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Hematology/oncology Clinics of North... Apr 2024Multiple myeloma is characterized by a highly heterogeneous disease distribution within the bone marrow-containing skeletal system. In this review, we introduce the... (Review)
Review
Multiple myeloma is characterized by a highly heterogeneous disease distribution within the bone marrow-containing skeletal system. In this review, we introduce the molecular mechanisms underlying clonal heterogeneity and the spatio-temporal evolution of myeloma. We discuss the clinical impact of clonal heterogeneity, which is thought to be one of the biggest obstacles to overcome therapy resistance and to achieve cure.
Topics: Humans; Multiple Myeloma; Bone Marrow; Clonal Evolution
PubMed: 38195308
DOI: 10.1016/j.hoc.2023.12.012 -
Journal of the American Society For... Dec 2023Monoclonal gammopathies are a group of blood diseases characterized by presence of abnormal immunoglobulins in peripheral blood and/or urine of patients. Multiple...
Monoclonal gammopathies are a group of blood diseases characterized by presence of abnormal immunoglobulins in peripheral blood and/or urine of patients. Multiple myeloma and plasma cell leukemia are monoclonal gammopathies with unclear etiology, caused by malignant transformation of bone marrow plasma cells. Mass spectrometry with matrix-assisted laser desorption/ionization and time-of-flight detection is commonly used for investigation of the peptidome and small proteome of blood plasma with high accuracy, robustness, and cost-effectivity. In addition, mass spectrometry coupled with advanced statistics can be used for molecular profiling, classification, and diagnosis of liquid biopsies and tissue specimens in various malignancies. Despite the fact there have been fully optimized protocols for mass spectrometry of normal blood plasma available for decades, in monoclonal gammopathy patients, the massive alterations of biophysical and biochemical parameters of peripheral blood plasma often limit the mass spectrometry measurements. In this paper, we present a new two-step extraction protocol and demonstrated the enhanced resolution and intensity (>50×) of mass spectra obtained from extracts of peripheral blood plasma from monoclonal gammopathy patients. When coupled with advanced statistics and machine learning, the mass spectra profiles enabled the direct identification, classification, and discrimination of multiple myeloma and plasma cell leukemia patients with high accuracy and precision. A model based on PLS-DA achieved the best performance with 71.5% accuracy (95% confidence interval, CI = 57.1-83.3%) when the 10× repeated 5-fold CV was performed. In summary, the two-step extraction protocol improved the analysis of monoclonal gammopathy peripheral blood plasma samples by mass spectrometry and provided a tool for addressing the complex molecular etiology of monoclonal gammopathies.
Topics: Humans; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Multiple Myeloma; Leukemia, Plasma Cell; Paraproteinemias; Plasma
PubMed: 37994781
DOI: 10.1021/jasms.3c00166 -
Haematologica May 2024
Topics: Humans; Multiple Myeloma
PubMed: 37981890
DOI: 10.3324/haematol.2023.284292 -
Cancer Biology & Medicine Sep 2023
Topics: Humans; Multiple Myeloma; Immunotherapy
PubMed: 37771140
DOI: 10.20892/j.issn.2095-3941.2023.0258 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2023Multiple myeloma is a hematologic malignancy that is typically associated with recurrent relapses. There are numerous frontline treatment regimens that are highly... (Review)
Review
INTRODUCTION
Multiple myeloma is a hematologic malignancy that is typically associated with recurrent relapses. There are numerous frontline treatment regimens that are highly effective for individual patients. The introduction of anti-CD38 monoclonal antibody therapy has shifted treatment decision-making in this setting, with many centers now considering the use of daratumumab as part of initial therapy regardless of patient eligibility for autologous stem cell transplantation (ASCT). Daratumumab has demonstrated clinical efficacy and acceptable toxicity in the first and later lines of therapy, increasing complexity in treatment selection and sequencing. Although daratumumab-containing regimens may not be appropriate for every patient, it is increasingly recognized that the most effective regimens should be used upfront, as high rates of attrition mean that many patients in real-world practice may see a limited number of lines of therapy.
METHODS
A panel of experts in multiple myeloma was convened to consider current evidence and treatment practices to inform a series of consensus statements on the optimal management of newly diagnosed multiple myeloma, including not only treatment selection, but the need for infection prophylaxis, route of administration, and mitigation of potential infusion-related reactions, among other clinical challenges.
RESULTS/CONCLUSIONS
The goal of the present review article is to encapsulate these consensus statements and the rationale for their development, which altogether may help inform treatment selection and clinical decision-making in the front line.
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; ADP-ribosyl Cyclase 1; Transplantation, Autologous; Neoplasm Recurrence, Local; Antineoplastic Agents; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37516547
DOI: 10.1016/j.clml.2023.07.001 -
Expert Opinion on Biological Therapy May 2024Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma... (Review)
Review
INTRODUCTION
Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory.
AREAS COVERED
We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6).
EXPERT OPINION
CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.
