GPRC5D-Targeted CAR T Cells for Myeloma.

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).

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.

[The characteristics and impact on prognosis of cytopenia after anti-BCMA-CAR-T therapy in patients with relapsed and refractory multiple myeloma].

Objective: To investigate the characteristics of cytopenia and its impact on prognosis in patients with relapsed and refractory multiple myeloma (RRMM) after B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) immunotherapy therapy. Methods: Clinical data of 36 RRMM patients received BCMA CAR-T therapy at the First Affiliated Hospital of Nanjing Medical University from April 2017 to March 2023 were retrospectively collected. Among them, there were 17 males and 19 females, with an age [M (Q1, Q3)] of 62 (53, 67) years. The follow-up deadline was August 31, 2023, and the follow-up time [M (Q1, Q3)] was 33 (10, 30) months. The characteristics of cytopenia at different time points before lymphodepleting chemotherapy and after CAR-T cell infusion in all patients were analyzed. Kaplan-Meier method was used to compare the differences in progression-free survival (PFS) and overall survival (OS) in patients with different clinical characteristics. Single-cell sequencing analysis was used to analyze the changes in hematopoietic stem cells in three patients after CAR-T cell therapy. Results: The incidence of cytopenia after BCMA CAR-T cell therapy in 36 RRMM patients reached 100%. The incidence of neutropenia peaked on the 7th and 28th day after cell infusion with a biphasic pattern of change.Patients with all grade neutropenia reached 61.1% (22/36) and grade 3 or higher reached 33.3% (12/36) on the 7th day, while patients with all grade neutropenia reached 67.9% (19/28) and grade 3 or higher reached 28.6% (8/28) on the 28th day (P<0.001),respectively. The occurrence rate of lymphopenia reached a peak on the day of CAR-T cell infusion [97.2% (35/36) patients showed lymphopenia, while 80.6% (29/36) patients showed grade 3 or higher lymphopenia] (P<0.001).The incidence of all grade of thrombocytopenia and severe thrombocytopenia (grade 3 or higher) peaked on the 14th day after cell infusion, with the rates of 69.4% (25/36) and 30.6% (11/36) respectively, which had a prolonged duration(P<0.001). Even after 12 months, 40% (8/20) of patients still experienced thrombocytopenia.The incidence of anemia peaked on the 7th and 14th day after cell infusion, with a rate of 100% (36/36) (P<0.001). 50% (10/20) of patients still had anemia even 12 months after cell infusion. Kaplan-Meier survival analysis showed that patients with thrombocytopenia < grade 3 had undefined OS, while patients with thrombocytopenia ≥grade 3 had shorter OS [17 (95%CI: 2-32) months, χ2=4.154, P=0.042], indicating a poorer prognosis. However, there was no statistically significant difference in the relationship between other cytopenia and survival (all P>0.05). Single-cell sequencing analysis of bone marrow cells revealed decreased proliferation, increased apoptosis, and cell cycle arrest of hematopoietic stem cells after CAR-T cell infusion. Conclusions: All patients experienced varying degrees of cytopenia after receiving BCMA CAR-T cell infusion, and patients with thrombocytopenia ≥grade 3 had shorter OS and poorer prognosis.

A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2.

Chimeric antigen receptor (CAR)-reprogrammed T cell therapy is a novel and powerful treatment against hematological malignancies. Cytokine release syndrome (CRS) and other potentially life-threatening toxicities are known side effects which need appropriate management and supportive care. Coagulopathy is a common and severe CAR-T-related adverse event, while a comprehensive profile of coagulopathy in patients with multiple myeloma (MM) undergoing CAR-T cell therapy has not been reported. Therefore, we performed a comprehensive analysis of coagulopathy in 51 patients with r/r MM given anti-B cell maturation antigen CAR-T cell therapy. We found that 49% of patients had coagulation disorders, and 29% of patients experienced disseminated intravascular coagulation (DIC). Severe CRS, abnormal liver function and higher tumor burden were risk factors for the CAR-T-related coagulopathy. We found that the serum IL-6 level and alanine aminotransferase level were potential indicators for CAR-T-related DIC. Furthermore, we found that coagulation disorders occurred within 1 month after CAR-T cell infusion, mainly between days 10 and 13, which was 2-5 days later than the beginning of CRS and simultaneous with the beginning of abnormal liver function and the peak of CRS. In addition, although patients with coagulation dysfunction had a trend for better outcomes and prognosis, no statistical significance was found. In conclusion, our research provided a comprehensive understanding of CAR-T-related coagulopathy in MM. Upon timely and standardized treatment, coagulopathy was manageable in most cases.

