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Objectives Methods Results Conclusion Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted.In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom‐PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom‐PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety.Patients were heavily pretreated with a median number of four prior therapies (range: 1–10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double‐class refractory, 40% were triple‐class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression‐free survival was 8.9 months (0.92–not reached [NR]) and median overall survival was 11.8 months (3–40.6). Pom‐PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed.Pomalidomide‐PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T (CAR‐T) cell therapy has emerged as a potent treatment for relapsed or refractory multiple myeloma, demonstrating significant clinical efficacy. Despite these advances, treatment‐related toxicities, particularly infections, pose a significant challenge to patient safety. Methods: This review synthesizes current knowledge on the mechanisms underlying post‐CAR‐T therapy infections, focusing on the interplay between immune dysfunction, host factors, and treatment‐induced toxicity. It provides a comprehensive analysis of the temporal and individual variability in infection characteristics and the confounding clinical presentation of cytokine release syndrome. Results: The review identifies that patients receiving CAR‐T cells are at increased risk of concurrent infections due to the heterogeneity in infection characteristics across different time periods, individuals, and patient groups. It highlights the diagnostic and therapeutic complexities introduced by the overlapping symptoms of infection and cytokine release syndrome. Conclusion: To enhance the infection control post‐CAR‐T therapy, this review proposes preventive strategies tailored to the early and long‐term management of patients. It underscores the need for a nuanced understanding of infection mechanisms and the importance of personalized prevention plans to improve clinical outcomes in multiple myeloma treatment. [ABSTRACT FROM AUTHOR]

Background: Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR‐T) cell therapy. However, a portion of MM patients do not respond to CAR‐T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR‐34a on the immunosuppressive polarization of macrophages obtained from MM patients. Methods: The levels of miR‐34a and TLR9 (Toll‐like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co‐culture experiments were conducted to evaluate the immunomodulatory impact of MM‐associated macrophages on CAR‐T cells. Results: There was an observed suppressed activation of macrophages and CD4+ T lymphocytes in the blood samples of MM patients. Overexpression of miR‐34a in MM‐associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co‐culture system and an animal model, MM‐associated macrophages suppressed the activity and tumoricidal effect of CAR‐T cells in a miR‐34a‐dependent manner. Conclusion: The findings imply that targeting the macrophage miR‐34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR‐T therapy in MM patients. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy targeting B‐cell maturation antigen (BCMA) has shown profound efficacy and manageable toxicity in patients with relapsed/refractory multiple myeloma (RRMM). However, determining the best course of treatment for post‐CAR‐T therapy relapse remains a significant challenge. We conducted a retrospective analysis of patients from the phase I LEGEND‐2 study (NCT03090659) enrolled at the Xi'an site, analysing the first salvage line of therapy and outcomes in patients with RRMM who progressed after receiving LCAR‐B38M CAR‐T therapy. Of 45 eligible patients, 34 (76%) had progressive disease (PD). Overall response rate (ORR) to salvage treatment was 50.0%. Median progression‐free survival (PFS) after starting salvage treatment was 16.3 months. Median PFS of patients receiving proteasome inhibitor (PI)‐based combination therapy was longer (28.2 months) than that of patients receiving a second BCMA CAR‐T (including LCAR‐B38M; 3.9 months, p = 0.0022) or chemotherapy (1.67 months, p = 0.0001). All patients with extramedullary disease at baseline (n = 11) progressed after CAR‐T therapy; ORR to salvage therapy was 25.0% and median PFS was 9.7 months. In conclusion, salvage therapy in patients with PD after receiving LCAR‐B38M CAR‐T cells produced moderate efficacy, with better outcomes for PI‐based salvage regimens. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy has become an important intervention in the management of relapsed and relapsed/refractory multiple myeloma (MM). Currently, B‐cell maturation antigen (BCMA) is the most targeted surface protein due to its ubiquitous expression on plasma cells, with increasing expression of this essential transmembrane protein on malignant plasma cells as patients develop more advanced disease. This review will explore the earliest CAR‐T trials in myeloma, discuss important issues involved in CAR‐T manufacturing and processing, as well as review current clinical trials that led to the approval of the two commercially available CAR‐T products, Idecabtagene vicleucel and ciltacabtagene autoleucel. The most recent data from trials investigating the use of CAR‐T as an earlier line of therapy will be presented. Finally, the problem of relapses after CAR‐T will be presented, including several theories as to why CAR‐T therapies fail and possible clinical caveats. The next generation of MM‐specific CAR‐T will likely include new targets such as G‐protein‐coupled receptor class C, Group 5, member D (GPRC5D) and signaling lymphocyte activation molecular Family 7 (SLAMF7). The role of CAR‐T in the treatment of MM will undoubtedly increase exponentially in the next decade. [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]

