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Multiple myeloma is characterized by frequent clinical relapses after conventional therapy. Recently, chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, although >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune-intrinsic mechanisms may contribute to this resistance. Although there were no preexisting T-cell features associated with clinical outcomes, we found that patients with a durable response to CAR T-cell treatment had greater persistence of their CAR T cells than patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T-effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR T cells. These cells expand in vivo early after infusion but express exhaustion markers (hepatitis A virus cellular receptor 2 [HAVCR2] and T-cell immunoglobulin and mucin domain-containing-3 [TIGIT]) and remain polyclonal. Finally, we demonstrate that nonclassical monocytes are enriched in the myeloma niche and may induce CAR T-cell dysfunction through mechanisms that include transforming growth factor β. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR T-cell therapy.

For patients with relapsed/refractory multiple myeloma with a relapse after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAbs) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval [CI], 13.2 to not reached [NR]). Fifty-eight patients received subsequent myeloma-directed therapies, with a total of 265 lines of therapy (LOTs). The overall response rate for firstline salvage therapy was 41% (95% CI, 28-55). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAbs (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least 1 line of salvage BCMA-directed therapy; median progression-free survival was 8.3 months (95% CI, 7.9 to NR), 3.6 months (95% CI, 1.4 to NR), and 1 month (95% CI, 0.9 to NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAbs can be effective salvage options after BCMA-directed CAR-T relapse; however, DORs appear limited, and further studies with new combinations and alternative targets are warranted.

Abstract\nKEY POINTSMEDI2228 is an antibody drug conjugate (ADC) comprised of a fully human B-cell maturation antigen (BCMA) antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer. This phase 1 trial evaluated MEDI2228 in patients with relapsed/refractory (R/R) multiple myeloma (MM), who received prior treatment with approved agents from 3 classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies). Primary endpoint was safety and tolerability; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. A total of 107 patients were treated and the maximum tolerated dose (MTD) was 0.14 mg/kg Q3W. Two patients had dose-limiting toxicities (DLTs; thrombocytopenia; 0.20 mg/kg Q3W). The most frequent treatment-related adverse events were photophobia (43.9%), rash (29.0%), and thrombocytopenia (19.6%). In MTD cohort A (n = 41), the objective response rate (ORR) was 56.1%, with 1 stringent complete response, 9 very good partial responses, and 13 partial responses. ORR was 53.3% in triple refractory patients. In cohort B (n=25), ORR was 32%. Although MEDI2228 demonstrated efficacy in R/R MM, ocular toxicity precluded further development of this drug.MEDI2228 is an ADC comprised of a fully human anti-BCMA antibody conjugated to the cytotoxic PBD payload, tesirine.MEDI2228 monotherapy demonstrated efficacy across all dose levels; and responses were observed in patients with triple refractory MM.This study further validates BCMA as a target for ADC-based therapy in MM; ocular toxicity precluded further clinical development. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of large B ⁃cell lymphoma, with a poor prognosis without standardized treatment protocols. Traditional therapeutic strategies, such as chemotherapy, proteasome inhibitors, immunomodulatory agents, CD30 and CD38 monoclonal antibodies, and autologous hematopoietic stem cell transplantation, have yielded suboptimal outcomes. Chimeric antigen receptor T (CAR⁃T) cell therapy has revolutionized the management of diffuse large B⁃cell lymphoma and multiple myeloma, offering hope for patients with PBL. However, clinical experience and data evidence supporting the application of CAR⁃T cell in PBL treatment remain scant. This paper reports a case of an elderly patient with PBL who achieved a complete response following B⁃cell maturation antigen CAR⁃T cell therapy. [ABSTRACT FROM AUTHOR]

UNLABELLED: BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

Objective To construct chimeric antigen receptors modified γδT cells targeting at BCMA (BCMA CAR-γδT) and to evaluate its efficacy of anti-multiple myeloma in vitro. Methods Lentiviral vectors containing BCMA single-chain variable fragment were constructed and transiently transfected into 293T cells. The expression of foreign genes was verified by fluorescence microscopy and Western blot; the lentivirus was packaged and the virus titer was determined by flow cytometry. Human peripheral blood αβT cells were infected and γδT cells were examined for its infection efficiency; LDH release method was used to detect the cytotoxic activity of BCMA CAR-γδT cells against human multiple myeloma cell lines in vitro, and the difference of cytotoxic activity between CAR-γδT cells and CAR-αβT cells was compared by Incucyte S3 Live-Cell Analysis Instrument. Results Twenty-four hours after BCMA-CAR lentiviral vector was transferred into 293T cells, the expression of exogenous ZsGreen was microscopied by fluorescence microscope; CD3ζ was detected by Western blot, which showed that BCMA-CAR could be successfully expressed. The lentivirus was packaged, collected and concentrated(virus titer of 2.23×108 Tu/mL). Infected αβT cells and γδT cells from human peripheral blood in MOI=5, and the results of flow cytometry showed that infection efficiency of αβT cells was 59.18%±2.56%, γδT cells was 48.15±9.86%. The cytotoxic activity of CAR-γδT cells against human myeloma cell lines MM1.S, H929 with high expression of BCMA and K562 cells with over-expression of BCMA was higher than that of empty vector control γδ T cells,which were significantly enhanced (P＜0.001), but there was no difference in cell lines negative for BCMA expression; Live-Cell Analysis Instrument results showed that the cytotoxic activity of BCMA CAR-γδT cells and BCMA CAR-αβT cells against H929 in vitro was significantly better than their vector control cells. There was no difference in the cytotoxic activities of BCMA CAR-γδT cells as compared with against BCMA negative cell lines, and so do BCMA CAR-T cells. Conclusions Cytotoxic activity of BCMA CAR-γδT targeting at BCMA in vitro was significantly enhanced ,which is expected to serve as a novel allogeneic γδT cell product for cell adoptive immunotherapy of multiple myeloma.

Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes. [ABSTRACT FROM AUTHOR]

Objective To construct chimeric antigen receptors modified γδT cells targeting at BCMA (BCMA CAR-γδT) and to evaluate its efficacy of anti-multiple myeloma in vitro. Methods Lentiviral vectors containing BCMA single-chain variable fragment were constructed and transiently transfected into 293T cells. The expression of foreign genes was verified by fluorescence microscopy and Western blot; the lentivirus was packaged and the virus titer was determined by flow cytometry. Human peripheral blood αβT cells were infected and γδT cells were examined for its infection efficiency; LDH release method was used to detect the cytotoxic activity of BCMA CAR-γδT cells against human multiple myeloma cell lines in vitro, and the difference of cytotoxic activity between CAR-γδT cells and CAR-αβT cells was compared by Incucyte S3 Live-Cell Analysis Instrument. Results Twenty-four hours after BCMA-CAR lentiviral vector was transferred into 293T cells, the expression of exogenous ZsGreen was microscopied by fluorescence microscope; CD3ζ was detected by Western blot, which showed that BCMA-CAR could be successfully expressed. The lentivirus was packaged, collected and concentrated(virus titer of 2.23×108 Tu/mL). Infected αβT cells and γδT cells from human peripheral blood in MOI=5, and the results of flow cytometry showed that infection efficiency of αβT cells was 59.18%±2.56%, γδT cells was 48.15±9.86%. The cytotoxic activity of CAR-γδT cells against human myeloma cell lines MM1.S, H929 with high expression of BCMA and K562 cells with over-expression of BCMA was higher than that of empty vector control γδ T cells,which were significantly enhanced (P＜0.001), but there was no difference in cell lines negative for BCMA expression; Live-Cell Analysis Instrument results showed that the cytotoxic activity of BCMA CAR-γδT cells and BCMA CAR-αβT cells against H929 in vitro was significantly better than their vector control cells. There was no difference in the cytotoxic activities of BCMA CAR-γδT cells as compared with against BCMA negative cell lines, and so do BCMA CAR-T cells. Conclusions Cytotoxic activity of BCMA CAR-γδT targeting at BCMA in vitro was significantly enhanced,which is expected to serve as a novel allogeneic γδT cell product for cell adoptive immunotherapy of multiple myeloma. [ABSTRACT FROM AUTHOR]

Elranatamab efficacy in the single-arm, registrational MagnetisMM-3 trial (NCT04649359) was compared with that of physician's choice of treatment (PCT) for triple-class refractory multiple myeloma. MagnestisMM-3 eligibility criteria were applied to two USA-based oncology electronic health record databases, COTA and Flatiron Health (FH), to identify cohorts for this study (NCT05932290). Applied statistical techniques accounted for cohort imbalances. MagnetisMM-3 (BCMA-naive; n = 123) outcomes were compared with those from COTA (n = 239) and FH (n = 152). Elranatamab was associated with a significantly higher objective response rate (risk ratios, 1.88–2.25), significantly longer progression-free survival (hazard ratios [HRs], 0.37–0.57), and, across most analyses, significantly longer overall survival (HRs, 0.46–0.66) versus PCT. BCMA-naive patients who were treated with elranatamab exhibited significantly better outcomes than patients treated in real-world clinical practice. Elranatamab is a new medicine for the treatment of people with multiple myeloma. In the ongoing clinical trial MagnetisMM-3, most people had fewer myeloma cells when treated with elranatamab. However, MagnetisMM-3 only looks at the effects of elranatamab without comparing it to other myeloma treatments. Therefore, a new study was designed to compare the effectiveness of elranatamab in the MagnetisMM-3 study with other treatments used in real-world clinical practice (not in a clinical trial). Data from people in MagnetisMM-3 was compared with data from two US databases (COTA and Flatiron Health) containing health records of patients treated for multiple myeloma in real-life clinical practice. The same criteria used to select patients for the MagnetisMM-3 trial (123 people) were used to identify people with similar characteristics in COTA (239 people) and Flatiron Health (152 people). More people treated with elranatamab had fewer myeloma cells in their bodies after treatment than people who received their doctor's choice of treatment in clinical practice. In fact, six out of ten people treated with elranatamab had fewer myeloma cells versus about three in ten people from each real-world database. People treated with elranatamab versus physician's choice of treatment lived longer without their disease getting worse and lived longer overall. In conclusion, this study found that more people treated with elranatamab responded to treatment and lived longer than similar people from the COTA and Flatiron Health databases who were given treatments available in a real-world clinical setting. Clinical Trial Registration: NCT05932290 (ClinicalTrials.gov) Executive summary Elranatamab is a BCMAxCD3 bispecific antibody under investigation for the treatment of relapsed or refractory multiple myeloma in the single-arm, registrational phase II MagnetisMM-3 trial (NCT04649359) of elranatamab. Although favorable clinical outcomes have been observed in patients treated with elranatamab in MagnetisMM-3, it can be difficult to compare these clinical results with those of other available therapies due to the single-arm design. The aim of this study (NCT05932290) was to contextualize efficacy data from patients naive to BCMA-directed therapy who received elranatamab in the MagnetisMM-3 trial with data from similar patients from two USA-based oncology electronic health record databases, COTA and Flatiron Health, as external real-world control arms. Trial inclusion and exclusion criteria were applied to each real-world database to obtain comparable patient populations. Statistical techniques (e.g., inverse probability of treatment weighting) were used to account for imbalances across cohorts on key confounding variables, including age, sex, cytogenetic risk, number of prior lines of therapy, Eastern Cooperative Oncology Group performance status, time since initial multiple myeloma diagnosis, penta-drug refractory status and International Staging System disease stage. Ultimately, outcomes of 123 patients from MagnetisMM-3 Cohort A (BCMA naive) were compared with those of 239 and 152 similar patients from the COTA and Flatiron Health databases, respectively. Elranatamab was associated with a significantly higher objective response rate, longer progression-free survival and generally longer overall survival compared with real-world treatments. Among BCMA-naive patients, those treated with elranatamab exhibited improved clinical outcomes compared with patients who received treatments used in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is still an incurable disorder despite improved antibody and cellular therapies against different MM antigens. Single targeted antigens have so far been ineffective against MM with most patients relapsing after initial response. Hence, sequential immunotherapies directed at different targets are expected to perform better than monotherapy alone. Here, we optimized and established in preclinical studies the therapeutic rationale of using targeted alpha therapy (TAT) directed against CD38 antigen (225Ac-DOTA-daratumumab) with CAR T cell therapy directed at CS1 antigen in a systemic MM model. The sequential therapies compared CAR T therapy followed by TAT to TAT followed by CAR T therapy. CAR T cell monotherapy increased median survival from 49 days (d) in untreated controls to 71d with a modest improvement to 89d for 3.7 kBq of TAT given 14d later. When CAR T was followed by 7.4 kBq of TAT 29d later, sequential therapy increased median survival from 47d in untreated controls to 106d, compared to 68d for CAR T monotherapy. When CAR T therapy was followed by untargeted alpha immunotherapy using 7.4 kBq of 225Ac-DOTA-trastuzumab (anti-HER2) antibody 29d later, there was only a slight improvement in response over CAR T monotherapy demonstrating the role of tumor targeting. TAT (7.4 kBq) followed by CAR T therapy was also effective when CAR T therapy was delayed for 21d vs 14d or 28d post TAT, highlighting the importance of timing sequential therapies. Sequential targeted therapies using CS1 CAR T or 225Ac-DOTA-CD38 TAT in either order shows promise over monotherapies alone.

