Multiple Myeloma Therapy Research Articles

Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer.

Cancer cells subvert multiple properties of normal cells, including escaping strict cell cycle regulation, gaining resistance to cell death, and remodeling the tumor microenvironment. The hallmarks of cancer have recently been updated and summarized. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also named NRF1) belongs to the cap'n'collar (CNC) basic-region leucine zipper (bZIP) family. It acts as a transcription factor and is indispensable for maintaining both cellular homoeostasis and organ integrity during development and growth, as well as adaptive responses to pathophysiological stressors. In addition, NFE2L1 mediates the proteasome bounce-back effect in the clinical proteasome inhibitor therapy of neuroblastoma, multiple myeloma, and triple-negative breast cancer, which quickly induces proteasome inhibitor resistance. Recent studies have shown that NFE2L1 mediates cell proliferation and metabolic reprogramming in various cancer cell lines. We combined the framework provided by "hallmarks of cancer" with recent research on NFE2L1 to summarize the role and mechanism of NFE2L1 in cancer. These ongoing efforts aim to contribute to the development of potential novel cancer therapies that target the NFE2L1 pathway and its activity.

The Challenging Approach to Multiple Myeloma: From Disease Diagnosis and Monitoring to Complications Management.

The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better stratify disease risk, development of more effective therapies and better management of side effects related to them. However, handling all these aspects requires an interdisciplinary approach involving multiple knowledge and collaboration of different specialists. The hematologist, faced with a patient with MM, must not only choose a treatment according to patient and disease characteristics but must also know when therapy needs to be started and how to monitor it during and after treatment. Moreover, he must deal not only with organ issues related to MM such as bone disease, renal failure or neurological disease but also with adverse events, often very serious, related to novel therapies, particularly new generation immunotherapies such as CAR T cell therapy and bispecific antibodies. In this review, we provide an overview on the newer MM diagnostic and monitoring strategies and on the main side effects of MM therapies, focusing on adverse events occurring during treatment with CAR T cells and bispecific antibodies.

NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in multiple myeloma

AbstractThe promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as natural killer (NK) cells that are mandatory for MM surveillance and therapy. Here, we performed a single-cell RNA sequencing analysis of NK cells from 10 patients with MM and 10 age/sex–matched healthy donors that revealed important transcriptomic changes in the NK cell landscape affecting both the bone marrow (BM) and peripheral blood compartment. The frequency of mature cytotoxic CD56dim NK cell subsets was reduced in patients with MM at the advantage of late-stage NK cell subsets expressing NF-κB and interferon-I inflammatory signatures. These NK cell subsets accumulating in patients with MM were characterized by low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced lymphocyte function-associated antigen 1 (LFA-1) integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM-infiltrating NK cells in a retrospective cohort of 177 patients with MM from the Intergroupe Francophone du Myélome (IFM) 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively affect patients’ clinical outcomes. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM–associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

Still high risk? A review of translocation t(14;16) in multiple myeloma.

Multiple myeloma (MM) is a heterogeneous and complex disease, both in mutational biology as well as in the clinical presentation of patients. While tailored and biomarker-targeted therapy remains the direct goal for patient-centric management, existing therapies in MM remain largely uniform. Translocation t(14;16) is a rare primary genetic event found in less than 5% of patients with newly diagnosed MM. Here, we present an overview of the biology of t(14;16), epidemiology, clinical presentation, prognostic impact, and discuss the future clinical and therapeutic strategies for targeting this rare yet high-risk group in MM to optimize patient outcomes.

The importance of oncological alertness in the differential diagnosis of inflammatory changes in the lungsdetected as a result of differential diagnosis of pneumonia

This article describes a case of lung cancer, the symptoms of which have long been regarded as manifestations of pneumonia; the stages of diagnostic search from the first symptoms of cancer to radical treatment are revealed. At the same time, the patient was diagnosed with monoclonal gammopathy of unknown significance, which at the stage of differential diagnosis suggested the development of synchronous cancer – lung cancer and the onset of multiple myeloma (MM). A number of literature sources were analyzed, according to the results of the analysis, it was found that at the moment six cases of the development of synchronous lung cancer and ММ have been described in the world, in most of which the age of patients was less than 70 years, which indicates a relatively early development of ММ. The issues of differential diagnosis of pneumonia and lung cancer are considered; the importance of early detection of malignant neoplasms (especially at the outpatient stage) is emphasized. It has been established that in some cases pneumonia can mask cancer, especially the detection of neoplasia after diagnosing pneumonia of the upper lobe localization. It has been suggested that the pathogenesis of lung cancer and ММ associated with intensive expression of CD38 may be common, and an example of a positive clinical effect on unresectable lung cancer with daratumumab is given (CD38-blocking monoclonal antibody used in MM therapy). At the same time, the revealed observation of the combined development of oncological diseases is very interesting, since in patients with different types of cancer, as a rule, each tumor tends to develop sequentially. However, our case was analyzed in comparison with literature data with cases of concomitant development of multiple myeloma and lung cancer simultaneously. At the same time, common genes and related pathogenesis of progression of two types of tumors were identified due to activation of the expression of the mitochondrial trans-2-enoyl-CoA reductase (MECR) concentrator gene.