Summary: Autologous patient‐derived adoptive T‐cell therapies have revolutionized the management of relapsed multiple myeloma (MM). However, the current manufacturing and quality control processes result in lengthy vein‐to‐vein time, making bridging therapy necessary for most patients. Yet the decision and choice of optimal bridging therapy are complex in the heavily pretreated relapsed MM patient. In this perspective piece, the authors provide their approach and considerations while selecting an optimal bridging regimen before autologous chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

The success of chimeric antigen receptor T‐cell (CAR‐T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co‐stimulatory molecules like 4‐1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second‐generation CAR‐T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR‐T infusions and improving sustainability of responses derived with CAR‐T therapy. Here, we summarize the clinical trial data leading to approval CAR‐T therapies in MM and NHL, discuss the limitations with current CAR‐T therapy strategies and review emerging strategies for overcoming these limitations. [ABSTRACT FROM AUTHOR]

Objectives: Multiple myeloma (MM) accounts for 10% of hematologic malignancies. However, most of the patients suffered from relapsed/refractory disease. We would like to expand CAR T cell therapy to treat MM using our current platform. Methods: BCMA CAR T lymphocytes were generated for volunteers or MM patients. The transduction efficiency was detected by the ddPCR technique. Immunophenotyping and exhaustion markers were monitored by flow cytometry. The efficacy of BCMA CAR T cells was tested using coculturing with BCMA CAR or mock, and the positive and negative targets, K562/hBCMA‐ECTM and K562, respectively. Results: BCMA CAR T cells were generated from consented volunteers or MM patients and could be detected CAR BCMA expression at a mean of 4.07 ± 1.95 or 4.65 ± 1.21 copies/cell, respectively. Those modified T cells were primarily effector memory T cells. Our BCMA CAR T cells could explicitly eradicate the K562/hBCMA‐ECTM cell line while the K562 cell line survived. Interestingly, the BCMA CAR, mock T cells, and peripheral blood mononuclear cells from MM patients expressed similar levels of the exhaustion makers, TIM‐3, LAG‐3, and PD1. Conclusions: Our BCMA CAR T cells, mainly effector/effector memory, could eliminate BCMA‐expressing cells in vitro and had similar levels of exhaustion markers among different populations. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains incurable. Two CAR‐T products, idecabtagene vicleucel (ide‐cel; Abecma) and ciltacabtagene autoleucel (cilta‐cel, Carvykti), have been FDA‐ and EMA‐approved for the treatment of relapsed/refractory MM (RRMM); both target B‐cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR‐T therapy, most patients will need subsequent treatment, and the optimal next‐line therapy is presently unclear. Commentary on: Liu et al. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA‐specific CAR‐T therapy: A retrospective analysis of LEGEND‐2. Br J Haematol 2024;204:1780‐1789. [ABSTRACT FROM AUTHOR]