Aim: We compared the effectiveness of teclistamab versus real-world physicians choice of therapy (RWPC) in triple-class exposed relapsed/refractory multiple myeloma. Materials & methods: MajesTEC-1 eligibility criteria were applied to the RWPC cohort. Baseline covariate imbalances were adjusted using inverse probability of treatment weighting. Overall survival, progression-free survival and time to next treatment were compared. Results: After inverse probability of treatment weighting, baseline characteristics were similar between cohorts (teclistamab, n = 165; RWPC, n = 364 [766 observations]). Teclistamab treated patients had numerically better overall survival (hazard ratio [HR]: 0.82 [95% CI: 0.59-1.14]; p = 0.233) and significantly greater progression-free survival (HR: 0.43 [0.33-0.56]; p

PurposeBased on the efficacy data from the previous study of B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell injection, we further examined the delayed toxicity for 8 weeks after a single dose of BCMA CAR T-cell injection to observe possible toxic reactions.MethodsB-NDG mice transplanted with multiple myeloma (MM) cells were given a single dose of BCMA CAR T-cell injection at two dosages or human normal T cells and then subjected to examinations including clinical signs, weight and food intake measurements, haematology, blood biochemical analysis, cytokine assay, T-lymphocyte subpopulation quantification and histopathology on days 28 and 56 after dosing. In addition, quantitative polymerase chain reaction (qPCR) was used to quantify DNA fragments in different tissues to assess the tissue distribution of CAR and provide a basis for its preclinical safety evaluation and clinical dosing.ResultsIn the delayed toxicity study, no mortality or significant toxic effects such as reductions in food intake, body weight, relevant biochemical parameters and target organ weights were observed in the BCMA CAR T-cell-treated groups. Compared to the model group, restorative changes in clinical signs and clinicopathology indicating therapeutic effects were seen in the BCMA CAR T-cell-treated groups. Human-derived cytokines interleukin-2 (IL-2), IL-4, IL-6, IL-12, IL-10, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ) could be detected in all cancer cell–bearing mice by cytokine level measurement. IFN-γ levels showed a geometric increase due to the graft versus host disease (GVHD) response induced in the mice, while the levels of the other cytokines did not show significant changes. Histopathological examination indicated that the BCMA CAR T-cell treatment groups showed mixed cellular infiltration of human-derived T cells, cancer cells, and inflammatory cells in several target organs including the liver, spleen, lung, and kidney, and some of them showed mild tissue damage, but the number of the animals and the severity of damage were significantly less than those of the T-cell control group as well as the model group. The results of the tissue distribution study showed that BCMA CAR T cells were mainly concentrated in the kidney, lung, bone marrow and the related immune organs/tissues, and the distribution of BCMA CAR T cells was highly consistent with that of MM cells, suggesting that BCMA CAR T cells could follow the cancer cells during metastatic targeting of the tissues.ConclusionsThe present study demonstrated a low toxicity of BCMA CAR T-cell injection, with manageable side effects and good anticancer activity and without observable adverse effects. This study provides data to support future clinical studies of BCMA CAR T-cell injection for MM.

Chimeric antigen receptor T cell (CAR-T) therapies are Food and Drug Administration (FDA)-approved for patients with triple refractory multiple myeloma (MM). Real-world access to CAR-T therapy remains challenging owing to supply chain limitations impacting manufacturing. The goal of this study was to evaluate the extent of this issue and how major centers are handling the challenges of CAR-T manufacturing slot allocation. MM CAR-T physician leaders at each CAR-T treatment center across the United States were surveyed. We received responses from 17 of 20 centers. A median of 1 slot is allocated per month per center, and the median number of patients per center on the waitlist since the FDAs approval of idecabtagene vicleucel is 20 (range, 5 to 100). As a result, patients remain on the waitlist for a median of 6 months (range, 2 to 8 months) prior to leukapheresis. For patient selection, all centers reported using a committee of experienced CAR-T physicians to ensure consistency. To ensure transparency, 15 centers make selection criteria, selection timelines, and priority scores readily available for CAR-T providers. Centers also reported using ethical values for selection: (1) equal treatment: time spent on waiting list (n = 12); (2) priority to the worst-off: limited therapeutic options (n = 14), MM burden (n = 11), high Hematopoietic Cell Transplantation Comorbidity Index (n = 5); (3) maximize benefit: most likely to complete apheresis (n = 13) or infusion (n = 13) or to achieve response (n = 8); and (4) social value: younger patients (n = 3). Maximizing benefit was considered the most important criterion by 10 centers. This study is the first attempt to evaluate existing issues with CAR-T access for patients with MM and the variability and challenges in patient selection. Integrating ethical resource allocation strategies, similar to those described here, into formal institutional policies would help streamline access to CAR-T therapy and protect the needs of both current and future patients and physicians.

Background: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B‐cell maturation antigen‐directed bispecific antibody approved for triple‐class–exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC‐1 study. Methods: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step‐up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2–4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines. Results: At a median follow‐up of 22.8 months (range, 0.3–33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID‐19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty‐one patients died from infections (18 from COVID‐19). Median time to first onset of any‐grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2–19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0–18.1]). Conclusion: Based on the infection profile of B‐cell maturation antigen–targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important. Clinical trial registration: NCT03145181/NCT04557098 (ClinicalTrials.gov) Plain Language Summary: Before starting teclistamab, patients should be up to date with vaccinations (including COVID‐19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections.Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment.Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3–6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia. In the MajesTEC‐1 study of the B‐cell maturation antigen × CD3‐bispecific antibody teclistamab in heavily pretreated patients with relapsed or refractory multiple myeloma, infections occurred in 80.0% of patients overall at a median follow‐up of 22.8 months (range, 0.3–33.6); grade 3/4 infections were reported in 55.2% and infection‐related deaths in 12.7%, with median time to first onset of any‐grade and grade 3–5 infections of 1.7 and 4.2 months, respectively. Close monitoring across a range of infection types, appropriate prophylaxis, and prompt intervention were key in ensuring the manageability of infections, hypogammaglobulinemia, and neutropenia during teclistamab treatment, and will be important from a clinical practice perspective. [ABSTRACT FROM AUTHOR]

