[Clinical analysis of the correlation between the expression of soluble B cell maturation antigen and the efficacy of chimeric antigen receptor T cell targeting B cell maturation antigen in patients with multiple myeloma].

Objective: The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified T-cell-targeting B cell maturation antigen (BCMA) in patients with multiple myeloma (MM) . Methods: This study involved 29 patients with relapsed or refractory MM (RRMM) who received humanized anti-BCMA CAR-T cell clinical trials from January 2018 to December 2021. The expression of sBCMA in bone marrow before and after anti-BCMA CAR-T cell treatment was detected by flow cytometry and compared. Results: ①Two months after BCMA CAR-T cell treatment, 20 patients (68.97%) achieved an overall response (OR), whereas nine patients had stable disease (SD) or miner emission (MR). ②The expression of sBCMA in the bone marrow of 20 patients with OR was higher before treatment than after [26 926 (18 215, 32 488) ng/L vs 9 968 (6 634, 11 459) ng/L; P<0.001]; no significant difference was observed in patients with MR and SD [41 187 (33 816, 47 046) ng/L vs. 33 954 (31 569, 36 256) ng/L; P=0.145]; sBCMA expression in patients with OR before CAR-T cell treatment was lower than in patients with MR and SD (P=0.005). ③No significant linear correlation was found between the peak value of CAR-T cells and sBCMA expression in the bone marrow of all 29 patients with RRMM (R(2)=0.035, P=0.330). ④No significant difference in sBCMA expression was found between grades 0-1 CRS group (13 patients) and grades 2-4 CRS group [16 patients; 32 045 (18 742, 40 801) ng/L vs 29 102 (24 679, 38 776) ng/L, P=0.879], nor between grade 0 ICANS group (22 patients) and grade 1-3 ICANS group [seven patients; 30 073 (19 375, 40 065) ng/L vs 33 816 (22 933, 43 459) ng/L, P=0.763]. Conclusion: sBCMA expression in the bone marrow is related to the efficacy of BCMA CAR-T cell therapy in patients with RRMM, but is not significantly correlated with the severity of adverse events. It may serve as a predictive biomarker for the efficacy of BCMA CAR-T cell therapy in these patients.

Multiple Myeloma: A Personal Account of My Journey With the Disease and Response to Teclistamab.

Multiple myeloma (MM) remains an incurable hematologic cancer leading to damage to the bone marrow that causes destructive bone lesions in addition to many other effects. I am a patient with MM who has undergone treatment to date since the diagnosis of this disease in December 2019. This paper reviews the treatments and observations made throughout this period. The salient results of such treatments are discussed in chronological order. During this period, my MM relapsed and then I was introduced to teclistamab treatment. The outcome of teclistamab treatment is quite promising, and I anticipate a longer life at a maintenance dose of this drug with a better quality of life. When writing this article, I am still receiving the teclistamab treatment cycles that maintain a constant normal level of my kappa-free light chain (FLC) and kappa/lambda ratio, with no significant side effects.

Anti-BCMA CAR-T cell-based therapies and bispecific antibodies in the immunotherapy era: are we ready for this?

INTRODUCTION: Therapeutic strategies against multiple myeloma (MM) have evolved dramatically in recent decades, with unprecedent results in the treatment landscape, culminating in the recent incorporation of novel agents in the anti-myeloma armamentarium. AREAS COVERED: BCMA represents one of the most promising targets in MM and currently available immune approaches, either approved or under active investigation, are clearly showing their greater potential over standard regimens. In this context, immunotherapies based on chimeric antigen receptor (CAR)-engineered T-cells and bispecific antibodies (BsAbs) have taken center stage, being the ones that are yielding the most promising results in clinical trials. This review focuses on the current landscape of BsAbs and CAR-T, summarizing the latest advances and possible future developments. EXPERT OPINION: CAR-T and BsAbs anti-BCMA strategies represent breakthrough therapies against MM. However, their inclusion in clinical practice is almost feared, due to the associated limitations, some of which have been addressed here. Meanwhile, all the efforts should be focused on individualizing and choosing the most suitable candidates for each treatment and to understand how to combine, or sequence, these therapies to improve efficacy and minimize toxicity, especially for those patients with limited available treatment options.