The emerging therapeutic landscape of relapsed/refractory multiple myeloma.

From a historic lens, treatment for patients with relapsed/refractory multiple myeloma (R/R MM) has advanced significantly since the advent of immunomodulatory agents (IMiDs) in the 1990s, proteasome inhibitors in the 2000s, monoclonal antibodies in the 2010s, and CAR-T treatments in the 2020s. However, the availability of multiple new therapies has also created significant ambiguity regarding therapy selection and sequencing, as consensus guidelines are limited, and cross-trial comparisons of the novel agents are challenging. In this focused review, we discuss the novel Food & Drug Administration (FDA)-approved medications for R/R MM, including the recently approved first-in-class BCMA-directed bispecific antibody teclistamab. We highlight the seminal clinical trials data and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on the two novel CAR-T cell products. We consider the limited tolerability of certain agents, prospects for our aging population, and financial aspects of these therapies. Finally, we spotlight ongoing trials involving promising agents making their way through the pharmacologic pipeline including the BCMA-directed bispecific antibody elranatamab and the GPRC5D-directed bispecific antibody talquetamab. We summarize our recommendations based on the best available evidence as we enter 2023.

Leveraging a physiologically-based quantitative translational modeling platform for designing B cell maturation antigen-targeting bispecific T cell engagers for treatment of multiple myeloma.

Bispecific T cell engagers (TCEs) are an emerging anti-cancer modality that redirects cytotoxic T cells to tumor cells expressing tumor-associated antigens (TAAs), thereby forming immune synapses to exert anti-tumor effects. Designing pharmacokinetically acceptable TCEs and optimizing their size presents a considerable protein engineering challenge, particularly given the complexity of intercellular bridging between T cells and tumor cells. Therefore, a physiologically-relevant and clinically-verified computational modeling framework is of crucial importance to understand the protein engineering trade-offs. In this study, we developed a quantitative, physiologically-based computational framework to predict immune synapse formation for a variety of molecular formats of TCEs in tumor tissues. Our model incorporates a molecular size-dependent biodistribution using the two-pore theory, extravasation of T cells and hematologic cancer cells, mechanistic bispecific intercellular binding of TCEs, and competitive inhibitory interactions by shed targets. The biodistribution of TCEs was verified by positron emission tomography imaging of [89Zr]AMG211 (a carcinoembryonic antigen-targeting TCE) in patients. Parameter sensitivity analyses indicated that immune synapse formation was highly sensitive to TAA expression, degree of target shedding, and binding selectivity to tumor cell surface TAAs over shed targets. Notably, the model suggested a "sweet spot" for TCEs' CD3 binding affinity, which balanced the trapping of TCEs in T-cell-rich organs. The final model simulations indicated that the number of immune synapses is similar (~55/tumor cell) between two distinct clinical stage B cell maturation antigen (BCMA)-targeting TCEs, PF-06863135 in an IgG format and AMG420 in a BiTE format, at their respective efficacious doses in multiple myeloma patients. This result demonstrates the applicability of the developed computational modeling framework to molecular design optimization and clinical benchmarking for TCEs, thus suggesting that this framework can be applied to other targets to provide a quantitative means to facilitate model-informed best-in-class TCE discovery and development.

Newly approved and forthcoming T-cell-redirecting bispecific antibodies for the treatment of relapsed/refractory multiple myeloma.

OBJECTIVE: Summarize the background, clinical trials, and place in therapy for the newly Food and Drug Administration (FDA) approved and forthcoming bispecific antibodies for relapsed/refractory (R/R) multiple myeloma. DATA SOURCES: A search of the PubMed database was conducted using the following search terms: B-cell maturation antigen (BCMA), teclistamab, myeloma, BsAbs, GPRC5D, and bispecific. Ongoing clinical trials as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents were evaluated. Prescribing information was also reviewed. SUMMARY: For patients with R/R multiple myeloma who have failed available therapies, treatment options are limited and survival is short. The FDA recently approved teclistamab, a T-cell-redirecting bispecific antibody, in patients with R/R multiple myeloma who have failed four prior lines of therapy. Teclistamab targets both CD3 expressed on T-cells and BCMA expressed on the surface of myeloma cells, mediating T-cell activation and lysis of plasma cells that express BCMA. Accelerated approval was granted based upon the results of the MajesTEC-1 study, which showed a durable response in a high proportion of heavily pretreated patients. Teclistamab is the first bispecific antibody approved for use in patients with multiple myeloma and the fourth approved agent targeting BCMA. Additional T-cell redirecting bispecific antibodies for use in multiple myeloma are also currently being studied. CONCLUSION: Teclistamab is the newest agent granted FDA approval for use in R/R multiple myeloma and represents a promising new option for patients. Ongoing trials are investigating teclistamab and other novel bispecific antibodies in the upfront and R/R setting.