Current Novel Targeted Therapeutic Strategies in Multiple Myeloma.

Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.

Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity (MRD2STOP).

106 Background: Measurable residual disease (MRD) negativity is a potential marker for the absence of disease in multiple myeloma (MM), which could be used to guide treatment cessation. MRD2STOP (NCT04108624) is a prospective study investigating outcomes among patients with sustained multimodal MRD negativity who discontinue maintenance therapy. Methods: Discontinuation of maintenance was permitted if MRD negative by PET/CT, flow cytometry (limit of detection [LoD] 10-5), and NGS by clonoSEQ (threshold 10-6). Patients underwent serial blood testing along with clonoSEQ, flow, and PET/CT annually for 3 years. Concurrent BM aspirate samples also underwent CD138+ immunomagnetic enrichment analyzed using clonoSEQ to achieve MRD 10-7 sensitivity. Primary endpoints were MRD resurgence rate at the 10-6threshold, along with progression-free survival (PFS) and overall survival among those MRD negative by the standard non-enriched clonoSEQ. Results: 83 patients were screened, and 47 patients met eligibility to discontinue maintenance as of 1/21/24. Median age was 66 years (range 39-84). 17 (36%) had high-risk disease at diagnosis (8 with 1q copy abnormalities, 5 with ISS stage 3, 2 with t(4;14), 1 with t(14;16), and 3 with del17p). Most (45/47, 96%) had one line of therapy; 26 (55%) received a triplet and 19 (40%) a quadruplet. Prior autologous transplant was received by 30 (64%) and multi-drug consolidation in 36 (77%) prior to single-agent maintenance. 96% received lenalidomide as maintenance. Median duration of consolidation/maintenance therapy prior to discontinuation was 36 months (range 12-95), including 14 (30%) with <27 months. Median follow-up was 30 months. Of 47 enrolled patients, 5 (11%) experienced disease progression and an additional 6 (13%) had MRD resurgence at 10-6. Of 11 MRD resurgent events, 4 (36%) were MRD 10-7 positive at baseline, and 3 (27%) were MRD 10-7 positive 1 year prior to MRD 10-6 resurgence. 2 second hematologic cancers occurred during follow-up: 1 Hodgkin lymphoma and 1 B-ALL, the latter which resulted in the only patient death on study. The estimated 3-year PFS was 85%, including 93% for patients MRD 10-7 negative (n=40) at baseline and 31% for those MRD 10-7 positive (n=7) at baseline (logrank p<0.001). Among the MRD evaluable patients (n=45), the 3-year MRD-free survival (MRD-FS) was 68%; 78% for patients MRD 10-7 negative (n=38) and 33% for patients MRD 10-7 positive (n=7) (logrank p<0.001). There were no differences in MRD-FS or PFS when stratified by high-risk disease, receipt of transplant, consolidation, or duration of maintenance. Conclusions: Discontinuation of maintenance therapy among patients with MM and multimodal MRD-negativity results in a high rate of sustained MRD-negativity and lack of disease progression. CD138+-enriched MRD samples using the clonoSEQ assay may help to even better identify patients who can discontinue therapy. Clinical trial information: NCT04108624 .

Exploring T cell subsets as predictors of response to BCMA targeting bispecific antibody therapy in multiple myeloma.

