Multiple Myeloma Patients Research Articles

Expression of γδ T cells and lymphocyte subsets in newly diagnosed multiple myeloma patients

ObjectiveTo retrospectively analyze the expression and significance of γδ T cells and lymphocyte subsets in peripheral blood on patients with multiple myeloma (MM). MethodsFifty-five patients with multiple myeloma admitted to Yangpu Hospital Affiliated to Tongji University from January 2022 to August 2023 were selected as the disease group, and were categorized into stage I group, stage II group and stage III group according to the International Staging System (ISS) of multiple myeloma. All included patients were consecutive visits. Another 30 cases of healthy people with physical examination were selected as the control group. Flow cytometry was used to detect the γδ T cells and lymphocyte subsets in the peripheral blood of the subjects. After clinical indicators of patients and healthy controls were collected, the statistical analysis was conducted. ResultsCompared with the control group, the percentage of γδ T cells and CD8+ T cells in the disease group were higher, while, the absolute numbers of total peripheral blood lymphocytes (LYMT) and CD19+ B cells, percentage of CD19+ B cells, CD3+ T cells, CD4+ T cells were lower (P​<​0.05). The percentage of γδ T cells (P​<​0.001), the percentage of CD19+ B cells (P​=​0.003), the absolute number of CD3+ T cells (P​=​0.010), the absolute number of CD8+ T cells (P​=​0.002) were the significant influential factors of MM. γδ T cells (P​=​0.004), neutrophils (P​<​0.001), neutrophil to lymphocyte ratio (P​=​0.003), and white blood cell count (P​<​0.001) were statistically different in different stages. ROC curve suggested that the area under the curve of the percentage of γδ T cells in predicting the MM were 0.973 (P​<​0.001) which had certain diagnostic value. Conclusionsγδ T cells and lymphocyte subsets (CD8+ T cells, CD19+ B cells, CD3+ T cells, etc.) in patients with newly diagnosis of MM can reflect the immune function of the patient’s organism, which is a key factor of MM. γδ T cells influence the staging of MM patients, and also have certain diagnostic value.

Leveraging diverse cellular stress patterns for predicting clinical outcomes and therapeutic responses in patients with multiple myeloma.

Tumour microenvironment harbours diverse stress factors that affect the progression of multiple myeloma (MM), and the survival of MM cells heavily relies on crucial stress pathways. However, the impact of cellular stress on clinical prognosis of MM patients remains largely unknown. This study aimed to provide a cell stress-related model for survival and treatment prediction in MM. We incorporated five cell stress patterns including heat, oxidative, hypoxic, genotoxic, and endoplasmic reticulum stresses, to develop a comprehensive cellular stress index (CSI). Then we systematically analysed the effects of CSI on survival outcomes, clinical characteristics, immune microenvironment, and treatment sensitivity in MM. Molecular subtypes were identified using consensus clustering analysis based on CSI gene profiles. Moreover, a prognostic nomogram incorporating CSI was constructed and validated to aid in personalised risk stratification. After screening from five stress models, a CSI signature containing nine genes was established by Cox regression analyses and validated in three independent datasets. High CSI was significantly correlated with cell division pathways and poor clinical prognosis. Two distinct MM subtypes were identified through unsupervised clustering, showing significant differences in prognostic outcomes. The nomogram that combined CSI with clinical features exhibited good predictive performances in both training and validation cohorts. Meanwhile, CSI was closely associated with immune cell infiltration level and immune checkpoint gene expression. Therapeutically, patients with high CSI were more sensitive to bortezomib and antimitotic agents, while their response to immunotherapy was less favourable. Furthermore, invitro experiments using cell lines and clinical samples verified the expression and function of key genes from CSI. The CSI signature could be a clinically applicable indicator of disease evaluation, demonstrating potential in predicting prognosis and guiding therapy for patients with MM.

Efficacy of CARVYKTI in CARTITUDE-4 versus other conventional treatment regimens for lenalidomide-refractory multiple myeloma using inverse probability of treatment weighting.

Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

Exploring the Link Between High-Risk Cytogenetics and Skeletal Lytic Lesions in African American (AA) Multiple Myeloma (MM) Patients: Insights From a Decade-Long Study

Exploring the Link Between High-Risk Cytogenetics and Skeletal Lytic Lesions in African American (AA) Multiple Myeloma (MM) Patients: Insights From a Decade-Long Study

Dose-Adjusted Melphalan Yields Comparable MRD-Negativity to Full-Dose Melphalan in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Dose-Adjusted Melphalan Yields Comparable MRD-Negativity to Full-Dose Melphalan in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Real-Life Management of Patients Aged 80 Years Old and Over With Multiple Myeloma: Results of the EMMY Cohort

Multiple myeloma patients aged 80 years and older are a population more prone to comorbidities and frailty. We aim to describe the real-life management and outcomes of this population. EMMY is a descriptive large-scale study. Between 2017 and 2021 we included 4383 patients of which 894 (20.3%) were aged ≥ 80 years. Four cohorts of patients aged ≥ 80 years were analysed: line 1 (L1), line 2 (L2), line 3 (L3) or line 4+ (L4+).The proportion of patients ≥ 80 years old was 20.8% in L1, 21.3% in L2, 20.9% in L3 and 17.8% in L4+. L1 patients received more treatment including a proteasome inhibitor (PI) (42.9%), L2 patients received mainly an immunomodulator (IMID) (65.9%) or an anti-CD38 (31.5%). For L3, IMID was used in 71.4% than an anti-CD38 (33.5%). L4+ patients received a PI (40.6%), IMID (33.2%) or an anti-CD38 (29.1%). Regarding efficacy, the median progression-free survival was 18.4 months in L1, 15.1 months in L2, 10.4 months in L3 and 6.5 months in L4+. The median overall survival was 49 months in L1, 31.3 months in L2, 21.4 months in L3 and 13.6 months in L4+.EMMY cohort confirmed that patients ≥ 80 years of age represent an important proportion of MM patients, in the de novo or relapse setting. This study is an important step in improving our comprehension and management of treatment in elderly patients.

Impact of MRD Status on Survival Rates in Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients: A Systematic Review and Meta-Analysis

Impact of MRD Status on Survival Rates in Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients: A Systematic Review and Meta-Analysis

Angiogenesis and multiple myeloma: Exploring prognostic potential of adrenomedullin.

Adrenomedullin (AM) is a multifunctional peptide which under basal conditions mainly regulates vasodilation and maintains vascular integrity but is also implicated in the pathogenesis of several malignancies, including multiple myeloma (MM). It has been shown that adrenomedullin is expressed by human myeloma cell lines and that it enhances MM-driven angiogenesis. However, the clinical impact of AM remains unknown. On that basis, we enrolled 32 newly diagnosed multiple myeloma patients (NDMM) and studied the potential of AM as a prognostic biomarker. We report that elevated levels of AM trend with suboptimal treatment response and inferior survival of NDMM patients.

ASCT: A Viable First-Line Treatment Option for Elderly Multiple Myeloma Patients Without Access to New Drugs

ASCT: A Viable First-Line Treatment Option for Elderly Multiple Myeloma Patients Without Access to New Drugs

831P Impact of chronic kidney disease on disease outcomes in hospitalized multiple myeloma patients: A National inpatient sample study from 2016 to 2020

831P Impact of chronic kidney disease on disease outcomes in hospitalized multiple myeloma patients: A National inpatient sample study from 2016 to 2020

Feasibility and Outcome of First-Line Autotransplant-Based Treatment in Newly Diagnosed Multiple Myeloma Patients Aged > 65 Years: Monocentric Retrospective Real-World Analysis.