To address the dearth of therapeutic options available for relapsed-refractory multiple myeloma (RRMM), attention has shifted to immunotherapeutic strategies, with most products in development targeting the B-cell maturation antigen (BCMA). BCMA is a transmembrane receptor of the tumor necrosis factor receptor superfamily, essential for plasma cell survival and minimally expressed on non-hematopoietic tissues; it represents an ideal therapeutic target. Three categories of BCMA-directed therapies exist, with distinct strengths and weaknesses. Antibody–drug conjugates (ADCs) are immediately available with modest single-agent efficacy in RRMM, but deliverability is hampered by corneal toxicity. CAR T-cells are the most effective class but face significant logistical and financial barriers. Bispecific antibodies offer superior efficacy and tolerability compared to ADCs, but prolonged exposure causes significant cumulative infectious risk. In this review, we will examine the role of BCMA in MM biology, the approved and emerging therapies targeting this antigen, and how these agents can be optimally sequenced. [ABSTRACT FROM AUTHOR]

The past decade has seen the development of immunotherapy for the treatment of multiple myeloma (MM), beginning with monoclonal antibodies (mAbs) in the relapsed and refractory setting and culminating in the market approval of chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs). The medical community is evaluating the efficacy and safety of these targeted immunotherapies, most of which currently target B-cell maturation antigen (BCMA) on the surface of plasma cells. Two anti-BCMA CAR-T products are available for treating relapsed or refractory MM: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Ide-cel and cilta-cel demonstrate the ability to induce deep responses in heavily pretreated diseases, including patients with triple-class-refractory and penta-refractory diseases. However, there are key similarities and differences regarding these agents, unknowns regarding their comparative efficacy and toxicity, and mechanisms underlying resistance to these new immunotherapies. This review discusses CAR-T cell therapy in relapsed refractory MM, with a focus on efficacy, toxicities, and the evolving trajectories of these therapies in the USA, as well as access in Turkey.

Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers but have shown limited efficacy in persistent, recurrent malignancies. Here, we introduce "CAR Pooling," a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with signaling domains derived from a range of immune cell lineages were evaluated in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several domains were identified from the tumor necrosis factor (TNF) receptor family that have been primarily associated with B cells. CD40 enhanced proliferation, whereas B cell-activating factor receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) promoted cytotoxicity. These functions were enhanced relative to clinical benchmarks after prolonged antigen stimulation, and CAR T cell signaling through these domains fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic transcriptional signature previously associated with positive clinical outcomes. We also observed that replacing the 4-1BB intracellular signaling domain with the BAFF-R signaling domain in a clinically validated B cell maturation antigen (BCMA)-specific CAR resulted in enhanced activity in a xenotransplant model of multiple myeloma. Together, these results show that CAR Pooling is a general approach for rapid exploration of CAR architecture and activity to improve the efficacy of CAR T cell therapies.

PurposeABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study.MethodsPatients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion.ResultsAs of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively.ConclusionABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

BackgroundTeclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.MethodsIn this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).ResultsAmong 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).ConclusionsTeclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the rapid proliferation of malignant plasma cells within the bone marrow. Standard therapies often fail due to patient resistance. The US FDA has approved second-generation chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (anti-BCMA-CAR2 T cells) for MM treatment. However, achieving enduring clinical responses remains a challenge in CAR T cell therapy. This study developed third-generation T cells with an anti-BCMA CAR (anti-BCMA-CAR3). The CAR incorporated a fully human scFv specific to BCMA, linked to the CD8 hinge region. The design included the CD28 transmembrane domain, two co-stimulatory domains (CD28 and 4-1BB), and the CD3ζ signaling domain (28BBζ). Lentiviral technology generated these modified T cells, which were compared against anti-BCMA-CAR2 T cells for efficacy against cancer. Anti-BCMA-CAR3 T cells exhibited significantly higher cytotoxic activity against BCMA-expressing cells (KMS-12-PE and NCI-H929) compared to anti-BCMA-CAR2 T cells. At an effector-to-target ratio of 10:1, anti-BCMA-CAR3 T cells induced lysis in 75.5 ± 3.8% of NCI-H929 cells, whereas anti-BCMA-CAR2 T cells achieved 56.7 ± 3.4% (p = 0.0023). Notably, after twelve days of cultivation, anti-BCMA-CAR3 T cells nearly eradicated BCMA-positive cells (4.1 ± 2.1%), while anti-BCMA-CAR2 T cells allowed 36.8 ± 20.1% to survive. This study highlights the superior efficacy of anti-BCMA-CAR3 T cells against both low and high BCMA-expressing MM cells, surpassing anti-BCMA-CAR2 T cells. These findings suggest potential for advancing anti-BCMA-CAR3 T cells in chimeric antigen receptor T (CAR-T) therapy for relapsed/refractory MM. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first‐in‐class, B‐cell maturation antigen‐binding antibody‐drug conjugate, eliminates myeloma cells through direct cell killing and an anti‐myeloma immune response. Methods: DREAMM‐2 (NCT03525678) was a phase 2, two‐arm, open‐label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti‐CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression‐free survival (PFS), overall survival (OS), safety, ocular symptoms, and health‐related quality of life (HRQOL). Results: This final analysis (cutoff date, March 31, 2022), N = 223, with median follow‐up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment. Conclusions: This final analysis of DREAMM‐2 confirms that in patients with triple‐class refractory RRMM, single‐agent belamaf results in durable and clinically meaningful responses with a manageable safety profile. Although much progress has been made in the treatment landscape for patients with relapsed/refractory multiple myeloma (RRMM), outcomes remain poor once the disease becomes refractory to multiple therapies. The results of the final analysis of the DREAMM‐2 trial further establish that treatment with single‐agent belamaf results in clinically meaningful responses with a manageable safety profile in patients with RRMM who had received at least three previous lines of therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy exhibits remarkable efficacy against refractory or relapsed multiple myeloma (RRMM); however, the immune deficiency following CAR-Ts infusion has not been well studied. In this study, 126 patients who achieved remission post-CAR-Ts infusion were evaluated for cellular immunity. Following lymphodepletion (LD) chemotherapy, the absolute lymphocyte count (ALC) and absolute counts of lymphocyte subsets were significantly lower than baseline at D0. Grade ≥ 3 lymphopenia occurred in 99% of patients within the first 30 days, with most being resolved by 180 days. The median CD4+ T-cell count was consistently below baseline and the lower limit of normal (LLN) levels at follow-up. Conversely, the median CD8+ T-cell count returned to the baseline and LLN levels by D30. The median B-cell count remained lower than baseline level at D60 and returned to baseline and LLN levels at D180. In the first 30 days, 27 (21.4%) patients had 29 infections, with the majority being mild to moderate in severity (21/29; 72.4%). After day 30, 44 (34.9%) patients had 56 infections, including 20 severe infections. One patient died from bacteremia at 3.8 months post-CAR-Ts infusion. In conclusion, most patients with RRMM experienced cellular immune deficiency caused by LD chemotherapy and CAR-Ts infusion. The ALC and most lymphocyte subsets gradually recovered after day 30 of CAR-Ts infusion, except for CD4+ T cells. Some patients experience prolonged CD4+ T-cell immunosuppression without severe infection. [ABSTRACT FROM AUTHOR]