[Optimization of treatment strategy for relapsed or refractory multiple myeloma].

The use of novel agents has improved the outcomes of patients with multiple myeloma. However, almost all patients eventually relapsed, became resistant to available treatments, and, thus, required further therapy. To improve the outcomes of relapsed and/or refractory, the best efficacy in each line of treatment should be achieved. Currently, the prognosis of patients who became refractory to triple-class agents including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies is extremely poor. Moreover, the best treatment regimen for these patients remains unclear. In Japan, the use of B-cell maturation antigen-targeting chimeric antigen receptor T-cell therapy for this patient group was approved. Furthermore, bispecific T-cell engagers and B-cell maturation-targeting antibody-drug conjugate are currently developed. Since it is challenging to identify the optimal sequences, it is important to apply each treatment individually based on clinical trial results. In the educational session, the framework to choose the most optimal treatment based on evidence of relapsed multiple myeloma therapies in each treatment line will be discussed.

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE-1 (phase 2) Japanese cohort.

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 × 106 CAR-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.

Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study.

BACKGROUND: There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma. METHODS: This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0·3-19·2 µg/kg [once every 2 weeks] or 19·2-720 µg/kg [once per week]) or subcutaneously (range 80-3000 µg/kg [once per week]) in different cohorts, with step-up dosing for 38·4 µg/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181. FINDINGS: Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 µg/kg, after 60 µg/kg and 300 µg/kg step-up doses (median follow-up 6·1 months, IQR 3·6-8·2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 [40%]). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48-79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7·1 months' median follow-up (IQR 5·1-9·1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported. INTERPRETATION: Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development. FUNDING: Janssen Research & Development.

Lenalidomide enhances the efficacy of anti-BCMA CAR-T treatment in relapsed/refractory multiple myeloma: a case report and revies of the literature.

We report successful clinical experience using anti-BCMA CAR-T combined with lenalidomide in a patient who was refractory to a previous CAR-T treatment. The patient was a 51-year-old man, and was diagnosed with IgD-λ multiple myeloma(MM) in October 2015. 10 courses of chemotherapy including immunomodulators and proteasome inhibitors were used for remission and autologous hematopoietic stem cell transplantation was performed. MM relapsed after 12 months of remission. His disease continued to progress after multiple chemotherapy regimens, mouse anti-BCMA CAR-T and human-derived anti-BCMA CAR-T therapy. After a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, patient took lenalidomide on day -1 and human-derived anti-BCMA CAR-T cells were infused on the next day. He suffered grade 2 cytokine-releasing syndrome(CRS) and grade 3 myelosuppression after infusion, and were resolved after symptomatic treatment. Very good partial response (VGPR) was achieved 14 days after CAR-T treatment, and had been maintained for more than 8 months. We demonstrated for the first time in patients that anti-BCMA CAR-T cell therapy combined with lenalidomide is feasible and effective in the treatment of RRMM. It provides a new strategy for RRMM patients who do not respond to anti-BCMA CAR-T cell therapy alone, and the adverse event is reversible.

B-cell maturation antigen targeting strategies in multiple myeloma treatment, advantages and disadvantages.

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.

Use of serum B-cell maturation antigen levels to predict outcomes for myeloma patients treated with ruxolitinib, lenalidomide and methylprednisolone.

