B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

Gagelmann, Nico; Ayuk, Francis; Atanackovic, Djordje

doi:10.1111/ejh.13380

Cited by 46 publications

(40 citation statements)

References 52 publications

(201 reference statements)

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“…Hence, at this stage, it is difficult to obtain a clear sight on the toxicity and efficacy that can be expected from this novel therapeutic approach in relapsed/refractory MM patients. To the best of our knowledge, there has been only one attempt so far to systematically aggregate the outcome data of BCMA CAR-T-cell clinical studies [18]. In that report, Gagelmann et al included 15 studies comprising a total of 285 patients.…”

Section: Introductionmentioning

confidence: 99%

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

et al. 2020

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Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. Methods We performed a database search using the terms “BCMA,” “CAR,” and “multiple myeloma” for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). Results Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0–88.2); 10.5% (6.8–16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3–26.7; I2 = 45%) versus 2.8% (1.3–6.1; I2 = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5–85.9); complete responses (CR) were observed in 44.8% (35.3–54.6). A pooled CR rate of 71.9% (62.8–79.6; I2 = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5–41.1; I2 = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4–17.4) months, which compared favorably to the expected PFS of 1.9 (1.5–3.7) months (HR 0.14; p < 0.0001). Conclusions Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

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Section: Introductionmentioning

confidence: 99%

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

et al. 2020

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“…However, it is postulated that CAR T-cell products generated in the RR setting display inferior clinical efficacy than products generated from patients after first-line induction therapy ( 167 ). In fact, a recent meta-analysis of 15 clinical trials (thereof 14 in RRMM, only 1 in NDMM) documented a CR rate of 36% with MRD negativity in 77% ( 208 ) and a mPFS of 10 months. Therefore, the curative potential in the respective patient cohorts is limited to date.…”

Section: Clinical and Logistical Challenges Of Incorporating Car T-cementioning

confidence: 99%

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

et al. 2020

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Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.

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“…Several ongoing Phase 2/3 studies continue to show the efficacy of CAR T therapy in RRMM [ 25 , 59 , 60 ]. Despite a high RR (≥70–100%) and increased survival by CAR-T cell therapy in the heavily pretreated RRMM patients who have no treatment options left [ 111 ], the high incidence of CRS and neurotoxicity, as well as the toxicity of conditioning chemotherapy are major concerns when selecting patients for this therapy ( Table 3 ). In patients with high tumor burden, the risk of CRS is even higher, resulting in exclusion from clinical studies [ 63 ].…”

Section: Which Anti-bcma Agent? Each Has Its Own Meritsmentioning

confidence: 99%

BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma

Cho

Lin

Xing

et al. 2020

Cancers

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The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients.

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B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

Cited by 46 publications

References 52 publications

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma

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