Cell Therapy In Multiple Myeloma Research Articles

Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

Overcoming Immune Evasion in CAR-T Cell Therapy: Mechanisms and Coping Strategies for Clonal Evolution in Multiple Myeloma

This paper addresses the issue of immune evasion in CAR-T cell therapy, exploring the mechanisms underlying clonal evolution in multiple myeloma and proposing corresponding coping strategies. Overcoming these challenges necessitates a comprehensive approach, incorporating alternative therapeutic modalities and the advancement of next-generation CAR-T cell therapy. Furthermore, prioritizing in-depth investigations into drug resistance and immune evasion mechanisms, tailoring treatment strategies to individual patients, and conducting clinical trials and regulatory initiatives emerge as key focal points for future research. These endeavors are anticipated to propel the advancement of CAR-T cell therapy in multiple myeloma, offering enhanced treatment prospects for patients.

Autologous stem cell boost improves persistent immune effector cell associated hematotoxicity following BCMA directed chimeric antigen receptor T (CAR T) cell therapy in multiple myeloma.

Persistent Immune Effector Cell Associated Hematotoxicity (ICAHT) is a significant side effect of BCMA CAR T-Cell therapy in patients with relapsed multiple myeloma (MM). The use of stem cell boosts in ICAHT has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience of ICAHT, defined by an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia with a platelet count ≤ 50,000 or/and anemia as hemoglobin (hgb) ≤9 g/dL, in patients who received BCMA CAR T therapy, and the effects of subsequent stem cell boost on hematopoietic reconstitution and clinical outcome. In this study, ICAHT was observed in 60% (n = 61/101) of patients at D + 21, and risk factors for its development included history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS. 28% of patients with ICAHT received a stem cell boost at a median of 116 days due to profound and prolonged cytopenias often requiring ongoing transfusion support. Stem cell boost significantly improved cytopenias at 3 and 6 months follow up without any adverse effects on PFS and OS, underscoring the safety of this procedure.

Comparing Bendamustine-Based Bridging to Standard Chemotherapy in CAR T Cell Therapy for Multiple Myeloma: An Analysis of Toxicity Profiles

Comparing Bendamustine-Based Bridging to Standard Chemotherapy in CAR T Cell Therapy for Multiple Myeloma: An Analysis of Toxicity Profiles

Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.

CAR T cell therapy for multiple myeloma.

CAR T cell therapy for multiple myeloma.

Characteristics of Clinical Trials for Multiple Myeloma and CAR-T Cell Therapy: A Cross Sectional Analysis

Background: In recent decades novel CAR-T cell therapies have proven efficacious in the treatment of multiple myeloma, leading to FDA approval. As CAR-T cell therapies continue to be developed in clinical trials, it is important to assess trends over time that can inform drug development and relate to equitable access and representation. This cross-sectional study was conducted to analyze the characteristics of clinical studies for multiple myeloma and CAR-T cell therapy registered in ClinicalTrials.gov (CTG). Methods: All multiple myeloma clinical studies registered on CTG from September 27, 2007 to July 15, 2023 were identified using Advanced Search feature in ClinicalTrials.gov. Trial characteristics were assessed through relative frequency calculations. Odds ratio and 95% confidence intervals were determined for key characteristics and significance of findings. Results: Out of the 390,301 studies registered in CTG during this period, a mere 0.63% (2,457 studies) were conducted for multiple myeloma, compared to 1.61% (6,287 studies) for lymphoma and 1.46% (5,699 studies) for leukemia. Among these multiple myeloma studies, 85.47% (2,100 studies) were interventional and 14.82% (364 studies) were observational. Further, a total of 184 studies for CAR-T cell therapy in multiple myeloma were found in CTG registered during this period. Among these, 124 studies are still ongoing, constituting around 12.53% of the total 990 ongoing multiple myeloma studies. In multiple myeloma, around 51.98% (1276 studies) were industry sponsored, while 12.75% (313 studies) received funding from the National Institutes of Health (NIH) and other U.S. federal agencies (FA). The remaining 36.7% (901 studies) were funded by all others including individuals, universities and other research organizations. Similar funding trends were observed for 984 ongoing clinical studies. Notably, there were statistically significant differences in funding trends for CAR-T cell therapy within multiple myeloma studies. Industry funded a higher percentage for CAR-T cell therapy, 66.3%, compared to the overall 51.98% multiple myeloma studies that were industry sponsored. Further, NIH/ FA provided funding in 12.5% studies for CAR-T for CAR-T cell therapy, compared to a much lower 4.9% of all multiple myeloma studies. Interestingly, the premature discontinuation rates for CAR-T cell therapy clinical studies in multiple myeloma were significantly lower than those observed in overall multiple myeloma studies (OR 0.33; CI 0.177 to 0.611; p<0.01). This is promising for adherence in a heavily pretreated population. However, the proportion of studies with unknown status were significantly higher when compared to the overall multiple myeloma studies. (OR 2.84; 95% CI 1.94 to 4.18; p<0.01). There was no statistically significant difference between the unknown status and premature discontinuation rates of CAR-T cell therapy studies in multiple myeloma are myeloma compared to those in lymphoma. Conclusion: This cross-sectional study demonstrates that CAR T-cell therapy for multiple myeloma remains of prominent interest to industry followed by NIH and other U.S. funding organizations. There were significant trends noted that can inform drug development policy and relate to access and representation in trials. While the trends in the study discontinuation trends are promising, there is a need to address the proportion of studies with unknown status. Improved reporting and research into clinical trial funding and design will optimize efforts in developing cellular therapies for patients with myeloma.