Previous retrospective studies have shown that serum B-cell maturation antigen (sBCMA) levels predict outcomes among patients with multiple myeloma (MM) undergoing new treatments. Specifically, baseline levels and changes during treatment of this protein predict both progression free survival (PFS) and overall survival. However, prospective studies are lacking evaluating sBCMA for determining outcomes among MM patients undergoing new treatments. Thus, we evaluated whether its baseline levels and changes during treatment in the amount of this serum marker predict outcomes among 38 relapsed/refractory MM patients treated with ruxolitinib, lenalidomide and methylprednisolone in a phase 1 trial. Patients with baseline sBCMA levels in the lowest three quartiles had longer PFS (median PFS 136 vs. 28 days; p < 0.0001). This was also shown for patients with baseline levels below the median (median PFS 140 vs. 77 days; p = 0.0225). PFS was shorter for patients whose sBCMA levels increased ≥25% through their first cycle (median PFS: 50 vs. 134 days, p = 0.0022), second cycle (median PFS: 50 vs. 141 days, p = 0.0273), and during the first three cycles of study treatment (median PFS: 50 vs. 220 days, p < 0.0001). No patient whose sBCMA increased ≥25% during cycle 1 responded whereas the majority (58%) of patients whose level increased <25% responded. This is the first prospective study to determine whether sBCMA levels predict outcomes for MM patients undergoing a non-BCMA directed treatment regimen and demonstrates that baseline levels and its changes during treatment predict PFS and the likelihood of responding to their treatment. These results add to the growing literature suggesting that this serum marker will be useful for determining outcomes for patients undergoing treatment for MM.

CAR-T cells for the treatment of relapsed/refractory multiple myeloma in 2022: efficacy and toxicity.

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.

The emergence of b-cell maturation antigen (BCMA) targeting immunotherapy in multiple myeloma.

OBJECTIVE: Multiple myeloma, a plasma cell neoplasm is the second most common hematological malignancy in the United States. Despite significant advances in treatment armamentarium over the last decade, multiple myeloma remains an incurable malignancy. B-cell maturation antigen (BCMA) is an antigen expressed on the surface on plasma cells that can be targeted by novel mechanisms of action including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapy. This review summarizes the clinical application and development of approved and investigational immunotherapies targeting BCMA. DATA SOURCES: A search of the PubMed database was conducted using the following search terms: BCMA, CAR T, myeloma, belantamab mafodotin, and bispecific. Ongoing clinical trials, as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents targeting BCMA were evaluated. Prescribing information was also reviewed. DATA SUMMARY: Since the discovery of BCMA as a target for myeloma, researchers have developed antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies as novel treatment modalities for myeloma patients. Belantamab mafodotin and idecabtagene vicleucel represent currently available therapies and ongoing trials have demonstrated the efficacy and safety of bispecifics and other BCMA targeting therapies. CONCLUSION: BCMA targeting antibody drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies have demonstrated clinical activity in myeloma patients and represent novel therapies in multiple myeloma treatment paradigm.

[Clinical development of chimeric antigen receptor T-cell therapy in multiple myeloma].

With the advent of new drugs, the treatment outcome of multiple myeloma (MM) has dramatically improved. However, cure for MM has been difficult to attain, and the prognosis of cases resistant to various treatments remains extremely poor. In March 2021, the United States Food and Drug Administration approved idecabtagene vicleucel (Ide-cel) -a B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell therapy -for the treatment of patients with relapsed/refractory MM. The Japanese Ministry of Health, Labor and Welfare approved Ide-cel in December 2021, and CAR T-cell therapy for MM will soon be available for clinical use. This review highlights the latest evidence regarding CAR T-cell therapy for MM.

Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy.

OBJECTIVE: To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy. METHOD: The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy. RESULTS: Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0) d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3-4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3-4 CRS were significantly higher in TLS patients than in non-TLS patients (all P<0.05). Multivariate logistic regression revealed that serum creatinine ( OR=1.015, P<0.01) and severe CRS ( OR=9.371, P<0.01) were independent risk factors of TLS. CONCLUSIONS: Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Risk factors of acute kidney injury during BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: To explore the risk factors of acute kidney injury (AKI) during B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma (MM). METHODS: The clinical data of 99 patients with relapsed/refractory MM who received BCMA CAR-T cell therapy in the First Affiliated Hospital of Zhejiang University School of Medicine from July 2018 to December 2021 was retrospectively analyzed. Dynamic changes of renal function before and after chemotherapy preconditioning and after CAR-T cell infusion were observed. Logistic regression was used to analyze the independent risk factors associated with the occurrence of AKI. RESULTS: Among 99 patients, the AKI occurred in 25 cases with an incidence rate of 25.3%, and the median time was 8.0 (5.5,11.0) d. The AKI grade 1, 2 and 3 accounted for 8.0%, 12.0% and 36.0%, respectively. Logistic regression analysis showed that serum creatinine (SCr) after chemotherapy preconditioning ( OR=1.020, P<0.001), and the grade of cytokine release syndrome (CRS) ( OR=6.501, P<0.01) were independent risk factors for AKI during treatment. The area under the ROC curve (AUC) of SCr after chemotherapy preconditioning in predicting AKI was 0.800 (95% CI: 0.694-0.904, P<0.001); using 83.0 µmol/L as cut-off value, the sensitivity, specificity and Youden index of SCr were 72.0%, 80.8% and 0.528, respectively. The incidence of AKI in patients with grade 3-4 CRS was 39.1%, while that was 13.2% in patients with CRS

Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: To analyze the clinical features of hemophagocytic syndrome (HLH) following B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma. METHODS: Ninety-nine patients with relapsed/refractory multiple myeloma (including 3 cases of plasma cell leukemia) undergoing BCMA CAR-T cell therapy (monocentric phaseⅠclinical trial, ChiCTR1800017404) in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were enrolled in the study. The baseline features, laboratory findings, treatment, and clinical response of these patients were analyzed. RESULTS: CAR-T cell associated HLH (carHLH) occurred in 20 patients (20.20%), and the median onset time was 7(0-19) d after cytokine release syndrome (CRS). Patients with carHLH were maily male patients, and manifested as high percentage of abnormal plasma cells, higher incidence of severe CRS (grade 3-4), and robust expansion of CAR-T cells in the peripheral blood (all P<0.05). The levels of interleukin (IL)-6, IL-10 and interferon (IFN)-γ, the peak value of international normalized ratio and D-dimer were elevated, and the valley value of fibrinogen was decreased in patients with carHLH (all P<0.01). All carHLH patients resolved with proper intervention (including 7 cases with tocilizumab, 5 with steroids, 6 with both). The objective response rate in carHLH patients was slightly higher than that in non-carHLH patients [100.0% (17/17) vs. 94.87% (74/78), P>0.05]. CONCLUSIONS: The incidence of carHLH is relatively high in BCMA CAR-T cell treated patients, which is closely related to pretreatment tumor cell percentage in bone marrow, expansion of CAR-T cells and the secretion of cytokines. Medication based on tocilizumab and steroids can achieve considerable therapeutic effects in patient with carHLH.

A matching-adjusted indirect comparison of the efficacy of elranatamab versus physician's choice of treatment in patients with triple-class exposed/refractory multiple myeloma.

INTRODUCTION: For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and effective treatment options are limited. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody which was approved by the US Food and Drug Administration in August 2023 and demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician's choice of treatment (PCT) in the absence of head-to-head comparative data, a matching-adjusted indirect comparison (MAIC) was conducted. METHODS: Individual patient data from MagnetisMM-3 (Cohort A [BCMA-naïve] N = 123, 14.7 months of follow-up) were reweighted to match published summary data from two real-world studies of PCT in patients with TCE/R MM (LocoMMotion and MAMMOTH) using a propensity score-type logistic regression. Unanchored MAIC analyses were conducted according to National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 guidance. RESULTS: Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher objective response rate (ORR rate difference: 37.52; 95% CI 26.20-48.83; odds ratio: 4.85; 95% CI 2.85-8.23) and complete or stringent complete response rate (≥CR rate difference: 42.29; 95% CI 31.84-52.74; odds ratio: 184.01; 95% CI 24.66-1372.86), longer progression-free survival (PFS HR 0.32; 95% CI 0.20-0.49), and overall survival (OS HR 0.62; 95% CI 0.40-0.94). Compared with PCT in MAMMOTH, elranatamab was associated with significantly higher ORR (rate difference: 28.14; 95% CI 16.77-39.52; odds ratio: 3.24; 95% CI 1.98-5.32) and ≥ CR (rate difference: 26.22; 95% CI 16.40-36.05; odds ratio: 5.48; 95% CI 2.88-10.44), as well as longer PFS (HR 0.25; 95% CI 0.17-0.37) and OS (HR 0.49; 95% CI 0.33-0.71). Sensitivity analysis results were consistent with the base case. CONCLUSION: In the MAIC, elranatamab was consistently associated with improved rates and depth of response and significantly longer PFS and OS versus PCT in LocoMMotion and MAMMOTH.