Search

Chimeric antigen receptor T-cell (CAR-T) therapy has ushered in a new era for the treatment of multiple myeloma (MM). Numerous clinical studies, especially those involving B-cell maturation antigen (BCMA)-directed CAR-T, have shown remarkable efficacy in patients with relapsed or refractory multiple myeloma (R/R MM). However, a considerable number of patients still experience disease recurrence or progression after BCMA CAR-T treatment, which is attributed to various factors, including antigen escape, CAR-T manufacturing factors, T cell exhaustion, inhibitory effects of tumor microenvironment and impact of prior treatments. The scarcity of effective treatment options following post-CAR-T disease recurrence, coupled with the lack of well-established salvage regimens, leaves patients who do relapse facing a bleak prognosis. In recent years, some academic institutions have achieved certain results in salvage treatments of patients with relapse after BCMA CAR-T treatment through secondary infusion of BCMA CAR-T, changing to non-BCMA-directed CAR-T, double-target CAR-T, bispecific antibodies or other novel therapies. This review summarizes the mechanisms of resistance or relapse after BCMA CAR-T administration and the available data on current salvage treatments, hoping to provide ideas for optimizing clinical salvage therapies. [ABSTRACT FROM AUTHOR]

Abstract Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p

Chimeric antigen receptor T-cell (CAR-T) therapy has ushered in a new era for the treatment of multiple myeloma (MM). Numerous clinical studies, especially those involving B-cell maturation antigen (BCMA)-directed CAR-T, have shown remarkable efficacy in patients with relapsed or refractory multiple myeloma (R/R MM). However, a considerable number of patients still experience disease recurrence or progression after BCMA CAR-T treatment, which is attributed to various factors, including antigen escape, CAR-T manufacturing factors, T cell exhaustion, inhibitory effects of tumor microenvironment and impact of prior treatments. The scarcity of effective treatment options following post-CAR-T disease recurrence, coupled with the lack of well-established salvage regimens, leaves patients who do relapse facing a bleak prognosis. In recent years, some academic institutions have achieved certain results in salvage treatments of patients with relapse after BCMA CAR-T treatment through secondary infusion of BCMA CAR-T, changing to non-BCMA-directed CAR-T, double-target CAR-T, bispecific antibodies or other novel therapies. This review summarizes the mechanisms of resistance or relapse after BCMA CAR-T administration and the available data on current salvage treatments, hoping to provide ideas for optimizing clinical salvage therapies.

Chimeric antigen receptor T (CAR-T)-cell therapy targeting B-cell maturation antigen (BCMA) is currently one of the promising treatment methods for relapsed/refractory multiple myeloma (MM). Herein, this study is a case report on a 41-year-old male patient with MM. Unfortunately, he still developed multidrug-resistant, refractory, and bone marrow suppression after receiving multiline high-intensity chemotherapy. After a detailed evaluation, the physician recommended autologous hematopoietic stem cell transplantation (ASCT) support, followed by sequential immunotherapy with autologous anti- BCMA CAR-T cells. The CAR-T product is a novel anti-BCMA CAR-T based on Retrovirus vectors (RV). It was worth noting that the patient achieved VGPR (very good partial remission) one month after infusion of anti-BCMA CAR-T cells. Recent tests have found that the M protein was no longer detectable and the patient has achieved CR (complete response). Although grade 3 cytokine release syndrome (CRS) appeared, the symptom was well controlled and immune effector cell-associated neurotoxicity syndrome (ICANS) did not occur. This was the first case report of RV prepared anti-BCMA CAR-T cells combined with ASCT for the treatment of MM patient in clinical practice, indicating that the RV-based anti-BCMA-CAR-T cells with ASCT have excellent therapeutic efficacy and high safety in triple-refractory MM patients.

Abstract Background BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. Methods Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score—composed of factors related to hematopoietic reserve and baseline inflammatory state—was determined prior to lymphodepleting chemotherapy. Results At lymphodepletion, 63 patients were HTlow (score 0–1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p