The Important Role of Cell Therapy in Multiple Myeloma: Three Reasons Why It’s Here to Stay

The Important Role of Cell Therapy in Multiple Myeloma: Three Reasons Why It’s Here to Stay

Development of a Phase 1 Study Evaluating the Activity of Modular CAR T for Multiple Myeloma (MCARTY) Targeting BCMA and CD19 for Improved Persistence

CONCLUSION BCMA directed CAR T cell therapy for multiple myeloma (MM) shows promise, but very long-term survival may be limited. Notably, BCMA CAR T persistence in MM is shorter than that seen in with CD19 CAR T cells in B cell malignancies where long-term CD19 CAR T persistence is associated with durable responses. Shorter BCMA CAR T persistence may be explained by the lower surface density of BCMA on tumour compared with that of CD19. Alternatively, CD19 CAR T persistence may be driven by recognition of continuous emergence of newly differentiated B cells. We sought to improve BCMA CAR T persistence by (a) developing a BCMA CAR with high sensitivity to BCMA, and (b) co-expression with a CD19 CAR. Notably, while CD19 is absent or expressed at low level on myeloma cells, CD19 may be expressed on a subpopulation of myeloma stem cells, providing an additional rationale for co-targeting CD19 in MM. We performed functional screening of several mid to high affinity BCMA binders in CAR format. We additionally explored whether a more stable CAR format would improve sensitivity. We explored co-expression of the new BCMA CAR with the CD19 CAR from obecabatagene autoleucel (also known as CAT19), which is known to drive long-term persistence. We also designed and started a clinical study (MCARTY, NCT04795882) testing the BCMA CAR alone or co-expressed with a CD19 CAR in patients with refractory Myeloma. The binding affinity for BCMA was determined for 13 antibody clones from a rat library, before being assessed functionally in single chain variable fragment (scFv) and fragment antigen-binding (Fab) formats in a second generation (41bbζ) CAR backbone. Noting superior target binding, functional efficacy and minimal basal activation of effector cells expressing the D8 binder in Fab format we then assessed this construct against standard BCMA targeting CARs based on the bb2121 and LCAR-B38M binders used in Ide-Cel and Cilta-Cel respectively. Compared to these competitor CARs, D8 demonstrated improved sensitivity to BCMA with improved activation, target kill, and cytokine release in a series of cocultures with plate bound antigen and cell targets expressing low level BCMA. Successful manufacture in an academic setting of dual targeting CAR T cells was achieved by double transduction of autologous CD4/CD8 selected T cells with separate lentiviral vectors titrated for equal transduction. Manufacture by CliniMACS Prodigy included AKT inhibitor VIII to reduce T cell differentiation and LentiBoost, a polaxamer-based transduction enhancer, in a protocol lasting 6-8 days. This resulted in 3 populations of CAR T cells (D8+CAT19-, D8-CAT19+, D8+CAT19+) which can be individually tracked in treated patients. The MCARTY trial is a single centre, Phase 1 dose escalation trial uniquely designed with two cohorts to evaluate the safety of D8 CAR T cells (Cohort 1) and D8/CAT19 CAR T cells (Cohort 2) in patients with relapsed/refractory MM at a dose of 50 or 150x10^6 CARs. Inclusion criteria are: progression or stable disease to last treatment, 3 or more previous lines of therapy, exposure to proteasome inhibitors (PI), immunomodulatory drugs (IMID) and CD38 antibodies, ECOG 0/1. There was no selection based on previous exposure to BCMA targeting agents or tumour BCMA expression. As of 11 July, 8 patients have been treated, 6 patients with D8 CAR alone (n=3 at each dose level) and 2 patients with the lower dose of dual targeting D8/CAT19 CAR T cells. Median age was 57 (range 33-66), high risk cytogenetics in 4 of 7 patients (57%), previous lines of therapy 4 (range 3-8). Doses were well tolerated with no cases of ICANS or CRS≥ grade 3. At a median follow up of 4.5 months (range 1-12), clinical responses ≥PR were seen in all patients (ORR: 100%). Of 6 patients, 5 (83%) CR/sCR, 1 (17%) PR at 3 months. We observed robust expansion of D8 CAR in Cohort 1, and of dual and single targeting CARs in Cohort 2. We report a unique approach to prolong CAR persistence in MM by developing a CAR T cell co-expressing a sensitive BCMA CAR construct and CD19 CAR with proven durability. We report feasibility of double transduction, the first clinical use of a FabCAR and a unique trial design allowing comparison of treatment with single vs dual targeting CAR constructs.