B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy (BCMA CAR-T) is an effective treatment of relapsed refractory multiple myeloma (MM). However, the pattern of infectious complications is not well elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1 year after BCMA CAR-T for MM from 2018 to 2020. Fifty-five patients with MM were treated with BCMA CAR-T. Before lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) before LD. In the first month after CAR-T, 98% patients had grade 3 to 4 neutropenia. At 1 year after infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% confidence interval, 4.7-7.4), there were a total of 47 infection events in 29 (53%) patients: 40% bacterial, 53% viral, and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of the infections (53%) occurred in the first 100 days after CAR-T infusion. Although no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post-CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess infectious complications after BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

BACKGROUND: On the basis of the DREAMM-2 study (ClinicalTrials.gov identifier NCT03525678), single-agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti-CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM-2 after 13 months of follow-up among patients who received belamaf 2.5 mg/kg. METHODS: DREAMM-2 is an ongoing, phase 2, open-label, 2-arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti-CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee. RESULTS: As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty-one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%-43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression-free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6-3.6 months), respectively. Response and survival outcomes in patients who had high-risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow-up. CONCLUSIONS: Extended follow-up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.

IntroductionChimeric antigen receptor T-cell therapy (CART) has revolutionised treatment of haematological malignancies; however, current reporting uses a modified intention-to-treat analysis (mITT) which over-estimates efficacy. We assessed what proportion of CD19 and B-cell maturation antigen (BCMA) CART trials report the number of patients not receiving CART after being enrolled by performing meta-analysis of the mITT and intention-to-treat (iTT) overall response rate (ORR).MethodsPubMed/MEDLINE, EMBASE and Cochrane databases were searched. All prospective clinical trials of CD19 and BCMA-targeting CART enrolling two or greater patients from 1st January 2013 to 1st November 2020 were included.ResultsA total of 28 BCMA CART and 74 CD19 CART trials were identified. These included 10 BCMA CART (35.7%) and 52 (70.2%) CD19 CART trials reporting total number of patients enrolled and number of patients treated with CART. For this cohort of trials, the mITT ORR for BCMA CART was 78.0% (95% confidence interval (CI) = 67.0-89.0%), and the iTT ORR was 70.0% (95% CI = 59.0-80.0%). For CD19 leukaemia CART, the mITT ORR was 87.2% (95% CI = 83.1-91.2), and the iTT ORR was 74.9 (95% CI = 64.8-85.0). For CD19 lymphoma CART, the mITT ORR was 70.7% (95% CI = 63.9-77.5), and the iTT ORR was 58.7% (95% CI = 49.7-67.7).ConclusionAcross BCMA and CD19 CART trials, there is a difference of up to 8-12% in the ORR between modified and iTT analyses and a paucity of information regarding reasons why patients did not receive the intended study treatment.

UNLABELLED: Despite many recent advances in therapy, there is still no plateau in overall survival curves in multiple myeloma. Bispecific antibodies are a novel immunotherapeutic approach designed to bind antigens on malignant plasma cells and cytotoxic immune effector cells. Early-phase clinical trials targeting B-cell maturation antigen (BCMA), GPRC5D, and FcRH5 have demonstrated a favorable safety profile, with mainly low-grade cytokine release syndrome, cytopenias, and infections. Although dose escalation is ongoing in several studies, early efficacy data show response rates in the most active dose cohorts between 61% and 83% with many deep responses; however, durability remains to be established. Further clinical trial data are eagerly anticipated. SIGNIFICANCE: Overall survival of triple-class refractory multiple myeloma remains poor. Bispecific antibodies are a novel immunotherapeutic modality with a favorable safety profile and impressive preliminary efficacy in heavily treated patients. Although more data are needed, bispecifics will likely become an integral part of the multiple myeloma treatment paradigm in the near future. Studies in earlier lines of therapy and in combination with other active anti-multiple myeloma agents will help further define the role of bispecifics in multiple myeloma.

A systematic review of published articles based on randomized clinical trials was conducted to ascertain the efficacy or perspective of using CAR-T cell therapy for refractory multiple myeloma. The PubMed database was searched with the combination of terms "multiple myeloma", "refractory multiple myeloma", "CAR T-cell", and the PRISMA criteria were followed. Of the 78 articles found, only 5 were selected. The studies used different treatment protocols and four different types of CAR-T cells. All studies obtained interesting results in terms of increased progression-free survival and negative minimal residual disease responses. Some authors detected an expansion of CAR-T cells and noted dose-dependent relationship between treatment effectiveness and serum BCMA levels. Although the results were promising, a small number of patients still relapsed a few months after CAR-T cell infusion. Therefore, this new line of therapy should be further investigated, as it significantly increases progression-free survival and improves quality of life.