7567 Background: BCMA targeting bispecific Antibody (bsAb) therapy has shown unprecedented response and survival rates in patients with relapsed/refractory multiple myeloma (MM). The clinical activity of bsAb therapy has been shown to depend on T-cell function, yet clinical parameters, such as absolute lymphocyte count (ALC) have not been found to be associated with response to bsAbs. The aim of the present study was to elucidate whether distinct T cell subsets, such as CD4 and CD8 counts as well as their proportion within the ALC are associated with outcome of BCMA targeting bsAb therapy. Methods: We retrospectively collected data on 79 patients who had been treated with at least one full dose of a BCMA targeting bsAb. T cell subsets, including ALC, total CD3, CD4 and CD8, were measured from peripheral blood within 7 days prior to bsAb therapy initiation. Statistical analysis was performed with SAS version 9.4 using univariate and multivariate logistic regression models. Results: Median age of the patient cohort was 72 (31-84) years with 40/79 (51%) being male and 15/79 (19%) being African American. Median lines of therapy was 5 (2-12) with 78/79 (99%) patients being triple class refractory and 50/79 (63%) being penta-drug refractory. 59/79 (75%) of patients had at least one prior stem cell transplant (SCT) with 35/79 (44%) having had at least two SCTs. 26/79 (33%) patients had prior exposure to BCMA targeting therapy, with 18/79 (23%) and 8/79 (10%) previously having received belantamab mafodotin or BCMA targeting Car-T cell therapy respectively. Cytokine release syndrome (CRS) occurred in 38/79 (48%) of patients with the majority (92%) being grade 1 with the remainder being grade 2. Median ALC was 1.02 (0.25-5) x103/mL, median CD4 count was 0.27 (0.04-1.13) x103/mL while median CD8 count was 0.5 (0.07-2.97) x103/mL. Overall response (OR) rate of the whole cohort was 82% (69/79) with best responders (³very good partial response) comprising 51% (40/79). While total ALC, CD4 and CD8 counts did not appear to impact response to BCMA targeting bsAb therapy, the ratio of CD4 to ALC proved to be significantly associated with OR (univariate p=0.04) and best response (univariate p= 0.004, multivariate p=0.01) . The CD8 to ALC ratio had no significant impact in this patient population. The only other factor to show a significant association with response was the number of prior lines of therapy with higher numbers being associated with worse response (p=0.046). Conclusions: Our study suggests that an increased proportion of CD4 cells within the ALC is significantly associated with better response to BCMA targeting bsAb. While future studies are needed to elaborate on CD4 function in bsAB therapy, our findings imply that therapeutic strategies to increase the CD4 proportion could lead to improved bsAb therapy effectiveness.

Efficacy and safety of GPRC5D-based monotherapies for relapsed/refractory multiple myeloma: A systematic review and meta-analysis.

e19503 Background: G protein-coupled receptor family C group 5 member D (GPRC5D), a highly expressed receptor in myeloma cells, is one of the novel emerging targets for relapsed/ refractory (R/R) multiple myeloma (MM). Among the GRPC5D therapies, currently one agent talquetamab has been approved while CAR-T therapies are under development. Methods: A literature search using electronic databases Pubmed, Embase, Scopus, Web of Science and Cochrane, including major conference abstracts was conducted from inception to December 31, 2023 focusing on GPRC5D therapies in MM. For multiple reports of the same study, the latest available report of the study describing the efficacy or safety was selected. Only GPRC5D based monotherapies were included, and combination regimens were excluded for this review. Data on safety and efficacy were extracted, evaluated and systematically analyzed using Comprehensive Meta-analysis 3.3. The study protocol was registered with PROSPERO (CRD42024497933). Results: After screening 562 articles, and removing duplicates, total seven studies with 581 patients were included (5 GPRC5D-CAR T studies with 137 patients and 2 GPRC5D-BsAb studies with 444 patients). The pooled overall response rate (ORR) for GRPC5D therapies in this cohort was 77.4%, with best response rate [very good partial response (VGPR) or better] of 59.2%. The pooled incidence rate of cytokine release syndrome (CRS), any grade and Immune effector cell-associated neurotoxicity syndrome (ICANS), any grade, was 78.8% and 9.6% respectively. Grade 3/4 hematological adverse events included neutropenia being the most common (69.6%), followed by thrombocytopenia (36.8%) and anemia (34.2 %). Subgroup analysis was performed for GPRC5D therapies- CAR T and BsAb as shown in the table. Conclusions: GPRC5D based therapies showed high response rates in R/R MM with distinct side effect profile including CRS and cytopenias. Further studies along with follow up of the ongoing trials is needed to understand the long-term outcomes. [Table: see text]

Neurocognitive testing to predict ICANS post-CAR T.