Incidence of Parkinsonism As a Complication of Anti-BCMA CAR-T Cell Therapy in Multiple Myeloma

Introduction: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has revolutionized the treatment for relapsed/refractory multiple myeloma (RRMM). Two BCMA-directed CAR T products, Idecabtagene Vicleucel (ide-cel) and Ciltacabtagene Autoleucel (cilta-cel), have received approval from the U.S. Food and Drug Administration (FDA). While these therapies have demonstrated remarkable efficacy, concerns regarding treatment-related neurotoxicities have emerged. The specific adverse effect of Parkinsonism associated with BCMA-directed CAR T therapy has not been adequately studied. Methods: We conducted an analysis utilizing the FDA Adverse Events Reports System (FAERS) database, covering the years 2021-2023. Our search focused on the reported incidence of Parkinsonism associated with BCMA-directed CAR T therapy. Results: Upon reviewing the FDA data, we identified a total of 177 patients with reported nervous system disorders related to Ide-cel therapy. Out of these patients, 2 had reported incidents of Parkinsonism. Similarly, for Cilta-cel therapy, there were 81 patients with reported nervous system disorders, with 5 reported incidents of Parkinsonism. Out of the total 7 reported patients with Parkinsonism, 5 were males, 2 were females, the average age was 67, the average weight was 68.9 kg, and 3 patients were also noted to have associated cytokine release syndrome. Conclusion: Our analysis of FAERS data highlights the occurrence of Parkinsonism associated with BCMA-directed CAR T-cell therapy. Further studies are required to quantify the need for neurological surveillance after initiating treatment with these novel agents.