Elranatamab in Japanese patients with relapsed/refractory multiple myeloma: results from MagnetisMM-2 and MagnetisMM-3.

BACKGROUND: Despite advances, most patients with multiple myeloma (MM) experience relapse and repeat multiple treatment lines, highlighting an unmet need for patients with relapsed or refractory MM (RRMM). Bispecific antibodies are a new option, but their efficacy and safety in Japanese patients are unknown. METHODS: This was an analysis of Japanese patients receiving elranatamab monotherapy in MagnetisMM-2 (NCT04798586) and MagnetisMM-3 (NCT04649359). Both studies evaluated a priming dose regimen of elranatamab followed by weekly subcutaneous doses, in patients with disease progression while receiving or who were intolerant to ≥3 prior therapies (≥1 proteasome inhibitor, ≥1 immunomodulatory drug and ≥1 anti-CD38 monoclonal antibody). The primary endpoints were dose limiting toxicities (DLTs) in MagnetisMM-2 and confirmed objective response rate (ORR) in MagnetisMM-3. In both, key secondary endpoints included safety, tolerability, duration of response, time to response, progression-free survival and overall survival. RESULTS: In MagnetisMM-2 (N = 4) and MagnetisMM-3 (n = 12), median ages were 68.5 and 66.5 years, respectively. No DLTs were observed in MagnetisMM-2. ORRs were 50.0% (95% CI, 6.8-93.2) and 58.3% (95% CI, 27.7-84.8) in MagnetisMM-2 and MagnetisMM-3, respectively. All patients experienced treatment-emergent adverse events in MagnetisMM-2 (grade 3/4: 75.0%) and MagnetisMM-3 (grade 3/4: 100%); cytokine release syndrome occurred in 100% (grade 3/4: 25.0%) and 58.3% (no grade 3/4) of patients, respectively. Neither study reported immune effector cell-associated neurotoxicity syndrome. CONCLUSIONS: No new safety signals were observed, and ORRs were similar to that of the overall MagnetisMM-3 trial population, supporting further studies of elranatamab in Japanese patients with RRMM. ClinicalTrials.gov identifier: NCT04798586 (MagnetisMM-2), NCT04649359 (MagnetisMM-3).

Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Complex association of body mass index and outcomes in patients with relapsed and refractory multiple myeloma treated with CAR-T cell immunotherapy.

BACKGROUND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

Therapeutic potential of third-generation chimeric antigen receptor T cells targeting B cell maturation antigen for treating multiple myeloma.

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.

BCMA-directed therapy, new treatments in the myeloma toolbox, and how to use them.

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.

Elranatamab efficacy in MagnetisMM-3 compared with real-world control arms in triple-class refractory multiple myeloma.

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).

The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma.

INTRODUCTION: Despite remarkable therapeutic advances over the last two decades, which have resulted in dramatic improvements in patient survival, multiple myeloma (MM) is still considered an incurable disease. Therefore, there is a high need for new treatment strategies. Genetically engineered/redirected chimeric antigen receptor (CAR) T cells may represent the most compelling modality of immunotherapy for cancer treatment in general, and MM in particular. Indeed, unprecedented response rates have led to the recent approvals of the first two BCMA-targeted CAR T cell products idecabtagene-vicleucel ('Ide-cel') and ciltacabtagene-autoleucel ('Cilta-Cel') for the treatment of heavily pretreated MM patients. In addition, both are emerging as a new standard-of-care also in earlier lines of therapy. AREAS COVERED: This article briefly reviews the history of the preclinical development of CAR T cells, with a particular focus on Cilta-cel. Moreover, it summarizes the newest clinical data on Cilta-cel and discusses strategies to further improve its activity and reduce its toxicity. EXPERT OPINION: Modern next-generation immunotherapy is continuously transforming the MM treatment landscape. Despite several caveats of CAR T cell therapy, including its toxicity, costs, and limited access, prolonged disease-free survival and potential cure of MM are finally within reach.

B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis.

B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.

In Vitro Functionality and Endurance of GMP-Compliant Point-of-Care BCMA.CAR-T Cells at Different Timepoints of Cryopreservation.