The introduction of chimeric antigen receptor (CAR) T cells revolutionized treatment of relapsed and refractory multiple myeloma (RRMM) in recent years. Currently, two CAR T cell products—idecabtagene vicleucel and ciltacabtagene autoleucel—are approved in the United States and the European Union to treat patients with three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti‐CD38 antibody. Moreover, seminal phase III trials of both agents in earlier lines of therapy have been published recently. Despite unprecedented rates of deep and lasting remissions in RRMM, there are still areas of uncertainty regarding the optimal use and distribution of CAR T cells in multiple myeloma. In the current review, we discuss the available data on approved CAR T cell products as well as unmet clinical needs and ongoing developments to optimize usage of this promising treatment modality in multiple myeloma. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T (CAR T) cell and bispecific antibody therapies have shown unprecedented efficacy in heavily pretreated patients with multiple myeloma (MM). However, their use is associated with a significant risk of severe infections, which can be attributed to various factors such as hypogammaglobulinemia, neutropenia, lymphopenia, T‐cell exhaustion, cytokine‐release syndrome and immune‐effector cell‐associated neurotoxicity syndrome. As these therapies have been recently approved by regulatory agencies, it is crucial to establish practical guidelines for infection monitoring and prevention until robust data from prospective clinical trials become available. To address this issue, a panel of experienced investigators from the Academic Consortium to Overcome Multiple Myeloma through Innovative Trials (COMMIT) developed consensus recommendations for mitigating infections associated with CAR T‐cell and bispecific antibody therapies in MM patients. [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]

Background: Chimeric antigen receptor (CAR)‐T‐cell therapies have revolutionized the management of acute lymphoblastic leukemia, non‐Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell‐associated neurotoxicity syndrome, and long‐term "on‐target off‐tumor" effects. Methods: All of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non‐relapse mortality after CAR‐T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post‐CAR‐T‐cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B‐cell maturation antigen (BCMA) CAR‐T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post‐infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion. Results: Bacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR‐T‐cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination. Conclusion: Risk stratification tools are available and may help distinguish between infectious and non‐infectious causes of fever post‐infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T (CAR‐T) cell therapy is highly effective in inducing complete remission in haematological malignancies. Severe cytokine release syndrome (CRS) is the most significant and life‐threatening adverse effect of this therapy. This multi‐centre study was conducted at six hospitals in China. The training cohort included 87 patients with multiple myeloma (MM), an external validation cohort of 59 patients with MM and another external validation cohort of 68 patients with acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL). The levels of 45 cytokines on days 1–2 after CAR‐T cell infusion and clinical characteristics of patients were used to develop the nomogram. A nomogram was developed, including CX3CL1, GZMB, IL4, IL6 and PDGFAA. Based on the training cohort, the nomogram had a bias‐corrected AUC of 0.876 (95% CI = 0.871–0.882) for predicting severe CRS. The AUC was stable in both external validation cohorts (MM, AUC = 0.907, 95% CI = 0.899–0.916; ALL/NHL, AUC = 0.908, 95% CI = 0.903–0.913). The calibration plots (apparent and bias‐corrected) overlapped with the ideal line in all cohorts. We developed a nomogram that can predict which patients are likely to develop severe CRS before they become critically ill, improving our understanding of CRS biology, and may guide future cytokine‐directed therapies. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) is an aggressive plasma cell malignancy, causing a number of deaths worldwide every year. Chimeric antigen receptor (CAR) transduced T‐cell therapy has been a promising immunotherapy against hematological malignancies. Methods: In this study, we developed a second‐generation CAR construct and generated CAR‐T cells targeting CD38 molecule. Then effects of CAR‐T cells against MM cell lines were evaluated. Results: CD38‐CAR‐T cells showed higher cytotoxicity to MM cell lines and primary MM cells than that of control T cells in vitro. Over 50% MM1.s and RPMI8226 cells were killed by CAR‐T cells even at effector to target ratio of 1:100. CAR‐T cells also showed an enhanced cytotoxicity against primary MM cells. CAR‐T cells could be activated and produced a variety of cytokines in a target‐dependent manner. In vivo test indicated that CAR‐T cells also showed significant antitumor effect on xenograft mice models. Conclusion: These results indicated a promising therapeutic strategy of CD38‐CAR‐T cells against MM. [ABSTRACT FROM AUTHOR]