e19003 Background: Since the approvals of chimeric antigen receptor T-cell (CAR T) therapy in acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), it has been increasingly offered in centers nationwide. Immune effector cell-associated neurotoxicity syndrome (ICANS) poses a potentially fatal risk with CAR-T. Identifying patients at risk of having high grade ICANS is a thus a priority. Scoring systems such as the EASIX scores have accounted for disease and comorbidity factors but haven’t addressed neurocognitive function. The St. Louis University Mental Status (SLUMS) Exam and the Montreal Cognitive Assessment (MoCA) have not been examined for validity and reliability in this population, so we performed a retrospective review of CAR T patients at the University of Kansas Medical Center to identify if incidence or severity of ICANS could be correlated with neurocognitive testing performed in the pre-infusion period. Methods: Patients receiving CAR T targeting CD19 or BCMA between December 2017 and December 2023 were included. Neurocognitive testing was performed by trained onco-psychology, neurology, or hematology-oncology staff. The SLUMS exam is an 11 question exam scored on a 30 point scale to predict normal neurocognitive function (27-30 points), mild neurocognitive disorders (21-26 points), and dementia (0-20 points). The MoCA is an 11 question exam scored on a 30 point scale to predict normal cognition (26-30 points), mild cognitive impairment (18-25 points), moderate cognitive impairment (10-17 points), and severe cognitive impairment (<10 points). Incidence of ICANS and severity of ICANS were compared between patients who had any detected cognitive dysfunction and those who had none, as well as between the tiered result system unique to each test. Results: We included 360 patients in this analysis, (257 NHL, 84 MM and 19 ALL) leading to comparisons of 276 CD19-directed CAR T patients and 84 BCMA-directed CAR T patients. In CD19-directed patients, there were no differences in ICANS incidence according to the SLUMS scores. There was a significant increase in ICANS incidence for patients who had a positive MoCA exam, p=0.006. Additionally, ICANS incidence was correlated with more severe MoCA results, p=0.01. No differences in ICANS severity were observed using any neurocognitive test. In BCMA-directed patients, no differences in ICANS were observed using the SLUMS or MoCA. Conclusions: Our results suggest that while the SLUMS exam does not predict ICANS, the MoCA may independently predict incidence of ICANS. Patients with a higher score correlating with normal cognition are less likely to develop ICANS and may be appropriate for outpatient therapy. For those with lower scores correlating with more severe neurocognitive disorders, inpatient monitoring and early intervention will continue to be important.

Metformin and cytokine release syndrome after immune effector cell therapy.

e14535 Background: Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor T cells (CAR-T) for hematologic malignancies. We hypothesized that patients undergoing CAR-T therapy who are on metformin will experience a lower incidence or severity of CRS than patients not on this medication. Methods: We evaluated all patients treated with CAR-T at Mayo Clinic Rochester between 1/1/2018 and 1/31/2023, and abstracted relevant clinical and laboratory characteristics to determine the incidence and severity of CRS, PFS as well as OS in patients who were, or were not, on metformin before and during CAR-T therapy for Type 2 diabetes mellitus. We used the Chi-Square test, Mann-Whitney test and the Kaplan-Meier method to analyze data. Results: In the 5-year interval under consideration 237 patients received CAR-T, 168 for non-Hodgkin lymphoma (NHL), and 69 for multiple myeloma (MM). 23 patients (15 NHL and 8 MM) were on metformin at the time of CAR-T. 15 patient developed CRS while on metformin and 175 patients not on metformin (p=0.05). Grade 3 or 4 CRS incidence was 4% in both groups (p=0.41). Of the 153 patients with NHL not on metformin, 121 developed any grade of CRS, while 10 of 15 patients on metformin developed CRS (p=0.268). 4 NHL patients developed CRS Grade ≥3 or higher, while 0 of 15 on metformin developed Grade ≥3 CRS (p=0.237). For the MM patients, the incidence of CRS was 49 patients not on metformin and 5 patients on metformin (p<0.001). 3 MM patients developed CRS Grade ≥3 or higher, while 0 of 8 on metformin developed Grade ≥3 CRS (p=0.346). 12 of 15 patients on metformin with NHL achieved CR compared to 92 of 153 patients not on metformin (p=0.1305). 3 of 8 patients with MM on metformin compared to 24 of 61 patients with MM not on metformin achieved CR or better post CAR-T (p=0.92). Tocilizumab was used in 40% of patients on metformin but in 66% of patients not on metformin (p=0.0016). In NHL patients, PFS from CAR-T infusion was not reached (range: 6.3 to NR) for patients on metformin versus 9.9 months (range: 6.3–19.5) in patients not on metformin (p = 0.3332). In the MM patients, progression-free survival (PFS) from CAR-T infusion was 8.4 months (95% CI: 7.9–not reached [NR]) for patients on metformin and 22.6 months (13.7–NR) for those not on metformin (p = 0.07). Median OS for NHL patients on metformin was not reached (9.766–NR) versus 32.6 months (18.6–NR) for patients not on metformin (p = 0.7022). Median OS was 17 months (95% CI: 8.3 to NR) for patients with MM on metformin vs NR (95% CI: 9.4 to NR) for patients not on metformin (p = 0.2559). Conclusions: In this retrospective study, the co-administration of metformin during CAR-T cell therapy for NHL and MM appears to be associated with a numerically reduced incidence of CRS. The effect appears to be particularly marked in patients with multiple myeloma. Metformin therapy did not seem to affect the response to CAR-T therapy in either NHL or MM.

Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32.

TPS7576 Background: Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit. Methods: MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator’s choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]). Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti–CD38 antibody–containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd. The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575 .

Comparison of infectious complications with BCMA-directed therapies in multiple myeloma

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25−0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31−3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05–3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21−0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17–0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

CAR-T Therapy in Multiple Myeloma: Looking Beyond

Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy.

The challenges and future of CAR T-cells for treating Multiple Myeloma

CAR T-cell therapy is a concept that modifies blood cells to fight against cancers. Studies have found that this hasn’t had long-term effects, and research has been conducted to find challenges that could cause this. Multiple different antigens are one of these challenges, as well as inefficiency in this method of therapy are challenge to this concept. There are many advancements that have been made that help resolve some of these challenges. Different generations of these CARs allow for stronger cells. These generations are different layers of protection that involve modifications to make the CARs more efficient. Dual-antigen specifically allows one CAR to target two different antigens, which could be present in the separate cells of the same cancer. NK-cell therapy is a different concept following the ideas of CAR T-cell therapy that could grow widely in the near future. This involves natural killer cells which are cells that are already programmed to kill these cells, making it unnecessary to modify them. This would also be much more efficient and has a lot of potential to become a commonly used treatment. These ideas were gathered through an in-depth exploration of CAR T-cell therapy for multiple myeloma discussing the current challenges and potential solutions within the field.

Factors determining utilization of stem cell transplant for initial therapy of multiple myeloma by patient race: exploring intra-racial healthcare disparities

Multiple myeloma (MM) therapeutics have evolved tremendously in recent years, with significant improvement in patient outcomes. As newer treatment options are developed, stem cell transplant (SCT) remains an important modality that provides excellent disease control and delays the progression of disease. Over the years, SCT use has increased overall in the U.S., but two distinct gaps remain, including suboptimal use overall and racial-ethnic disparities. We evaluated the National Cancer Database (NCDB) to study what sociodemographic factors might play a role within a given racial-ethnic group leading to disparate SCT utilization, such that targeted approaches can be developed to optimize SCT use for all. In nearly 112,000 cases belonging to mutually exclusive categories of non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA), and others, we found certain factors including age, comorbidity index, payor type, facility type (academic vs. community) and facility volume to be uniformly associated with SCT use for all the racial-ethnic groups, while gender was not significant for any of the groups. There were several other factors that had a differential impact on SCT utilization among the various race-ethnicity groups studied, including year of diagnosis (significant for NHW, NHB, and Hispanics), income level (significant for NHW and Hispanics), literacy level (significant for NHW and NHB), and geographic location of the treatment facility (significant for NHW and NHA). The suboptimal SCT utilization overall in the U.S. suggests that there may be room for improvement for all, even including the majority NHW, while we continue to work on factors that lead to disparities for the traditionally underserved populations. This study helps identify sociodemographic factors that may play a role specifically in each group and paves the way to devise targeted solutions such that resource utilization and impact can be maximized.

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma

Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.

