significant safety issues, as exemplified by "on‐target off‐tumour" cytotoxicity due to lack of strict antigen specificity. In addition, uncontrolled massive activation of infused CAR T cells may create severe systemic inflammation with cytokine release syndrome and neurotoxicity. These challenges call for a need to combine nanotechnology and optogenetics with immunoengineering to develop spatiotemporally‐controllable CAR T cells, which enable wireless photo‐tunable activation of therapeutic immune cells to deliver personalised therapy in the tumour microenvironment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with relapsed or refractory hematologic malignancies often have poor response to traditional chemotherapy, and the response rates are worsening with subsequent lines of therapy. The treatment of hematologic malignancies has been the focus of a new type of immunotherapy known as chimeric antigen receptor (CAR) T-cell therapy. OBJECTIVE: To review the currently approved CAR T-cell therapies for the management of patients with certain hematologic malignancies. DISCUSSION: CAR T-cell therapy uses the collective knowledge of the immune system to engineer genetically T-cells that can target various hematologic malignancies. To date, 5 CAR T-cell therapies have been approved by the US Food and Drug Administration, including tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and idecabtagene vicleucel. Currently, these drugs are indicated for the management of pediatric acute lymphoblastic leukemia (ALL), large B-cell lymphomas, mantle-cell lymphomas, follicular lymphoma, and multiple myeloma, and they result in high response rates and increased survival compared with historical treatments. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common adverse events associated with CAR T-cell therapies, and are man- aged with supportive care, tocilizumab, and corticosteroids. This article reviews the 5 drugs' mechanism of action, response rates, survival rates, and incidence of CRS and ICANS. CONCLUSION: CAR T-cell therapy offers a relatively new treatment approach with high response rates for patients with relapsed or refractory ALL, various types of B-cell lymphomas, and multiple myeloma; however, the use of these therapies also involves a high incidence of serious side effects, namely, CRS and ICANS. [ABSTRACT FROM AUTHOR]

Collectively, hematological malignancies account for the fourth most common malignancy. Myeloma and lymphoma are the most common types of hematological malignancies. Unfortunately, the management of refractory myeloma and lymphoma remains challenging. The discovery of new immunological therapies, namely chimeric antigen receptors T cells (CAR-T), outlined unprecedented B cell malignancies results. In this context, the CAR-T-based approach has led to the proliferation of many clinical studies. In this review, we will deal with the CAR-T structure, and we will summarize the primary clinical studies assessing the risks and benefits of CAR-T cell therapy. We will also deal with the adverse events and management of cytokine release syndromes/immune effector cell-associated neurotoxicity syndrome (ICANS). Subsequently, we will review potential future improvements to overcome refractoriness and improve expansion while decreasing CAR-T's off-target effects. The advances in the CAR-T platform represent a step forward with promising unlimited future possibilities that made it a paradigm-shifting for the management of B cell malignancies. [ABSTRACT FROM AUTHOR]

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CART cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) remains an incurable hematologic malignancy, despite the development of numerous innovative therapies during the past two decades. Immunotherapies are changing the treatment paradigm of MM and have improved the overall response and survival of patients with relapsed/refractory (RR) MM. B cell maturation antigen (BCMA), selectively expressed in normal and malignant plasma cells, has been targeted by several immunotherapeutic modalities. Chimeric antigen receptor (CAR) T cells, the breakthrough in cancer immunotherapy, have revolutionized the treatment of B cell malignancies and remarkably improved the prognosis of RRMM. BCMA-targeting CAR T cell therapy is the most developed CAR T cell therapy for MM, and the US Food and Drug Administration has already approved idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) for MM. However, the development of novel BCMA-targeting CAR T cell therapies remains in progress. This review focuses on BCMA-targeting CAR T cell therapy, covering all stages of investigational progress, including the innovative preclinical studies, the initial phase I clinical trials, and the more developed phase II clinical trials. It also discusses possible measures to improve the efficacy and safety of this therapy. [ABSTRACT FROM AUTHOR]