Low Target Antigen Expression Mediates Resistance to BCMA CAR T Cell Therapy

Introduction: BCMA-targeted CAR T cell therapies have shown promising responses, but many patients have residual disease post therapy, and relapses are common. Prior studies with CD19-targeted CAR T cells have shown that antigen density is an important determinant of response, with CARs requiring several hundred (Mansilla-Soto et al. Nat Med 2021) to a few thousand (Spiegel et al. Nat Med 2021) target molecules per cell for effective tumor recognition and control. Methods: To determine how antigen levels affect response to BCMA-directed CAR T-cell therapy, we performed quantitative flow cytometric measurements of BCMA antibody binding capacity (ABC) on fresh tumor samples from patients with rel/refractory multiple myeloma (RRMM), including 27 patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel. ABC of GPRC5d was measured as control. To model the impact of antigen levels on CAR T cell response, we generated CRISPR-Cas9 edited leukemia (NALM6) and myeloma (MM1s) clones with varying levels of CD19 and BCMA antigen expression, respectively, and quantitatively assessed CAR T cell function against these target antigen-titrated lines in vitro and in vivo. Results: Antigen levels were measured in a cohort of 32 patients with RRMM with a median of 6 (range 3-12) prior lines of therapy, including seven patients previously treated with BCMA targeted antibody-drug conjugates. Median BCMA ABC was 670 mol/cell (range undetectable - 2460 mol/cell), consistent with prior estimates (Salem et al. Leuk Res 2018). Among patients treated with commercial BCMA-targeted CAR T-cell therapy (n=27), median BCMA expression was 670 (IQR 380-850) mol/cell prior to treatment. At the time of measurable residual disease or progression, median antigen abundance had decreased to 390 (IQR 290-490) mol/cell (15 patients, p = 0.011). The majority of relapsed patients displayed low-level detectable BCMA. Expression of control antigen GPRC5d was unchanged pre- and post-treatment. In vitro modeling showed that CAR T cell tumor lysis and cytokine production (IFNγ, IL-2) were gradually impaired as antigen levels decreased from 2000 to 200 mol/cell, and were absent at < 50 mol/cell. In an in vivo xenograft model, BCMA-directed CAR T cells cured an unmodified MM1s line expressing > 5,000 BCMA mol/cell, whereas animals bearing an MM1s.13 antigen low cell line expressing 600 (+/- 150) mol/cell initially controlled tumor but relapsed by day 40. Conclusion: BCMA expression in patients with RRMM is lower than CD19 expression typically seen in patients with B cell malignancies. Furthermore, while complete loss of BCMA after CAR T cell therapy is uncommon, resistant or relapsed disease frequently expresses low levels of antigen. In vitro and in vivo modeling show that these levels are below the threshold required for optimal CAR T cell function. These data suggest that low antigen expression may be an important mechanism of relapse in BCMA CAR T cell therapy for multiple myeloma.

CRISPR-Cas9 system: a novel and promising era of genotherapy for beta-hemoglobinopathies, hematological malignancy, and hemophilia.

Gene therapy represents a significant potential to revolutionize the field of hematology with applications in correcting genetic mutations, generating cell lines and animal models, and improving the feasibility and efficacy of cancer immunotherapy. Compared to different genetic engineering tools, clustered regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated protein 9 (Cas9) emerged as an effective and versatile genetic editor with the ability to precisely modify the genome. The applications of genetic engineering in various hematological disorders have shown encouraging results. Monogenic hematological disorders can conceivably be corrected with single gene modification. Through the use of CRISPR-CAS9, restoration of functional red blood cells and hemostasis factors were successfully attained in sickle cell anemia, beta-thalassemia, and hemophilia disorders. Our understanding of hemato-oncology has been advanced via CRIPSR-CAS9 technology. CRISPR-CAS9 aided to build a platform of mutated genes responsible for cell survival and proliferation in leukemia. Therapeutic application of CRISPR-CAS9 when combined with chimeric antigen receptor (CAR) T cell therapy in multiple myeloma and acute lymphoblastic leukemia was feasible with attenuation of CAR T cell therapy pitfalls. Our review outlines the latest literature on the utilization of CRISPR-Cas9 in the treatment of beta-hemoglobinopathies and hemophilia disorders. We present the strategies that were employed and the findings of preclinical and clinical trials. Also, the review will discuss gene engineering in the field of hemato-oncology as a proper tool to facilitate and overcome the drawbacks of chimeric antigen receptor T cell therapy (CAR-T).

Significance of alkaline Phosphatase After Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma

BackgroundThe inexpensive and readily available biomarkers for cytokine release syndrome (CRS) grading and prognosis assessment in chimeric antigen receptor (CAR)-T therapy are currently lacking. This study examined the significance of alkaline phosphatase (ALP) after CAR-T therapy in patients with relapsed/refractory multiple myeloma (MM). MethodsThis cohort study included 27 patients with relapsed/refractory MM who were treated with CAR-T cells between December 2017 and October 2021. Patients were classified into 2 groups: normal ALP group (peak ALP <125 U/L, n = 10) and high ALP group (peak ALP ≥125 U/L, n = 17). ResultsWithin 1 month of CAR-T cell infusion, the incidence of ALP increases was 63%. We found that ALP levels began to rise in the second week, peaked in the third and fourth weeks, and began to decline in the second month. Moreover, the ALP levels in previous chemotherapy-responsive period were significantly lower than those after CAR-T therapy. Statistical analysis found that patients with increased ALP exhibited higher alanine aminotransferase and aspartate aminotransferase levels, higher and longer CAR-T cell proliferation, more serious CRS, higher cytokine and ferritin levels, and higher initial response rates. In addition, the duration of ALP increase was parallel to the duration of CAR-T expansion. Multivariable Cox‐regression analysis showed that peak ALP was the independent predictor for progression‐free survival (PFS) (HR = 0.029, 95% CI: 0.002-0.369). ConclusionsOur results suggest that the ALP levels after CAR-T therapy could serve as a suitable biomarker for monitoring CAR-T cell proliferation, CRS grading, and prognosis in patients with MM.