We performed a phase I study of weekly selinexor, carfilzomib, and dexamethasone (wSKd) in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to identify the maximum tolerated dose (MTD) of wSKd. Secondary endpoints included overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Prior exposure/refractoriness to carfilzomib was permitted. Thirty patients were enrolled; 26 (87%) had triple‐class exposed disease and 6 (20%) received chimeric antigen receptor (CAR) T‐cell therapy. Dose level 2 (carfilzomib 70 mg/m2 Intravenous [IV] on Days 1, 8, and 15; selinexor 100 mg PO on Days 1, 8, 15, 22; dexamethasone 40 mg on Days 1, 8, 15, 22 of 28‐day cycles) was chosen as the MTD, with no DLTs having occurred. The most common hematologic adverse events (AE) were thrombocytopenia (83%), anemia (70%), lymphopenia (50%), and neutropenia (50%). The most common nonhematologic AE were fatigue (70%), nausea (70%), diarrhea (53%), and anorexia (47%). The ORR was 21/30 (70%) overall and 18/23 (78%) at the MTD. At a median follow‐up of 12.3 months, the median PFS was 5.3 months and median OS 23.3 months. Responses were similar in carfilzomib naïve and exposed patients. Long‐term efficacy of wSKd is modest; wSKd could be employed as a bridging strategy to immunotherapies. [ABSTRACT FROM AUTHOR]

Over the last decade, the emergence of several novel therapeutic approaches has changed the therapeutic perspective of human malignancies. Adoptive immunotherapy through chimeric antigen receptor T cell (CAR‐T), which includes the engineering of T cells to recognize tumor‐specific membrane antigens and, as a result, death of cancer cells, has created various clinical benefits for the treatment of several human malignancies. In particular, CAR‐T‐cell‐based immunotherapy is known as a critical approach for the treatment of patients with hematological malignancies such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and non‐Hodgkin's lymphoma (NHL). However, CAR‐T‐cell therapy of hematological malignancies is associated with various side effects. There are still extensive challenges in association with further progress of this therapeutic approach, from manufacturing and engineering issues to limitations of applications and serious toxicities. Therefore, further studies are required to enhance efficacy and minimize adverse events. In the current review, we summarize the development of CAR‐T‐cell‐based immunotherapy and current clinical antitumor applications to treat hematological malignancies. Furthermore, we will mention the current advantages, disadvantages, challenges, and therapeutic limitations of CAR‐T‐cell therapy. [ABSTRACT FROM AUTHOR]

Summary: The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta‐analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end‐point was progression‐free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p‐score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08–0.20; p‐score 0.9796). There was no evidence of significant heterogeneity (I2, 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three‐drug regimens including anti‐CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T‐cell treatments and bispecific T‐cell engager therapies. [ABSTRACT FROM AUTHOR]

The aims of this work were to develop a population pharmacokinetic (PK) model for chimeric antigen receptor (CAR) transgene after single intravenous infusion administration of ciltacabtagene autoleucel in adult patients with relapsed or refractory multiple myeloma. CAR transgene level in blood were measured by quantitative polymerase chain reaction (qPCR) from 97 subjects in a phase Ib/II CARTITUDE‐1 study (NCT03548207), with a targeted cilta‐cel dose of 0.75 × 106 (range 0.5–1.0 × 106) CAR positive viable T‐cells per kg body weight. The population PK model development was primarily guided by the current mechanistic understanding of CAR‐T kinetics and the principles of building a parsimonious model. Cilta‐cel PK was adequately described by a two‐compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of four transit compartments with a lag time empirically representing the process from infused CAR‐T cell to measurable CAR transgene. No apparent relationship was observed between cilta‐cel dose (i.e., the actual number of CAR positive viable T‐cells infused), given the narrow dose range, and the observed transgene level. Based on covariate search and subgroup analysis of maximum systemic CAR transgene level (Cmax) and area under curve from the first dose to day 28 (AUC0–28d), none of the investigated subjects' demographics, baseline characteristics, and manufactured product characteristics had significant effects on cilta‐cel PK. The developed model is deemed robust and adequate for enabling subsequent exposure‐safety and exposure‐efficacy analyses. [ABSTRACT FROM AUTHOR]