IntroductionPatients with relapsed or refractory multiple myeloma (RRMM) are likely to be living with persistent symptoms, especially bone pain and fatigue, and experiencing restrictions in their physical and social functioning, which reduce health-related quality of life.MethodsThis qualitative interview study evaluated patients’ perspectives about living with RRMM and their treatment with belantamab mafodotin, using interviews embedded in the Phase II DREAMM-2 trial (NCT03525678) with belantamab mafodotin. Patients consented to participate in up to 2 recorded telephone interviews (at treatment cycle 4 [C4] and at end of treatment [EOT]) comprising open-ended questions.ResultsA total of 142 interviews were conducted with 111 unique patients. At C4, common symptoms included neuropathy, fatigue, and bone or joint pain. Improvements in symptom severity were reported by patients who responded to belantamab mafodotin. Symptoms associated with visual impairment, eye irritation, and eye pain reported during the trial were reported to be at- or near-resolution by the EOT interview. Regarding impacts of underlying MM, patients most commonly expressed concerns about changes in daily performance and lifestyle for both responders (67.5% of all impact expressions) and non-responders (63.2%). Overall, interview participants reported being satisfied with belantamab mafodotin treatment.DiscussionThis qualitative patient interview study provides valuable insight into patients’ symptomatic experience with belantamab mafodotin for their RRMM treatment and may help healthcare providers better anticipate their patients’ real-world experience and needs when prescribing this novel agent in the clinic.

Belantamab mafodotin, a B-cell maturation antigen-targeting antibody–drug conjugate (ADC), was investigated in Japanese patients with relapsed/refractory multiple myeloma in Part 1 of the phase I DREAMM-11 study. Patients who had received ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory agent were eligible. Eight patients received belantamab mafodotin monotherapy at 2.5 mg/kg (n = 4) or 3.4 mg/kg (n = 4) by intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. Primary objectives were tolerability and safety, and secondary objectives included pharmacokinetics (PK) and efficacy. The most common Grade ≥ 3 adverse event was thrombocytopenia/platelet count decreased (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]), and no dose-limiting toxicities were observed. Ocular events, including keratopathy findings, were observed in most patients (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]) and were managed with dose modifications. All resolved within the study period. Overall response rates were 50% (2/4) in the 2.5 mg/kg cohort and 25% (1/4) in the 3.4 mg/kg cohort. Although PK profiles in Japanese patients varied, individual exposures overlapped with previous results in Western populations. Belantamab mafodotin monotherapy was generally well-tolerated and demonstrated clinical activity at both doses. [ABSTRACT FROM AUTHOR]

Cilta-cel, a BCMA-targeting chimeric antigen receptor T-cell therapy for multiple myeloma, was approved in USA on 28 February 2022, for patients with relapsed or refractory disease who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Approval in the EU followed for patients with ≥3 prior therapies. At median 28-month follow-up, the pivotal CARTITUDE-1 trial showed a 98% response rate (83% stringent complete response); median progression-free survival had not been reached, and adverse events could be managed with supportive therapy. Cilta-cel efficacy and safety in earlier lines of therapy, and its optimal sequencing in a complex treatment landscape are important areas of investigation. [ABSTRACT FROM AUTHOR]

Background: Teclistamab, a B‐cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC‐1 study. Cytokine release syndrome (CRS), a known manifestation of T‐cell redirection, was observed in 119 of 165 patients (72.1%). Methods: Patients received once‐weekly teclistamab 1.5 mg/kg subcutaneously after two step‐up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. Results: Most cases of CRS occurred during the step‐up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. Conclusions: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T‐cell–engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. Plain language summary: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC‐1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation.Most CRS occurred during the step‐up schedule, requiring vigilance during treatment initiation.Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step‐up schedule or administering the next teclistamab dose, to avoid exacerbating CRS.Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab.No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity. In the MajesTEC‐1 study of the B‐cell maturation antigen × CD3 bispecific antibody teclistamab, cytokine release syndrome (CRS) occurred in 72.1% of heavily pretreated patients with relapsed or refractory multiple myeloma. Most cases of CRS occurred during the step‐up dosing schedule of teclistamab and were grade 1 or 2 and manageable; tocilizumab reduced the incidence of subsequent CRS in patients who received it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. [ABSTRACT FROM AUTHOR]

Relapsed/refractory multiple myeloma remains a challenging disease necessitating the development of more effective treatment options. In the past decade, myeloma therapies have made significant advancements with the introduction of new treatment modalities. One of the new major targets for these novel therapeutics has been B-cell maturation antigen (BCMA), which is expressed on mature B-lymphocytes and plasma cells. There are three main categories of BCMA-targeted therapies currently available, including bispecific antibodies (BsAbs), antibody drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies. In this review, we discuss the existing BCMA-targeted therapies and provide insights into currently available treatment and future developments, with a particular focus on clinical efficacy and common drug-related adverse events. [ABSTRACT FROM AUTHOR]

Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference- and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell surface expression of the multiple myeloma immunotherapy antigen B-cell maturation antigen (BCMA). We discovered that pharmacologic inhibition of HDAC7 and the Sec61 complex increased cell surface BCMA, including in primary patient cells. Pharmacologic Sec61 inhibition enhanced the antimyeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference chimeric antigen receptor T cells (CAR-T cells) coculture screen enabled us to identify both antigen-dependent and antigen-independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study shows the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti-PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

The purpose of these studies was to develop and characterize B-cell maturation antigen (BCMA)-specific peptide-encapsulated nanoparticle formulations to efficiently evoke BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) with poly-functional immune activities against multiple myeloma (MM). Heteroclitic BCMA72-80 [YLMFLLRKI] peptide-encapsulated liposome or poly(lactic-co-glycolic acid) (PLGA) nanoparticles displayed uniform size distribution and increased peptide delivery to human dendritic cells, which enhanced induction of BCMA-specific CTL. Distinct from liposome-based nanoparticles, PLGA-based nanoparticles demonstrated a gradual increase in peptide uptake by antigen-presenting cells, and induced BCMA-specific CTL with higher anti-tumor activities (CD107a degranulation, CTL proliferation, and IFN-γ/IL-2/TNF-α production) against primary CD138+ tumor cells and MM cell lines. The improved functional activities were associated with increased Tetramer+/CD45RO+ memory CTL, CD28 upregulation on Tetramer+ CTL, and longer maintenance of central memory (CCR7+ CD45RO+) CTL, with the highest anti-MM activity and less differentiation into effector memory (CCR7- CD45RO+) CTL. These results provide the framework for therapeutic application of PLGA-based BCMA immunogenic peptide delivery system, rather than free peptide, to enhance the induction of BCMA-specific CTL with poly-functional Th1-specific anti-MM activities. These results demonstrate the potential clinical utility of PLGA nanotechnology-based cancer vaccine to enhance BCMA-targeted immunotherapy against myeloma.

