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Nature Communications May 2024Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors...
Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.
Topics: Multiple Myeloma; Humans; Chromosomes, Human, Pair 1; DNA-Binding Proteins; Transcription Factors; Gene Expression Regulation, Neoplastic; Plasma Cells; Mutation; Neoplasm Recurrence, Local; Tumor Suppressor Protein p53; Drug Resistance, Neoplasm; Gene Amplification
PubMed: 38755140
DOI: 10.1038/s41467-024-48327-9 -
Hematology/oncology Clinics of North... Dec 2023Multiple myeloma is the second most common hematological malignancy with an approximate incidence of up to 8.5 cases per 100,000 persons per year. Over the last decade,... (Review)
Review
Multiple myeloma is the second most common hematological malignancy with an approximate incidence of up to 8.5 cases per 100,000 persons per year. Over the last decade, therapy for multiple myeloma has undergone a revolutionary change. Chimeric antigen receptor (CAR) T-cell therapy has played a major role in this evolution. In this review, we discuss the existing state of CAR T-cell therapy in myeloma while evaluating several newer therapies and targets expected in the near future.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37563077
DOI: 10.1016/j.hoc.2023.05.008 -
International Journal of Molecular... Nov 2023Multiple myeloma (MM) is a hematological malignancy originated in the bone marrow and characterized by unhindered plasma cell proliferation that results in several... (Review)
Review
Multiple myeloma (MM) is a hematological malignancy originated in the bone marrow and characterized by unhindered plasma cell proliferation that results in several clinical manifestations. Although the main role of blood platelets lies in hemostasis and thrombosis, platelets also play a pivotal role in a number of other pathological conditions. Platelets are the less-explored components from the tumor microenvironment in MM. Although some studies have recently revealed that MM cells have the ability to activate platelets even in the premalignant stage, this phenomenon has not been widely investigated in MM. Moreover, thrombocytopenia, along with bleeding, is commonly observed in those patients. In this review, we discuss the hemostatic disturbances observed in MM patients and the dynamic interaction between platelets and myeloma cells, along with present and future potential avenues for the use of platelets for diagnostic and therapeutic purposes.
Topics: Humans; Blood Platelets; Multiple Myeloma; Hemorrhage; Hemostasis; Thrombosis; Cell Communication; Drug Delivery Systems; Tumor Microenvironment
PubMed: 37958838
DOI: 10.3390/ijms242115855 -
Life Sciences Nov 2023This study aimed to investigate the effect and mechanism of methylcrotonyl-CoA carboxylase subunit 1 (MCCA) on multidrug resistance in multiple myeloma (MM).
AIMS
This study aimed to investigate the effect and mechanism of methylcrotonyl-CoA carboxylase subunit 1 (MCCA) on multidrug resistance in multiple myeloma (MM).
MATERIALS AND METHODS
The apoptosis kit and CCK-8 reagent were used to detect drug-induced cell apoptosis and viability. Immunoprecipitation, immunofluorescence staining, and protein structural simulation were used to detect the interaction between MCCA and Bad. Immunodeficient mice were injected with ARD cells and treated with bortezomib. Changes in tumor burden were recorded by bioluminescence imaging, and κ light chain content in the blood of mice was detected by enzyme-linked immunoassay.
KEY FINDINGS
Patients with high MCCA expression from a primary MM dataset had superior overall survival. After treatment with different anti-MM drugs, MCCA knockdown MM (MCCA-KD) cells had higher survival rates than control knockdown (CTR-KD) cells (p < 0.05). Mechanistic studies have revealed that MCCA-KD cells had dysfunctional mitochondria with decreased Bax and Bad levels and increased Bcl-xl and Mcl-1 levels. Furthermore, that MCCA and Bad demonstrated protein-protein interactions. The half-life of Bad in MCCA-KD cells is significantly shorter than that in CTR-KD cells (7.34 vs. 2.42 h, p < 0.05). In a human MM xenograft mouse model, we confirmed that MCCA-KD tumors had a poor response to anti-MM drugs in vivo. Finally, we showed that MCCA might contribute to multidrug resistance in different human cancers, particularly in solid tumors.
SIGNIFICANCE
Our findings demonstrated a novel function of MCCA in multidrug resistance. The lack of MCCA expression promoted antiapoptotic cell signaling in MM cells.