Background: It is not clear if all Americans have benefitted equally from the availability of chimeric antigen receptor T‐cell (CART) therapy. We aimed to evaluate if demographic differences existed among adult patients who received CART therapy and to assess predictors of CART treatment outcomes. Methods: Records of patients ≥18 years who received CART therapy for non‐Hodgkin's lymphoma, acute lymphoblastic leukemia, and multiple myeloma in 2018 were evaluated in the National Inpatient Sample. Acute complications and inhospital mortality were compared between two groups of CART recipients: Whites and non‐Whites. Logistic regression analysis was used to evaluate the association between sociodemographic factors and inhospital mortality. Results: Of 1275 CART recipients that met inclusion criteria, there were 40.4% of females, 66.9% of Whites, Blacks (4.2%), Hispanics (13.3%), Asians or Pacific Islanders (4.2%), and Native Americans (1.3%). Up to 96.8% of CART procedures were performed in urban teaching hospitals, and 85.3% of CART recipients lived in metropolitan counties. Non‐Whites, compared to Whites, were younger at the time of CART therapy (p < 0.001). The inhospital mortality rate was higher in non‐Whites, though not statistically significant (5.4% vs. 4.4%, p = 0.764). There were no differences in length of hospital stay, hospital charges, or rates of acute toxicities between the two race groups. We found no association between race and treatment outcomes. Gender, neurotoxicity, and Charlson Comorbidity Index were significant predictors of inhospital mortality. Conclusions: CART therapy recipients in the United States were more likely to be Whites and more likely to be residents of metropolitan areas. These observed demographic differences were not associated with treatment outcomes or inhospital mortalities. [ABSTRACT FROM AUTHOR]

Hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, particularly considering patients who manifest multiple refractory diseases. Recently, chimeric antigen receptor (CAR)‐T cell therapy has emerged as a potential treatment option for relapsed/refractory B cell malignancies, which have motivated the Food and Drug Administration approval of a series of products based on this technique. The objective of this systematic review was to assess the efficacy and safety of CAR‐T cell therapy for patients with hematological malignancies. A comprehensive literature search was conducted in the electronic databases (CENTRAL, Embase, LILACS, and MEDLINE), clinical trials register platforms (Clinicaltrials.gov and WHO‐ICTRP), and grey literature (OpenGrey). The Cochrane Handbook for Reviews of Interventions was used for developing the review and the PRISMA Statement for manuscript reporting. The protocol was prospectively published in PROSPERO database (CRD42020181047). After the selection process, seven RCTs were included, three of which with available outcome results. The available results are from studies assessing axicabtagene, lisocabtagene, and tisagenlecleucel for patients with B cell lymphoma, and the certainty of evidence ranged from very low to low for survival and progression‐related outcome and for safety outcomes. Additionally, four randomized controlled trials comparing CAR‐T cell therapy to the standard treatment for various types of relapsed/refractory B cell non‐Hodgkin lymphomas and multiple myeloma included in this systematic review still did not have available outcome data. The results of this review may be used to guide clinical practice but evidence concerning the safety and efficacy of CAR‐T Cell therapy for hematological malignancies is still immature to recommend its application outside of clinical trials or compassionate use context for advanced and terminal cases. It is expected the results of the referred comparative studies will provide further elements to subsidize the broader application of this immunotherapy. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplant remains an option for patients with myeloma. Given the unfortunate inevitability of the majority of patients, relapsing salvage therapy options are needed. Although there is a potential concern for subsequent T‐cell redirection therapy in these patients, Hammons et al. provide a retrospective look at patients treated this way with no new significant adverse safety or efficacy signal. Commentary on: Hammons et al. Chimeric antigen receptor and bispecific T‐cell engager therapies in multiple myeloma patients with prior allogeneic transplantation. Br J Haematol 2024;204:887‐891. [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]

Immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs) and anti‐CD38 monoclonal antibodies (MoAbs) are the pillars of modern multiple myeloma (MM) therapy. The prognosis of patients with MM that became refractory to these three classes (triple‐class refractory [TCR]) is historically poor. Observational studies indicate an overall response rate of ~30% and overall survival inferior to 1 year with existing therapies. While no randomised trial has been completed in this setting, several agents exploring new mechanisms of action showed activity in TCR MM in single‐arm trials, including anti‐B‐cell maturation antigen (BCMA) chimeric antigen receptor T cells, anti‐BCMA antibody‐drug conjugates and exportin 1 (XPO1) inhibitors. Among agents in development, anti‐BCMA bispecific T‐cell engagers (TCE), and non‐BCMA TCEs demonstrated activity in most patients. Additionally, specific agents may exhibit unique activity in biologically defined patient subsets, as exemplified by venetoclax in t(11;14) MM. The main open questions in TCR MM are preferred sequence of existing therapies, the utility of sequential use of agents with similar mechanism of action, but different immunotherapy target and the relative efficacy of the different anti‐BCMA platforms. Here, we summarise the existing literature and provide general guidance on selecting therapy for this challenging and heterogenous group of patients. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy has shown great success in treating certain types of hematological malignancies, such as B-cell acute lymphoblastic leukemia (ALL), large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. However, there are still challenges to overcome, including improving safety, reducing relapses, lowering costs, and addressing barriers in solid tumors. This special issue focuses on the management of CAR-T cell therapy, including apheresis, implementation, toxicities, and long-term survivorship care. The issue also explores optimizations of CAR-T design and biomarkers for predicting toxicities and detecting relapses. [Extracted from the article]

Summary: Treatment outcomes in multiple myeloma (MM) have improved dramatically over the past 10 years. However, patients with high‐risk disease such as those with Stage III disease by the Revised International Staging System, the presence of adverse cytogenetics, or who are refractory to proteosome inhibitors, immunomodulatory drugs and monoclonal antibodies may have dismal outcomes. These patients represent an urgent ongoing need in MM. One of the hallmarks of MM is immune dysfunction and a tumour‐permissive immune microenvironment. Ameliorating the immune‐paresis could lead to improved outcomes. The role of immunotherapies has been growing at an exponential pace with numerous agents under development in clinical trials. In the present review, we provide an overview of immunotherapies in MM, focussing on bispecific antibodies (BsAbs). We review efficacy outcomes from the published clinical trials and consider the important safety aspects of these therapies, in particular the risk of cytokine‐release syndrome and immune effector cell‐associated neurotoxicity syndrome, and how these compare with patients receiving chimeric antigen receptor T cells. We discuss the MM epitopes being targeted by BsAbs, either in clinical or preclinical stages, and we consider where these therapies might best fit within the future ever‐changing paradigm of MM treatment. [ABSTRACT FROM AUTHOR]

Summary: Chimaeric antigen receptor T‐cell (CAR T) therapy has revolutionized the management of many haematological malignancies. It is associated with impressive disease responses in relapsed or refractory high‐grade B‐cell non‐Hodgkin lymphoma (B‐NHL) and acute lymphoblastic leukaemia (B‐ALL) with durable remissions in a subset of patients. Historically, haematopoietic cell transplantation (HCT) has been the standard consolidation strategy for many of these patients who are now being treated with CAR T. Relapses are frequent after CD19 CAR T therapy in B‐ALL and consolidation with allogeneic HCT (allo‐HCT) may improve survival of patients with high‐risk disease. There appears to be a clear difference in B‐ALL outcomes between paediatric and adult patients, with the latter having a much higher risk of relapse after CAR T therapy. Late relapses are infrequent in patients with B‐NHL and consolidation with allo‐HCT may not be needed in patients who achieve a complete remission after CAR T therapy. Future registry‐based and prospective studies will hopefully provide the needed data in the future to risk‐stratify the recipients of CAR T therapy. Meanwhile, we provide guidance on patient selection and practical issues with performing allo‐HCT after CAR T therapy. [ABSTRACT FROM AUTHOR]

Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose‐exposure‐response relationship of CAR‐T cells in patients is poorly understood. Moreover, the key drug‐specific and system‐specific determinants leading to favorable clinical outcomes are also unknown. Here we have developed a multiscale mechanistic pharmacokinetic (PK)‐pharmacodynamic (PD) model for anti‐B‐cell maturation antigen (BCMA) CAR‐T cell therapy (bb2121) to characterize (i) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying effector to target cell ratios, (ii) preclinical in vivo tumor growth inhibition and blood CAR‐T cell expansion in xenograft mice, and (iii) clinical PK and PD biomarkers in patients with multiple myeloma. Our translational PK‐PD relationship was able to effectively describe the commonly observed multiphasic CAR‐T cell PK profile in the clinic, consisting of the rapid distribution, expansion, contraction, and persistent phases, and accounted for the categorical individual responses in multiple myeloma to effectively calculate progression‐free survival rates. Preclinical and clinical data analysis revealed comparable parameter estimates pertaining to CAR‐T cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels toward overall extent of exposure after CAR‐T cell infusion. Virtual patient simulations also suggested a very steep dose‐exposure‐response relationship with CAR‐T cell therapy and indicated the presence of a "threshold" dose, beyond which a flat dose‐response curve could be observed. Our simulations were concordant with multiple clinical observations discussed in this article. Moving forward, this framework could be leveraged a priori to explore multiple infusions and support the preclinical/clinical development of future CAR‐T cell therapies. [ABSTRACT FROM AUTHOR]

Background: Relapsed/refractory (R/R) multiple myeloma (MM) patients and primary plasma cell leukemia (PCL) have an unfavorable prognosis and no effective treatment. This study was designed to assess the safety and preliminary efficacy of a novel anti‐B‐cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell in R/R MM and PCL. Methods: Between February 22, 2017, and June 25, 2018, 28 R/R and two R/R primary PCL patients received a median dose of 11.2 × 106 CAR+ cells/kg. The subjects were refractory to a proteasome inhibitor and/or an immunomodulatory agent. Fludarabine and cyclophosphamide were given as lymphodepletion chemotherapy. Results: Results for these 30 consecutive patients who received an anti‐BCMA CAR T cell infusion are reported. The patients had received a median of four prior lines of therapy. A total of 44 different types of adverse events were recorded, and hematologic toxic effects were the most common events of any grade during treatment. Hematologic toxic effects were also the most common events of grade 3 or higher. A total of 29 patients (96.7%) had cytokine release syndrome, which was of grade 1 or 2 in 24 patients (80%) and grade 3 in five patients (16.7%). Neurologic toxic effects only occurred in one patient (3.3%) and were of grade 1. The objective response rate was 90%, and the complete response rate was 43.3%. With a median follow‐up of 12.6 months, the median progression‐free survival (PFS) and overall survival were 5.2 months and 14.0 months. One of the two primary PCL achieved a complete response with a PFS of 307 days. The other patients achieved a very good partial response with a PFS of 117 days. Conclusions: Anti‐BCMA CAR T cell treatment is safe and highly active in R/R multiple myeloma. [ABSTRACT FROM AUTHOR]

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy. [ABSTRACT FROM AUTHOR]