Topics: Multiple Myeloma; Humans; Immunotherapy, Adoptive; B-Cell Maturation Antigen; Biological Products; Receptors, Chimeric Antigen
PubMed: 38738379
DOI: 10.1080/14712598.2024.2352591 -
European Journal of Medicinal Chemistry Dec 2023Multiple myeloma (MM) is a common hematological malignancy. Although recent clinical applications of immunomodulatory drugs, proteasome inhibitors and CD38-targeting... (Review)
Review
Multiple myeloma (MM) is a common hematological malignancy. Although recent clinical applications of immunomodulatory drugs, proteasome inhibitors and CD38-targeting antibodies have significantly improved the outcome of MM patient with increased survival, the incidence of drug resistance and severe treatment-related complications is gradually on the rise. This review article summarizes the characteristics and clinical investigations of several MM drugs in clinical trials, including their structures, mechanisms of action, structure-activity relationships, and clinical study progress. Furthermore, the application potentials of the drugs that have not yet entered clinical trials are also reviewed. The review also outlines the future directions of MM drug development.
Topics: Humans; Multiple Myeloma; Proteasome Inhibitors; Antibodies, Monoclonal; Hematologic Neoplasms; Immunomodulating Agents
PubMed: 37879169
DOI: 10.1016/j.ejmech.2023.115875 -
Immunity, Inflammation and Disease Nov 2023Multiple myeloma (MM) ranks second among the most prevalent hematological malignancies. Recent studies have unearthed the promise of cuproptosis as a novel therapeutic...
BACKGROUND
Multiple myeloma (MM) ranks second among the most prevalent hematological malignancies. Recent studies have unearthed the promise of cuproptosis as a novel therapeutic intervention for cancer. However, no research has unveiled the particular roles of cuproptosis-related genes (CRGs) in the prediction of MM diagnosis.
METHODS
Microarray data and clinical characteristics of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed gene analysis, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms were applied to identify potential signature genes for MM diagnosis. Predictive performance was further assessed by receiver operating characteristic (ROC) curves, nomogram analysis, and external data sets. Functional enrichment analysis was performed to elucidate the involved mechanisms. Finally, the expression of the identified genes was validated by quantitative real-time polymerase chain reaction (qRT-PCR) in MM cell samples.
RESULTS
The optimal gene signature was identified using LASSO and SVM-RFE algorithms based on the differentially expressed CRGs: ATP7A, FDX1, PDHA1, PDHB, MTF1, CDKN2A, and DLST. Our gene signature-based nomogram revealed a high degree of accuracy in predicting MM diagnosis. ROC curves showed the signature had dependable predictive ability across all data sets, with area under the curve values exceeding 0.80. Additionally, functional enrichment analysis suggested significant associations between the signature genes and immune-related pathways. The expression of the genes was validated in MM cells, indicating the robustness of these findings.
CONCLUSION
We discovered and validated a novel CRG signature with strong predictive capability for diagnosing MM, potentially implicated in MM pathogenesis and progression through immune-related pathways.
Topics: Humans; Algorithms; Databases, Factual; Multiple Myeloma; Nomograms; ROC Curve; Apoptosis; Copper
PubMed: 38018590
DOI: 10.1002/iid3.1058 -
The Journal of Molecular Diagnostics :... Mar 2024Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in post-treatment settings can be crucial for relapse risk stratification in patients...
Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in post-treatment settings can be crucial for relapse risk stratification in patients with B-cell and plasma cell neoplasms. Prior studies have focused on validation of various technical aspects of the MRD assays, but more studies are warranted to establish the performance characteristics and enable standardization and broad utilization in routine clinical practice. Here, the authors describe an NGS-based IGH MRD quantification assay, incorporating a spike-in calibrator for monitoring B-cell and plasma cell neoplasms based on their unique IGH rearrangement status. Comparison of MRD status (positive or undetectable) by NGS and flow cytometry (FC) assays showed high concordance (91%, 471/519 cases) and overall good linear correlation in MRD quantitation, particularly for chronic lymphocytic leukemia and B-lymphoblastic leukemia/lymphoma (R = 0.85). Quantitative correlation was lower for plasma cell neoplasms, where underestimation by FC is a known limitation. No significant effects on sequencing efficiency by the spike-in calibrator were observed, with excellent inter- and intra-assay reproducibility within the authors' laboratory, and in comparison to an external laboratory, using the same assay and protocols. Assays performed both at internal and external laboratories showed highly concordant MRD detection (100%) and quantitation (R = 0.97). Overall, this NGS-based MRD assay showed highly reproducible results with quantitation that correlated well with FC MRD assessment, particularly for B-cell neoplasms.
Topics: Humans; Reproducibility of Results; Multiple Myeloma; Leukemia, Lymphocytic, Chronic, B-Cell; High-Throughput Nucleotide Sequencing; Neoplasm, Residual
PubMed: 38103591
DOI: 10.1016/j.jmoldx.2023.11.009 -
Blood Advances Aug 2023Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed... (Observational Study)
Observational Study
Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited.
Topics: Humans; Female; Male; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Retrospective Studies; Standard of Care; Neoplasms, Plasma Cell; Cytokine Release Syndrome
PubMed: 37307173
DOI: 10.1182/bloodadvances.2023009766