We performed a monocentric, retrospective real-world analysis (RWA) to evaluate the feasibility and the main results of an autologous stem cell transplantation (ASCT)-based program in a cohort of 90 newly diagnosed multiple myeloma patients aged &gt; 65 years who were deemed eligible to such program on the basis of a simplified frailty score. Seventy-six patients received at least one ASCT and 14 patients received also the second. Median progression-free survival was 42 months and overall survival was 84 months. These results compare well with those of other RWAs, and pave the way to further improvements upon incorporation of an anti-CD38+ monoclonal antibody in the ASCT programs.

IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

DrugFormer: Graph-Enhanced Language Model to Predict Drug Sensitivity.

Drug resistance poses a crucial challenge in healthcare, with response rates to chemotherapy and targeted therapy remaining low. Individual patient's resistance is exacerbated by the intricate heterogeneity of tumor cells, presenting significant obstacles to effective treatment. To address this challenge, DrugFormer, a novel graph-augmented large language model designed to predict drug resistance at single-cell level is proposed. DrugFormer integrates both serialized gene tokens and gene-based knowledge graphs for the accurate predictions of drug response. After training on comprehensive single-cell data with drug response information, DrugFormer model presents outperformance, with higher F1, precision, and recall in predicting drug response. Based on the scRNA-seq data from refractory multiple myeloma (MM) and acute myeloid leukemia (AML) patients, DrugFormer demonstrates high efficacy in identifying resistant cells and uncovering underlying molecular mechanisms. Through pseudotime trajectory analysisunique drug-resistant cellular states associated with poor patient outcomes are revealed. Furthermore, DrugFormer identifies potential therapeutic targets, such as COX8A, for overcoming drug resistance across different cancer types. In conclusion, DrugFormer represents a significant advancement in the field of drug resistance prediction, offering a powerful tool for unraveling the heterogeneity of cellular response to drugs and guiding personalized treatment strategies.

Genetic Alteration of p18INK4C and its Expression in Peripheral Blood Mononuclear Cells Were Not Associated With Progression-free Survival of Multiple Myeloma Patients After Autologous Stem Cell Transplant.

The tumor suppressor CDKN2C (also designed as p18INK4C or p18) is deleted in approximately 7% to 40% of multiple myeloma (MM) patients, indicative of its potential association with myeloma pathogenesis. A quantitative real-time PCR-based assay was developed to determine p18 deletion in DNA from peripheral blood mononuclear cells (PBMCs) in a cohort of 108 multiple myeloma patients after autologous stem cell transplant (ASCT). Additionally, the p18 mRNA expression level in PBMCs was quantitatively assessed using Taqman® gene expression assays. p18 was homozygously and hemizygously deleted in PBMCs from 3 (2.8%) and 5 (4.6%) patients, respectively. Neither the p18 deletion nor the p18 mRNA levels in PBMCs were associated with progression-free survival (PFS), 90-day response, and the occurrence of severe mucositis in these patients (all p-values >0.20). Neither p18 deletion nor p18 mRNA expression in PBMCs can be used as a prognostic biomarker in MM patients.

Developing and validating a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways using a national clinical registry.

Multiple myeloma is a haematological malignancy typically characterised by neoplastic plasma cell infiltration of the bone marrow. Treatment for multiple myeloma consists of multi-line chemotherapy with or without autologous stem cell transplantation and has been rapidly evolving in recent years. However, clinical trials are unable to provide patients and clinicians with long-term prognostic information nor policymakers with the full body of evidence needed to perform economic evaluation of new therapies or make reimbursement decisions. To address these limitations of the available evidence, this study aimed to develop and validate the EpiMAP Myeloma model, a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways. Risk equations were estimated using the Australian and New Zealand Myeloma & Related Diseases Registry after multiple imputation of missing data. Risk equation coefficients were combined with multiple myeloma patients at diagnosis from the Registry to perform the simulation. The model was validated with 100 bootstraps of an out-of-sample prediction analysis using a 70/30 split of the 4,121 registry patients diagnosed between 2009 and 2023, resulting in 2,884 and 1,237 patients in the training and validation cohorts, respectively. For 90% of the 120 months in the 10-year post-diagnosis period, there was no significant difference in overall survival between the validation and simulated cohorts. These results highlight that the EpiMAP Myeloma model is robust at predicting multiple myeloma disease outcomes and treatment pathways in Australia & New Zealand. In the future, clinicians will be able to use the EpiMAP Myeloma model to provide personalised estimates of life expectancy to patients based on their specific characteristics, disease stage, and response to treatment. Policymakers will also be able to use the model to perform economic evaluation, to forecast the number of patients receiving treatment at different stages, and to determine the downstream impact of listing new, effective therapies.