Background aims: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS. Methods: Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed. Results: Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. Themedian time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-g [IFN-g], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5-8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3-10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CART cell expansion, and corticosteroid use. Conclusion: TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk. [ABSTRACT FROM AUTHOR]

Summary: The delivery of bispecific antibodies (BsAbs) targeting B‐cell maturation antigen (BCMA) and CD3 using the gene therapy approach is a promising alternative for BsAb administration in patients with multiple myeloma (MM). In the present study, we evaluated the efficacy of this approach using a xenograft model. Tumour growth was significantly delayed in mice treated with single electroporation‐enhanced intramuscular injection of plasmid DNA encoding BCMA/CD3 BsAb in contrast to the vehicle control‐treated group. Limited toxicity was observed following treatment. This study demonstrates that the gene therapy‐based approach for the delivery of BCMA/CD3 BsAb is effective and safe for the treatment of MM. [ABSTRACT FROM AUTHOR]

Aim: We compared the effectiveness of teclistamab versus real-world physician’s choice of therapy (RWPC) in triple-class exposed relapsed/refractory multiple myeloma. Materials & methods: MajesTEC- 1 eligibility criteria were applied to the RWPC cohort. Baseline covariate imbalances were adjusted using inverse probability of treatment weighting. Overall survival, progression-free survival and time to next treatment were compared. Results: After inverse probability of treatment weighting, baseline characteristics were similar between cohorts (teclistamab, n = 165; RWPC, n = 364 [766 observations]). Teclistamab treated patients had numerically better overall survival (hazard ratio [HR]: 0.82 [95% CI: 0.59– 1.14]; p = 0.233) and significantly greater progression-free survival (HR: 0.43 [0.33–0.56]; p < 0.0001) and time to next treatment (HR: 0.36 [0.27–0.49]; p < 0.0001) versus the RWPC cohort. Conclusion: Teclistamab offered clinical benefit over RWPC in triple-class exposed relapsed/refractory multiple myeloma.

Chimeric antigen receptor (CAR) T cells targeting B‐cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE‐1 study of ciltacabtagene autoleucel (cilta‐cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2), patients received a single cilta‐cel infusion at a target dose of 0.75 × 106 (range, 0.5–1.0 × 106CAR‐positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta‐cel. Thirteen patients underwent apheresis, nine of whom received cilta‐cel infusion. Eight patients who received cilta‐cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below‐target dose of cilta‐cel also achieved a best response of VGPR. MRD negativity (10−5 threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta‐cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR‐T cell neurotoxicity was reported. A positive benefit/risk profile for cilta‐cel was established for heavily pretreated Japanese patients with relapsed or refractory MM. [ABSTRACT FROM AUTHOR]

BLyS and APRIL have the capability to bind to B cells within the body, allowing these cells to evade elimination when they should naturally be removed. While BLyS primarily plays a role in B cell development and maturation, APRIL is linked to B cell activation and the secretion of antibodies. Thus, in theory, inhibiting BLyS or APRIL could diminish the population of aberrant B cells that contribute to SLE and reduce disease activity in patients. Telitacicept functions by binding to and neutralizing the activities of both BLyS and APRIL, thus hindering the maturation and survival of plasma cells and fully developed B cells. The design of telitacicept is distinctive; it is not a monoclonal antibody but a TACI-Fc fusion protein generated through recombinant DNA technology. This fusion involves merging gene segments of the TACI protein, which can target BLyS/APRIL simultaneously, with the Fc gene segment of the human IgG protein. The TACI-Fc fusion protein exhibits the combined characteristics of both proteins. Currently utilized for autoimmune disease treatment, telitacicept is undergoing clinical investigations globally to assess its efficacy in managing various autoimmune conditions. This review consolidates information on the mechanistic actions, dosing regimens, pharmacokinetics, efficacy, and safety profile of telitacicept—a dual-targeted biological agent. It integrates findings from prior experiments and pharmacokinetic analyses in the treatment of RA and SLE, striving to offer a comprehensive overview of telitacicept's research advancements. [Display omitted] • Summarized the mechanism and pharmacokinetics of Telitacicept in the treatment of autoimmune diseases. • Summarized the efficacy and safety data of Telitacicept in the treatment of autoimmune diseases. • More attention are needed to the improvement effect of Telitacicept on the involvement of various organ systems. [ABSTRACT FROM AUTHOR]

Abstract B cell maturation antigen (BCMA), a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17), highly expressed on the plasma cells of Multiple myeloma (MM) patients, as well as the normal population. BCMA is used as a biomarker for MM. Two members of the TNF superfamily proteins, including B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), are closely related to BCMA and play an important role in plasma cell survival and progression of MM. Despite the maximum specificity of the monoclonal antibody technologies, introducing the tumor-specific antigen(s) is not applicable for all malignancies, such as MM that there plenty of relatively specific antigens such as GPCR5D, MUC1, SLAMF7 and etc., but higher expression of BCMA on these cells in comparison with normal ones can be regarded as a relatively exclusive marker. Currently, different monoclonal antibody (mAb) technologies applied in anti-MM therapies such as daratuzumab, SAR650984, GSK2857916, and CAR-T cell therapies are some of these tools that are reviewed in the present manuscript. By the way, the structure, function, and signaling of the BCMA and related molecule(s) role in normal plasma cells and MM development, evaluated as well as the potential side effects of its targeting by different CAR-T cells generations. In conclusion, BCMA can be regarded as an ideal molecule to be targeted in immunotherapeutic methods, regarding lower potential systemic and local side effects.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a malignancy of mature appearing clonal B lymphocytes where there is a progressive accumulation of leukemic cells in peripheral blood, bone marrow, and secondary lymphoid tissues as a consequence of defective apoptosis and survival signals derived from the microenvironment. The soluble CD23 (sCD23) is a 25 kDa fragment that can be found in serum, plasma, and urine in patients with CLL. It is a B-cell growth factor. B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor superfamily, it enhances the survival and proliferation of mature B cells and plasma cells through signal transduction of the B-cell activating factor and a proliferation-inducing ligand. AIMS: The aims of this study were to assess the serum levels of sCD23 and BCMA in newly diagnosed CLL patients and to correlate them with clinical Binet staging and other hematological and clinical parameters. PATIENTS, MATERIALS AND METHODS: This study was conducted on 54 newly diagnosed CLL patients and 27 healthy controls. Diagnosis of CLL patients was based on lymphocyte count of >5 × 109/L and immunophenotyping. The serum levels of sCD23 and BCMA were measured in both groups using an enzyme-linked immunosorbent assay. RESULTS: Serum levels of sCD23 and BCMA were significantly higher in CLL patients in comparison with control group (P < 0.001 for both). There was a significant direct association between serum levels of sCD23 and BCMA with the clinical Binet stage of the disease (P < 0.001 for both). sCD23 showed significant correlation with hemoglobin (Hb) level (P < 0.001), total white blood cell (WBC) count (P = 0.001), lymphocyte count (P < 0.001), platelet count (P = 0.017), B-symptoms (P = 0.001), and splenomegaly (P = 0.019), whereas BCMA has significant correlations with Hb level, total WBC count, lymphocyte count (P < 0.001 for each one), B-symptoms (P < 0.001), lymphadenopathy (P = 0.001), splenomegaly (P = 0.024), and hepatomegaly (P = 0.04). CONCLUSIONS: The levels of serum sCD23 and serum BCMA increase with advancing Binet stages of the disease indicating their possible usefulness as good and reliable parameters for prognostic evaluation in CLL patients. The significant correlation of serum sCD23 and serum BCMA with hematological parameters and clinical features render them as reliable tumor burden markers in CLL patients.