The search for target antigens for CAR-T cell therapy against multiple myeloma defined the B-cell maturation antigen (BCMA) as an interesting candidate. Several studies with BCMA-directed CAR-T cell therapy showed promising results. Second-generation point-of-care BCMA.CAR-T cells were manufactured to be of a GMP (good manufacturing practice) standard using the CliniMACS Prodigy® device. Cytokine release in BCMA.CAR-T cells after stimulation with BCMA positive versus negative myeloma cell lines, U266/HL60, was assessed via intracellular staining and flow cytometry. The short-term cytotoxic potency of CAR-T cells was evaluated by chromium-51 release, while the long-term potency used co-culture (3 days/round) at effector/target cell ratios of 1:1 and 1:4. To evaluate the activation and exhaustion of CAR-T cells, exhaustion markers were assessed via flow cytometry. Stability was tested through a comparison of these evaluations at different timepoints: d0 as well as d + 14, d + 90 and d + 365 of cryopreservation. As results, (1) Killing efficiency of U266 cells correlated with the dose of CAR-T cells in a classical 4 h chromium-release assay. There was no significant difference after cryopreservation on different timepoints. (2) In terms of endurance of BCMA.CAR-T cell function, BCMA.CAR-T cells kept their ability to kill all tumor cells over six rounds of co-culture. (3) BCMA.CAR-T cells released high amounts of cytokines upon stimulation with tumor cells. There was no significant difference in cytokine release after cryopreservation. According to the results, BCMA.CAR-T cells manufactured under GMP conditions exerted robust and specific killing of target tumor cells with a high release of cytokines. Even after 1 year of cryopreservation, cytotoxic functions were maintained at the same level. This gives clinicians sufficient time to adjust the timepoint of BCMA.CAR-T cell application to the patient's course of the underlying disease.

Use of CAR-T cells for the treatment of relapsed and refractory multiple myeloma: a systematic review / Uso de células CAR-T no tratamento de mieloma múltiplo recidivado e refratário: uma revisão sistemática

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.

Uma revisão sistemática de artigos publicados com base em ensaios clínicos randomizados foi realizada para verificar a eficácia ou perspectiva do uso da terapia com células CAR-T para mieloma múltiplo refratário. Foi pesquisada a base de dados PubMed com a combinação dos termos "multiple myeloma", "refratory multiple myeloma", "CAR T-cell" e foram seguidos os critérios PRISMA. Dos 78 artigos encontrados, apenas 5 foram selecionados. Os estudos utilizaram diferentes protocolos de tratamento e quatro tipos diferentes de células CAR-T. Todos os estudos obtiveram resultados interessantes em termos de aumento da sobrevida livre de progressão e respostas negativas à doença residual mínima. Alguns autores detectaram uma expansão das células CAR-T e observaram uma relação dose-dependente entre a eficácia do tratamento e os níveis séricos de BCMA. Embora os resultados tenham sido promissores, um pequeno número de pacientes ainda apresentou recaída alguns meses após a infusão de células CAR-T. Portanto, esta nova linha de terapia deve ser mais investigada, pois aumenta significativamente a sobrevida livre de progressão e melhora a qualidade de vida.

Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Analytical assessment and validation of the ProteinSimple ELLA serum B-cell maturation antigen assay.

Objectives: Soluble B-Cell Maturation Antigen (sBCMA) is a degradation product of plasma cell-bound BCMA found in serum. Serum sBCMA concentrations correlate with bone marrow plasma cellularity, making it an attractive biomarker for monitoring plasma cell disorders, such as multiple myeloma. Here we evaluated the automated BCMA immunoassay for the ProteinSimple ELLA, for the analysis of sBCMA. Design & methods: Inter and intra-run precision was assessed through replicate sBCMA measurements at 3 different concentration levels. Linearity was determined through serial dilution of a high sBMCA patient sample. Accuracy was assessed through split specimen analysis on two separate lots of reagents. Stability was assessed at 3 temperature levels over 14 days. Cross-reactivity was assessed on BCMA targeting and non-targeting chemotherapeutics. A reference range was established through the analysis of 146 healthy donor samples. The effect of endogenous interferents was assessed through spiking and recovery studies. Results: Inter and intra-run precision studies afforded CVs of <10% at all three concentration levels. Analytical measurement range was confirmed from 0.1 to 7 ng/mL. Accuracy studies afforded a slope of 0.976, intercept of 1.22, R2 of 0.996. Assayed sBCMA values were unaffected by endogenous interferents and non-BMCA targeting antibodies. BCMA targeting therapeutics negatively affected assayed sBCMA concentrations. The reference range was established at 19-58 ng/mL sBCMA is analytically stable. Conclusions: The ProteinSimple ELLA sBCMA assay shows acceptable performance for the clinical assessment of sBCMA. The assay was highly affected by BCMA targeting therapeutics, thereby patients undergoing this therapy should not have their sBCMA levels assessed by this method.