CAR T cell therapy in multiple myeloma, where are we now and where are we heading for?

The introduction of chimeric antigen receptor (CAR) T cells revolutionized treatment of relapsed and refractory multiple myeloma (RRMM) in recent years. Currently, two CAR T cell products-idecabtagene vicleucel and ciltacabtagene autoleucel-are approved in the United States and the European Union to treat patients with three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. Moreover, seminal phase III trials of both agents in earlier lines of therapy have been published recently. Despite unprecedented rates of deep and lasting remissions in RRMM, there are still areas of uncertainty regarding the optimal use and distribution of CAR T cells in multiple myeloma. In the current review, we discuss the available data on approved CAR T cell products as well as unmet clinical needs and ongoing developments to optimize usage of this promising treatment modality in multiple myeloma.

Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies.

e20049 Background: In patients with heavily pretreated relapse and refractory multiple myeloma (MM), novel approaches such as immunotherapies and B-cell maturation antigen (BCMA) targeted therapies have been utilized to show favorable responses Despite these therapies however, patients continue to have disease progression leaving them with fewer options. A need exists to investigate the optimal sequencing strategies in the treatment approach for MM with novel bispecific antibodies (BsAbs) and CAR T cell therapy in patients previously exposed to BCMA-directed therapies. Methods: A comprehensive review of active clinical trials, published primary literature, and meeting abstracts was performed to gather efficacy endpoints and overall response rates (ORR) in patients receiving BsAbs or CAR T therapy with previous exposure to BCMA directed therapy. Results: A variety of BCMA and non-BCMA directed BsAbs along with CAR T cell therapy have been evaluated for ORR in patients who received previous BCMA-targeted therapies. Teclistamab, a BCMA BsAb induced an adequate response of 40% in patients who received previous BCMA directed antibody drug conjugate (ADC) or CAR-T- cell therapy, with a deepening of response observed in 28%. Elranatamab, an investigational BCMA-targeted BsAb demonstrated a preliminary ORR of 54% in a cohort of 13 pts. Talquetamab, a first in class GPRC5D BsAb induced an ORR of 50% in pts with previous BCMA-directed therapy as monotherapy and resulted in an ORR of 72% in combination with daratumumab. Cevostamab, an investigational FcRH5 directed BsAb demonstrated an adequate ORR of 47% in 20 pts who received previous BCMA-directed therapy. In parallel to evaluating responses for BsAbs, CAR T cell therapies including cilta-cel and ida-cel have also induced favorable and durable responses in their prior BCMA therapy exposed cohorts with an ORR of 60.0% and 74% respectively. Comparable safety profiles across both BCMA treatment exposed and BCMA treatment-naive cohorts were observed among all studies. Additional endpoints including minimal residual disease and incidence of infections are to be included in final results. Conclusions: This analysis indicates that sequencing BsAbs and CAR -T cell therapy after previous BCMA-targeted treatments offers meaningful clinical benefit with durable response rates in patients who have few other options. Longer follow up and larger studies are needed to further evaluate their enhanced benefit and generate greater insight for optimal sequencing strategies in heavily pretreated MM patients who have exhausted other options. [Table: see text]

Immune dysregulation in multiple myeloma: the current and future role of cell-based immunotherapy.

Immune dysregulation is a hallmark of clinically active multiple myeloma (MM). Interactions between malignant clonal cells and immune cells within the bone marrow microenvironment are associated with the formation of a milieu favorable to tumor progression. IL-10, TGF-β and other immunoregulatory pathways are upregulated, promoting angiogenesis, tumor cell survival and inhibition ofthenative immune response. Transcriptomic evaluation of the bone marrow microenvironment reveals polarization of the T cell repertoire towards exhaustion and predominance of accessory cells with immunosuppressive qualities. These changes facilitate the immune escape of tumor cells and functional deficiencies that manifest as an increased risk of infection and a reduction in response to vaccinations. Immunotherapy with Chimeric Antigen Receptor (CAR) T cells and other cellular-based approaches have transformed outcomes for patients with advanced MM. Characterization of the immune milieu and identification of biomarkers predictive of treatment response are essential to increasing durability and allowing for the incorporation of novel strategies such as cancer vaccines. This paper will review the current use of cancer vaccines and CAR T cell therapy in MM as well as potential opportunities to expand and improve the application of these platforms.