Abstract Background BCMA CAR-T is highly effective for relapsed/refractory multiple myeloma(R/R-MM) and significantly improves the survival of patients. However, the short remission time and high relapse rate of MM patients treated with BCMA CAR-T remain bottlenecks that limit long-term survival. The immune microenvironment of the bone marrow (BM) in R/R-MM may be responsible for this. The present study aims to present an in-depth analysis of resistant mechanisms and to explore potential novel therapeutic targets for relapse of BCMA CAR-T treatment via single-cell RNA sequencing (scRNA-seq) of BM plasma cells and immune cells. Methods This study used 10X Genomic scRNA-seq to identify cell populations in R/R-MM CD45+ BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. Cell Ranger pipeline and CellChat were used to perform detailed analysis. Results We compared the heterogeneity of CD45+ BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We found that the proportion of monocytes/macrophages increased, while the percentage of T cells decreased at relapse after BCMA CAR-T treatment. We then reclustered and analyzed the alterations in plasma cells, T cells, NK cells, DCs, neutrophils, and monocytes/macrophages in the BM microenvironment before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We show here that the percentage of BCMA positive plasma cells increased at relapse after BCMA CAR-T cell therapy. Other targets such as CD38, CD24, SLAMF7, CD138, and GPRC5D were also found to be expressed in plasma cells of the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Furthermore, exhausted T cells, TIGIT+NK cells, interferon-responsive DCs, and interferon-responsive neutrophils, increased in the R/R-MM patient at relapse after BCMA CAR-T cell treatment. Significantly, the proportion of IL1βhi Mφ, S100A9hi Mφ, interferon-responsive Mφ, CD16hi Mφ, MARCO hi Mφ, and S100A11hi Mφ significantly increased in the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Cell–cell communication analysis indicated that monocytes/macrophages, especially the MIF and APRIL signaling pathway are key players in R/R-MM patient at relapse after BCMA CAR-T cell therapy. Conclusion Taken together, our data extend the understanding of intrinsic and extrinsic relapse of BCMA CAR-T treatment in R/R-MM patient and the potential mechanisms involved in the alterations of antigens and the induced immunosuppressive microenvironment, which may provide a basis for the optimization of BCMA CAR-T strategies. Further studies should be performed to confirm these findings.

Background: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. Methods: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score—composed of factors related to hematopoietic reserve and baseline inflammatory state—was determined prior to lymphodepleting chemotherapy. Results: At lymphodepletion, 63 patients were HTlow (score 0–1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). Conclusions: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates. [ABSTRACT FROM AUTHOR]

Background: BCMA CAR-T is highly effective for relapsed/refractory multiple myeloma(R/R-MM) and significantly improves the survival of patients. However, the short remission time and high relapse rate of MM patients treated with BCMA CAR-T remain bottlenecks that limit long-term survival. The immune microenvironment of the bone marrow (BM) in R/R-MM may be responsible for this. The present study aims to present an in-depth analysis of resistant mechanisms and to explore potential novel therapeutic targets for relapse of BCMA CAR-T treatment via single-cell RNA sequencing (scRNA-seq) of BM plasma cells and immune cells. Methods: This study used 10X Genomic scRNA-seq to identify cell populations in R/R-MM CD45+ BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. Cell Ranger pipeline and CellChat were used to perform detailed analysis. Results: We compared the heterogeneity of CD45+ BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We found that the proportion of monocytes/macrophages increased, while the percentage of T cells decreased at relapse after BCMA CAR-T treatment. We then reclustered and analyzed the alterations in plasma cells, T cells, NK cells, DCs, neutrophils, and monocytes/macrophages in the BM microenvironment before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We show here that the percentage of BCMA positive plasma cells increased at relapse after BCMA CAR-T cell therapy. Other targets such as CD38, CD24, SLAMF7, CD138, and GPRC5D were also found to be expressed in plasma cells of the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Furthermore, exhausted T cells, TIGIT+NK cells, interferon-responsive DCs, and interferon-responsive neutrophils, increased in the R/R-MM patient at relapse after BCMA CAR-T cell treatment. Significantly, the proportion of IL1βhi Mφ, S100A9hi Mφ, interferon-responsive Mφ, CD16hi Mφ, MARCO hi Mφ, and S100A11hi Mφ significantly increased in the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Cell–cell communication analysis indicated that monocytes/macrophages, especially the MIF and APRIL signaling pathway are key players in R/R-MM patient at relapse after BCMA CAR-T cell therapy. Conclusion: Taken together, our data extend the understanding of intrinsic and extrinsic relapse of BCMA CAR-T treatment in R/R-MM patient and the potential mechanisms involved in the alterations of antigens and the induced immunosuppressive microenvironment, which may provide a basis for the optimization of BCMA CAR-T strategies. Further studies should be performed to confirm these findings. [ABSTRACT FROM AUTHOR]

Richter transformation is still a serious risk in the era of innovative therapies, despite the fact that targeted therapy with Bruton's tyrosine kinase inhibitor has significantly improved the prognosis for chronic lymphocytic leukemia (CLL). We report a rare case of a 61-year-old male patient's CLL transforming into a synchronous clonal related plasmablastic lymphoma (PBL) after receiving ibrutinib. During COVID-19, the patient stopped taking ibrutinib, which caused the illness to worsen. Histology revealed that PBL was present in the right supraclavicular mass and that CLL had penetrated the bone marrow. Three cycles of CHP (cyclophosphamide, doxorubicin, and prednisone) were administered together with venetoclax and brentuximab vedotin. After receiving BCMA CAR-T cell treatment, the patient was in complete remission. For PBL transformation, a condition with a worse prognosis and few therapy choices, our results suggest the use of BCMA CAR-T and novel target agents. [Display omitted] • Chronic lymphocytic leukemia (CLL) remains the most frequent adult leukemia in Western countries. • Few cases of synchronous CLL toplasmablastic lymphoma (PBL) transformation have been documented. • Our results suggest the use of BCMA CAR-T and novel target agents for PBL transformation. [ABSTRACT FROM AUTHOR]