CAR NK92 Cells Targeting BCMA Can Effectively Kill Multiple Myeloma Cells Both In Vitro and In Vivo.

Multiple myeloma (MM) is a hematological malignancy caused by malignant proliferation of plasma cells in bone marrow. Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents. However, MM remains an incurable neoplastic plasma cell disorder. In addition, almost all MM patients inevitably relapse due to drug resistance. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. In this study, NK92 cells were engineered to express the third generation of BCMA CAR. In vitro, BCMA CAR-engineered NK92 cells displayed higher cytotoxicity and produced more cytokines such as IFN-γ and granzyme B than NK92 cells when they were co-cultured with MM cell lines. Furthermore, BCMA CAR-engineered NK92 cells released significantly higher amounts of cytokines and showed higher cytotoxicity when they were exposed to primary cells isolated from MM patients. The cytotoxicity of BCMA CAR NK92 cells was enhanced after MM cells were treated with bortezomib. Additionally, BCMA CAR NK92 cells exhibited potent antitumor activities in subcutaneous tumor models of MM. These results demonstrate that regional administration of BCMA CAR NK92 cells is a potentially promising strategy for treating MM.

BCMA-targeting chimeric antigen receptor T cell therapy for relapsed and/or refractory multiple myeloma.

Recently, many new therapies have improved the outcomes of patients with relapsed and/or refractory multiple myeloma (RRMM). Nevertheless, recurrence is still unavoidable, and better treatment choices for RRMM are urgently needed. The clinical success of Chimera antigen receptor (CAR) T cell therapy in many hematological diseases, including leukemia and lymphoma, has drawn considerable attention to RRMM. As CAR T cell therapy continues to mature and challenge traditional therapies, it is gradually changing the treatment paradigm for MM patients. The B cell maturation antigen (BCMA), expressed in malignant plasma cells but not normal ones, is an ideal target for MM treatment, due to its high expression. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) has approved two BCMA-targeting CAR T cell products, idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel), for use in RRMM. In this review, we focus on data from RRMM patients involved in clinical trials of Ide-cel and Cilta-cel and discuss the present situation and future direction of CAR T cell therapy for this condition.

Teclistamab Improves Patient-Reported Symptoms and Health-Related Quality of Life in Relapsed or Refractory Multiple Myeloma: Results From the Phase II MajesTEC-1 Study.

INTRODUCTION: Patients with relapsed or refractory multiple myeloma (RRMM) report significantly lower HRQoL compared with patients with newly diagnosed MM and experience further deterioration in HRQoL with each relapse and subsequent treatment. Therefore, consideration of the impact of treatment on HRQoL in addition to clinical outcomes is vital. PATIENTS AND METHODS: In the phase I/II MajesTEC-1 (NCT03145181, NCT04557098) study, patients with RRMM who received teclistamab, an off-the-shelf, T-cell redirecting BCMA × CD3 bispecific antibody, had deep and durable responses with manageable safety. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30-item and the EuroQol 5 Dimension 5 Level descriptive questionnaire. Changes over time from baseline were measured with a repeated measures mixed-effects model. Proportions of patients with clinically meaningful improvement after starting treatment and time to clinically meaningful worsening were assessed. RESULTS: Compliance was maintained throughout the study. Compared with baseline, positive changes were observed for pain, global health status, and emotional functioning with treatment; other assessments were largely unchanged from baseline. Post hoc analysis showed patients with deeper clinical response generally reported improved HRQoL outcomes. Following an initial decline in HRQoL in some scales, the proportion of patients reporting clinically meaningful improvements increased, while the proportion reporting clinically meaningful worsening decreased over time. Clinically meaningful improvements in pain were reported in ≥40% of patients at most assessment time points. CONCLUSIONS: These results complement previously reported clinical benefits and support teclistamab as a promising therapeutic option for patients with RRMM.

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study.

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.