Summary: Belantamab mafodotin (BLMF) is a B‐cell maturation antigen‐directed antibody‐drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF‐induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity‐related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2–not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent. [ABSTRACT FROM AUTHOR]

Belantamab mafodotin (BLMF) is an interesting therapeutic alternative for multiple myeloma (MM) patients pretreated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Scientific evidence on BLMF provides immature data about progression-free survival and overall survival by short follow-up of patients with poor prognoses. Cases with long follow-ups could provide additional information about BLMF. This case reports a patient with MM treated with BLMF who had received nine previous lines of therapy with a follow-up of 11 months. No complete response was obtained. However, no disease progression was observed and the patient was still alive at the end of this work. BLMF showed manageable adverse effects. Our patient presented advanced disease, good functional status at the beginning of BLMF treatment, and elevated levels of lactate dehydrogenase during BLMF therapy. The influence of these last two factors was not evaluated in clinical trials. This relationship should be assessed more deeply in future studies. [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]

Chimeric antigen receptor (CAR)-T cells are a new treatment modality in various hematological malignancies, including relapsed/refractory multiple myeloma (RRMM). RRMM patients have a poor prognosis, and their treatment options are limited. Currently available data from clinical trials on CAR-T cell therapy have demonstrated efficacy and manageable toxicity in RRMM. The CAR-T cells in RRMM mostly focus on already known cellular targets, such as B-cell maturation antigen (BCMA). CAR-T cells focusing on other targets have been analyzed in various clinical trials as well. Cytokine release syndrome (CRS), specific neurotoxicity, and hematological toxicity are the main adverse events (AE); according to the clinical trials, they are mostly mild with a low incidence of grade 3 or higher toxicities. The autologous CAR-T cell therapy against BCMA (ide-cel and cilta-cel) shows the best efficacy with an overall response rate and a median progression-free survival in RRMM. Both ide-cel and cilta-cel have already been approved by the FDA. Currently, the main controversies in the routine use of CAR-T cells are high treatment costs and unknown long-term efficacy. In this review, we summarize the current overview of CAR-T cell therapies in RRMM in 2021 with various targets for CAR-T cells and their efficacy, safety, and possible limitations. Future prospective clinical trials are needed to clarify the optimal role of CAR-T cells in MM therapy. [ABSTRACT FROM AUTHOR]

Despite the success of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory multiple myeloma (RRMM), failure after CAR T-cell therapy remains an unmet medical need. An effective consolidation therapy after CAR T-cell therapy may improve the prognosis of RRMM. To investigate the effects of consolidation therapy with autologous hematopoietic stem cell transplantation (AHCT) after B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy on the prognosis of RRMM patients. This retrospective study included 39 RRMM patients who received BCMA-targeted CAR T-cell therapy. Basic clinical, therapy, and outcome data were collected, and factors associated with survival were analyzed. Among the 39 RRMM patients included in the study, 15 had high-risk cytogenetics and 11 had extramedullary disease (EMD). All 39 patients reached peak CAR T-cell expansion within 28 days after infusion. Twenty-six patients developed cytokine release syndrome, including 12 grade 1 and 14 grade 2 cases. Survival analysis revealed that high-risk cytogenetics, high tumor load (International Staging System [ISS] stage III), and EMD were negatively associated with progression-free survival (PFS) and overall survival (OS). Thirteen patients received consolidation AHCT therapy 50-276 days after CAR T-cell therapy, with a median interval of 92 days. No serious complications occurred after consolidation AHCT. Survival analysis showed that consolidation AHCT effectively improved OS and PFS over maintenance chemotherapy. Moreover, Cox regression analysis identified low tumor load (ISS stage I/II) and consolidation AHCT as independent predictors of superior PFS and OS and high-risk cytogenetics as an independent risk factor for poor PFS. Consolidation AHCT after CAR T-cell therapy in RRMM patients can improve patient survival., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM), a cancer of plasma cells, remains difficult to treat due to its incurability and high recurrence rates. Recent advancements in immunotherapies, such as CAR T cells, bispecific antibodies, and bispecific T cell engagers (BITEs) targeting B-cell maturation antigen (BCMA), have improved treatment options for relapsed and refractory MM (RRMM). However, these therapies face challenges, including complex manufacturing, high cost, and severe side effects. In this study, we developed a stable cell line that produces anti-BCMA × anti-CD3 BITEs and generated BITE-armed T cells (BATs) as a novel MM treatment approach. These αBCMA × αCD3 BATs specifically targeted BCMA-expressing cells, promoting T cell activation, proliferation, and cytotoxicity. BATs demonstrated superior cytotoxicity compared to unarmed T cells, likely due to enhanced antigen specificity and targeting efficiency, even at low effector-to-target ratios. The antitumor activity of BATs against BCMA-expressing cells was antigen-specific and dose-dependent. BATs also triggered T cell expansion and significant cytokine release (IL-2, TNF-α, IFN-γ) without increasing IL-6, suggesting a lower risk of cytokine release syndrome (CRS). Our findings indicate that BCMA-targeting BATs offer a promising and accessible therapeutic strategy for MM, with a simple, rapid, and cost-effective production process. These results support future development of BITE-armed T cells as a novel cancer treatment to enhance therapeutic outcomes for MM patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All experiments were conducted at the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. The authors declare that the research was carried out without any commercial or financial relationships that could have influenced the reported findings., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)