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies.

Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export (SINEs), and T cell redirecting bispecific antibodies. However, MM remains an incurable neoplastic plasma cell disorder, and almost all MM patients inevitably relapse due to drug resistance. Encouragingly, B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in the treatment of relapsed/refractory (R/R) MM and brought new hopes for R/R MM patients in recent years. Due to antigen escape, the poor persistence of CAR-T cells, and the complicated tumor microenvironment, a significant population of MM patients still experience relapse after anti-BCMA CAR-T cell therapy. Additionally, the high manufacturing costs and time-consuming manufacturing processes caused by the personalized manufacturing procedures also limit the broad clinical application of CAR-T cell therapy. Therefore, in this review, we discuss current limitations of CAR-T cell therapy in MM, such as the resistance to CAR-T cell therapy and the limited accessibility of CAR-T cell therapy, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-T cells and armored CAR-T cells, optimizing manufacturing processes, combing CAR-T cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy after CAR-T cell therapy as salvage therapy or maintenance/consolidation therapy.

Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising efficacy in multiple myeloma (MM) patients, leading to FDA approval of two B cell maturation antigen (BCMA)-specific CAR-T cell therapies (ide-cel and cilta-cel). Despite the remarkable response rates and response depth of MM patients to CAR-T cell therapy, patients inevitably relapse. A growing body of evidence suggests that the activity of CAR-T cells is affected by the immunosuppressive tumor microenvironment (TME). In this review we have summarized the main challenges that CAR-T cells face in the TME, including various immunosuppressive cells, structural components, hypoxia, nutrient starvation, and metabolism. Moreover, we also discussed some candidate strategies for CAR-T cell therapy to overcome immunosuppressive TME and improve the efficacy of CAR-T cell therapy in the treatment of MM.

Pomalidomide enhances the maturation of dendritic cells derived from healthy donors and multiple myeloma patients.

Objective: To explore the effect of pomalidomide on the maturation of monocyte-derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients. Methods: MoDCs were generated by the incubation of monocytes from peripheral blood mononuclear cells (PBMCs) for 7days in a medium consisting of 800U/ml granulocyte-macrophage colony stimulating factor (GM-CSF), 500U/ml interleukin-4 (IL-4), RPMI 1,640 medium, 5% human serum, 100U/ml penicillin and 0.1mg/ml streptomycin. Meanwhile, the incubation system was administrated with 10µM pomalidomide or 1 × PBS as the control group. On the eighth day, cells were harvested and analyzed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as moDCs in the FACS analyzing system. After that, the expression of CD40 and HLA-DR on moDCs was analyzed. Meanwhile, the supernatant from the incubation system was evaluated for the secretion of cytokines interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein 1α (MIP-1α) by enzyme-linked immunosorbent assay (ELISA). Results: When analyzing all the HD-moDCs together (n = 15), pomalidomide significantly increased the mean fluorescence intensity (MFI) of CD40 expression and HLA-DR expression on moDCs compared with the control group (p = 0.003, p = 0.040). Meanwhile, the proportion of CD40+ moDCs and HLA-DR+ moDCs in total moDCs was significantly higher in the pomalidomide group than in the control group (p = 0.008, p = 0.032). When analyzing all MM patient-moDCs together (n = 11), pomalidomide significantly increased the MFI of CD40 expression and HLA-DR expression on moDCs compared with the control group (p = 0.047, p = 0.006). Meanwhile, the proportion of HLA-DR+ moDCs in total DCs was significantly higher in the pomalidomide group than in the control group (p < 0.001). Moreover, HD-moDCs (n = 8) treated with pomalidomide secreted 192% IL-12, 110% TNF-α, and 112% MIP-1α of the untreated moDCs (p = 0.020, p = 0.006, p = 0.055). However, when analyzing MM patient-moDCs (n = 10) together, the secretion of IL-12, TNF-α and MIP-1α from moDCs showed no significant difference between the pomalidomide group and the control group (p = 0.458, p = 0.377, p = 0.248). Conclusion: In vitro, 10µM pomalidomide enhances the maturation of moDCs derived from both HDs and MM patients. Pomalidomide shows potential to be applied as a DC adjuvant for DC-based immunotherapy, such as the DC vaccine and DC cell therapy in MM.