FIRST ITALIAN CASE OF TRANSCATHETER TREATMENT OF AORTIC REGURGITATION IN L–VAD PATIENT WITH A DEDICATED DEVICE

Abstract In patients with L–VADs, aortic valve regurgitation is a relatively frequent complication often associated with high mortality. Surgical approaches are extremely complex and often lead to poor outcomes. TAVI can be a feasible solution but it is usually extremely challenging due to the absence of calcification and stenosis. We report the case of a 56–year–old man who underwent LVAD implantation 4years ago as destination therapy for dilated myocardiopathy and chronic multiple myeloma. During the last year, he progressively developed severe pure aortic regurgitation. Last month, he was admitted to our center for heart failure symptoms and recurrent ventricular arrhythmias (VT/VF). The patient was considered at high risk for surgery and evaluated for a transcatheter approach. Due to the absence of calcification and a relatively large annulus, we decided to use the JenaValve Trilogy prosthesis, the only THV CE approved for aortic regurgitation treatment. Unlike other types of THV (self– or balloon expandable), this is specifically designed for AR and does not require significant oversizing to allow correct anchoring. Another advantage in this setting is the possibility of avoiding the reduction of the LVAD flow due to the reduced risk of embolization and the possibility of proceeding to direct implantation without ventricular rapid pacing thanks to the direct anchoring method onto the native aortic leaflets. In this patient, a JenaValve size L bioprosthesis was implanted transfemorally under general anesthesia with an excellent result. The post–operative echocardiography showed a perfectly implanted prosthesis with no intraprosthesis regurgitation and only a mild anterior paravalvular leak with a subsequent improvement of all hemodynamic parameters. In our opinion, when feasible, the JenaValve implant can be a safe and effective therapeutic option in patients with active LVAD devices at high operative risk.

Construction of CD138-targeted chimeric antigen receptor- modified T cells and their effect in multiple myeloma therapy

Objective: To construct a novel chimeric antigen receptor T (CAR-T) cell targeting CD138 and to investigate its cytotoxicity against myeloma cells. Methods: The hybridoma strain that can stably secrete the CD138 monoclonal antibody (mAb) was prepared and obtained through monoclonal antibody screening technology. The hybridoma strain cells were intraperitoneally injected into mice to produce ascites containing monoclonal antibodies, which were then collected and purified to obtain pure CD138 mAb. Further examinations were performed to assess the biological characteristics of CD138 mAb. The variable region sequence of this antibody was amplified through reverse transcription polymerase chain reaction and was used as the antigen recognition domain of CD138 CAR, which was subsequently expressed on the surface of T cells by lentiviral infection. Flow cytometry was employed to assess the phenotype of CD138 CAR-T cells. In vitro cytotoxicity and degranulation assays were performed to evaluate their antitumor effects. Results: ① We successfully prepared anti-human CD138 antibody hybridoma cell lines and screened a hybridoma cell strain, 5G2, which could persistently and stably secrete the anti-CD138 antibody. ② The purified CD138 (5G2) mAb can especially recognize CD138(+) cells with a binding affinity constant (K(D)) of 6.011×10(-9) mol/L and showed no significant binding activity with CD138(-) cells. ③The variable region sequence of the CD138 (5G2) antibody was obtained using molecular cloning technology, and CD138 (5G2) CAR was successfully constructed and expressed on T cells through lentivirus infection and, concurrently, demonstrated effective binding to recombinant human CD138 protein.④ The proliferation of T cells transduced with the CD138 (5G2) CAR was highly efficient. The phenotype analysis revealed that CD138 (5G2) CAR-T cells exhibited a greater tendency to differentiate into central memory T cells and memory stem T cells, with a reduced proportion of terminally differentiated effector memory subsets. ⑤CD138 (5G2) CAR-T cells demonstrated specific cytotoxicity against CD138(+) myeloma cell line H929, whereas CD138(-) cell line K562 remained unaffected. The percentage of residual H929 cells was (12.92±8.02) % after co-culturing with CD138 (5G2) CAR-T cells, while (54.25±15.79) % was left in the Vector-T group (E∶T=1∶2; P<0.001). ⑥Results of degranulation assays demonstrated a significant activation of CD138 (5G2) CAR-T cells after co-culture with the H929 cell line, whereas no significant activation was observed in Vector-T cells [ (25.78±3.35) % vs (6.13±1.30) %, P<0.001]. ⑦After co-culturing with CD138(+) cells, CD138 (5G2) CAR-T cells exhibited a significant increase in cytokine secretion compared to the Vector-T group [interleukin-2: (1 697.52±599.05) pg/ml vs (5.07±1.17) pg/ml, P<0.001; interferon-γ: (3 312.20±486.38) pg/ml vs (9.28±1.46) pg/ml, P<0.001; and tumor necrosis factor-α: (1 837.43±640.49) pg/ml vs (8.75±1.65) pg/ml, P<0.001]. However, no significant difference was observed in cytokine secretion levels between the two groups after co-culturing with CD138(-) cells. Conclusion: This study successfully prepared a novel monoclonal antibody against CD138, and CAR-T cells constructed with the antigen recognition domain derived from this 5G2 mAb demonstrated effective antitumor activity against myeloma cells. This can be used as a new option for the detection of the CD138 antigen and proposes a novel strategy for multiple myeloma immunotherapy.