Keywords: selinexor; chimeric antigen receptor T cell refractory; multiple myeloma; carfilomib; bortezomib EN selinexor chimeric antigen receptor T cell refractory multiple myeloma carfilomib bortezomib e126 e130 5 05/19/20 20200515 NES 200515 Recent reports indicate that chimeric antigen receptor T cell (CAR-T) therapy can induce deep and durable responses for many patients with heavily-pretreated multiple myeloma (MM), with median progression-free or event-free survival ranging between 7 and 12 months (Zhao I et al. i , [14]; Cho I et al. i , [6]; Raje I et al. i , [9]; Xu I et al. i , [13]). One patient was treated on the STORM study (NCT02336815) with selinexor (80 mg twice-weekly, days 1 and 3) plus dexamethasone (20 mg twice-weekly, days 1 and 3); one patient was treated with selinexor (100 mg once-weekly) plus bortezomib (1-3 mg/m SP 2 sp once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly) in the compassionate use program; and five patients were treated with selinexor (100 mg once-weekly) plus carfilzomib (20/56 or 20/70 mg/m SP 2 sp ) and dexamethasone (40 mg once-weekly or 20 mg twice-weekly) in the NCT02199665 trial. As of the date of data cutoff, the median time on a selinexor-based regimen was 6-0 months (range: 3-7-8-3 months); four patients' disease had progressed, one patient had withdrawn consent, and two patients were still responding and on therapy. [Extracted from the article]

Introduction: Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in clinical studies for relapsed/refractory multiple myeloma (RRMM). We performed a systematic literature review to summarize the current body of evidence on the role of anti‐BCMA CAR T cells for RRMM. Objectives and Methods: Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included using a conventional meta‐analysis. Main efficacy outcomes were response, relapse, and survival. Safety outcomes were cytokine release syndrome (CRS) and neurotoxicity. Results: Anti‐BCMA CAR T cells resulted in a pooled overall response of 82% (95% confidence interval [CI], 74%‐88%) and complete response of 36% (24%‐50%). Higher CAR+ cell doses were associated with higher response rates. The pooled relapse rate of responders was 45% (27%‐64%), and median progression‐free survival was 10 months. Present extramedullary disease did not show worse outcome. Severe CRS grades 3‐4 and neurotoxicity occurred in 15% (10%‐23%) and 18% (10%‐31%). Conclusion: Anti‐BCMA CAR T cells showed high response rates, even in patients with present extramedullary disease, while relapse occurred in half of the patients who achieved a response. Larger studies with longer follow‐up especially evaluating the association of response and survival are needed. [ABSTRACT FROM AUTHOR]

By increasing disease‐free survival and offering the potential for long‐term cure, chimeric antigen receptor (CAR) T‐cell therapy has dramatically expanded therapeutic options among those with high‐risk B‐cell malignancies. As CAR T‐cell utilization evolves however, novel challenges are generated. These include determining how to optimally integrate CAR T cells into standard of care and overcoming mechanisms of resistance to CAR T‐cell therapy, such as evolutionary stress induced on cancer cells leading to immunophenotypic changes that allow leukemia to evade this targeted therapy. Compounding these challenges are the limited ability to determine differences between various CAR T‐cell constructs, understanding the generalizability of trial outcomes from multiple sites utilizing unique CAR manufacturing strategies, and comparing distinct criteria for toxicity grading while defining optimal management. Additionally, as understanding of CAR behavior in humans has developed, strategies have appropriately evolved to proactively mitigate toxicities. These challenges offer complimentary insights and guide next steps to enhance the efficacy of this novel therapeutic modality. With a focus on B‐cell malignancies as the paradigm for effective CAR T‐cell therapy, this review describes advances in the field as well as current challenges and future directions. [ABSTRACT FROM AUTHOR]

The introduction of chimeric antigen receptor ( CAR)-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. However, so far, clinical efficacy has only been demonstrated for CD19-positive B cell lymphomas. For Multiple Myeloma ( MM), the second most common haematological malignancy, there are currently no clinical results supporting the usefulness of the adoptive transfer of CAR-modified T cells. This might be related to the fact that an ideal surface target has not yet been identified or the presence of strong local immunosuppression in the tumour microenvironment, which is a hallmark of MM. In this review, we provide a comprehensive overview of promising target molecules for CAR T cell approaches in MM and we outline a number of ways in which the local immunosuppression in MM can be overcome. By providing a strategy for the design of CAR T cell treatments for MM we hope to transform this new therapeutic approach into a valuable tool within the therapeutic armamentarium for MM. [ABSTRACT FROM AUTHOR]