The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

Exosomal Vesicles as a Promising Strategy for Severe COVID-19 in Multiple Myeloma Patients

Exosomal Vesicles as a Promising Strategy for Severe COVID-19 in Multiple Myeloma Patients

MM-357 Systematic Literature Review and Meta-Analysis of Clinical Trials of Fourth Line or Higher Treatment for Relapsed/Refractory Multiple Myeloma Patients

ObjectiveTreatment options for relapsed/refractory multiple myeloma (RRMM) have expanded, but clinical burden remains high, particularly for heavily pretreated patients. This systematic literature review and meta-analysis was conducted to synthesize outcomes from clinical trials evaluating fourth line or higher (4L+) treatment regimens. MethodologySearches using Embase, MEDLINE, and CENTRAL were conducted (January 2012-March 2024), and publications from key conferences were hand-searched. Eligible studies were clinical trials that included the phase 2 dose of a National Comprehensive Cancer Network recommended intervention and whose population was ≥80% 4L+. Meta-analyses were conducted to synthesize outcomes by treatment class (CAR T-cell therapies [CAR T], bispecific antibodies [BsAb], and Other) using random effects models where possible. For outcomes where Kaplan-Meier curves were available, meta-analyses were conducted using survival function parameters fitted to each curve. ResultsThe meta-analysis included 34 trials (5 CAR T, 3 BsAb, and 26 Other). All CAR T and 2 BsAb trials investigated BCMA-targeting interventions. The estimated overall response rates for CAR T, BsAb, and Other were 85.5% (95% confidence interval: 72.7, 92.9), 67.6% (62.0, 72.8), and 40.5% (33.3, 48.1), respectively. The 1-year overall survival was 84.4% (79.1, 88.4) for CAR T, 70.4% (66.6, 73.9) for BsAb, and 59.5% (55.8, 63.1) for Other. The 1-year progression-free survival was 59.0% (53.7, 64.0) for CAR T, 48.4% (44.2, 52.3) for BsAb, and 20.9% (17.9, 24.0) for Other. Infections occurred in 67.1% (59.6, 73.8) with CAR T, 69.2% (60.9, 76.5) with BsAb, and 60.2% (48.6, 70.9) with Other. For adverse events specific to the immune effector cell therapies of CAR T and BsAb, overall neurotoxicity occurred in 18.8% (10.0, 32.3) and 10.2% (7.2, 14.2), respectively, and cytokine release syndrome (CRS) in 92.3% (85.2, 96.2) and 71.4% (63.4, 78.3). Additional outcomes data will be presented. ConclusionsThis study offers a comprehensive and up-to-date synthesis of clinical trial outcomes for recommended interventions in 4L+ treatments for RRMM. While efficacy outcomes are improving with more recently approved interventions, there remains an unmet need for durable treatments with an improved safety profile in this population.

Systematic Literature Review and Meta-Analysis of Clinical Trials of Fourth Line or Higher Treatment for Relapsed/Refractory Multiple Myeloma Patients

Systematic Literature Review and Meta-Analysis of Clinical Trials of Fourth Line or Higher Treatment for Relapsed/Refractory Multiple Myeloma Patients

Lenalidomide Maintenance Therapy After Autologous Stem Cell Transplant in Multiple Myeloma Patients: Assessing Real-World Impact on Treatment Outcomes and Beyond

Lenalidomide Maintenance Therapy After Autologous Stem Cell Transplant in Multiple Myeloma Patients: Assessing Real-World Impact on Treatment Outcomes and Beyond