Topics: Humans; Animals; Mice; Multiple Myeloma; Acyl Coenzyme A; Bortezomib; Apoptosis; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm
PubMed: 37805164
DOI: 10.1016/j.lfs.2023.122157 -
Trends in Pharmacological Sciences Aug 2023Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma.... (Review)
Review
Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Mitochondria; Immunotherapy; Drug Resistance, Neoplasm
PubMed: 37344251
DOI: 10.1016/j.tips.2023.05.006 -
Annals of Hematology Apr 2024Recently, many new therapies have improved the outcomes of patients with relapsed and/or refractory multiple myeloma (RRMM). Nevertheless, recurrence is still... (Review)
Review
Recently, many new therapies have improved the outcomes of patients with relapsed and/or refractory multiple myeloma (RRMM). Nevertheless, recurrence is still unavoidable, and better treatment choices for RRMM are urgently needed. The clinical success of Chimera antigen receptor (CAR) T cell therapy in many hematological diseases, including leukemia and lymphoma, has drawn considerable attention to RRMM. As CAR T cell therapy continues to mature and challenge traditional therapies, it is gradually changing the treatment paradigm for MM patients. The B cell maturation antigen (BCMA), expressed in malignant plasma cells but not normal ones, is an ideal target for MM treatment, due to its high expression. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) has approved two BCMA-targeting CAR T cell products, idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel), for use in RRMM. In this review, we focus on data from RRMM patients involved in clinical trials of Ide-cel and Cilta-cel and discuss the present situation and future direction of CAR T cell therapy for this condition.
Topics: United States; Humans; Multiple Myeloma; Immunotherapy, Adoptive; B-Cell Maturation Antigen; Receptors, Chimeric Antigen; Neoplasms, Plasma Cell; Cell- and Tissue-Based Therapy
PubMed: 37704875
DOI: 10.1007/s00277-023-05444-7 -
Hematology/oncology Clinics of North... Apr 2024Treatment options have expanded rapidly and widely in the past two decades for patients with multiple myeloma. Triplet novel agent-based induction regimens have been... (Review)
Review
Treatment options have expanded rapidly and widely in the past two decades for patients with multiple myeloma. Triplet novel agent-based induction regimens have been accepted as the standard practice wordwide over the last decade both for transplant-eligible and non-eligible patients. The addition of anti-CD38 monoclonal antibodies as part of quadruplet regimens has led to even deeper and longer-lasting responses. The impressive results shown by the quadruplets havebeen practice-changing where accessible in recent years. Chimeric antigen receptor T cell therapy and bispecific antibodies are being tested in the upfront setting and have the potential to once again shift the paradigm of treatment of newly diagnosed MM.
Topics: Humans; Multiple Myeloma; Antineoplastic Agents; Immunotherapy, Adoptive
PubMed: 38171937
DOI: 10.1016/j.hoc.2023.12.007 -
Problemy Radiatsiinoi Medytsyny Ta... Dec 2023The review presents data from the literature on the role of Tumor necrosis factor-α (TNF-α) and ionizing radiation (IR) in the pathogenesis and treatment of plasma... (Review)
Review
The review presents data from the literature on the role of Tumor necrosis factor-α (TNF-α) and ionizing radiation (IR) in the pathogenesis and treatment of plasma cell myeloma (PCM). There was analyzed disturbance of regulation of functioning of this cytokine, which affects the interaction of the immune system with substrate plasma cells under the influence of negative external factors, including ionizing radiation IR. Modern directions of therapy of this disease using the latest technologies are presented, in particular CAR T-cell therapy, which will allow to optimize in the future treatment of this disease and, thus, improve the quality and life expectancy of PCM patients.
Topics: Humans; Tumor Necrosis Factor-alpha; Multiple Myeloma; Cytokines; Radiation, Ionizing
PubMed: 38155115
DOI: 10.33145/2304-8336-2023-28-65-74 -
Biomaterials Science Jul 2023Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with...
Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with advances in therapeutic modalities over the past two decades, MM remains incurable, necessitating the development of new and potent therapies. Herein, we engineered a daratumumab-polymersome-DM1 conjugate (DPDC) based highly potent and CD38-selective immuno-nano-DM1 toxin for depleting MM cells . DPDC with controllable daratumumab density and disulfide-linked DM1 is of small size (51-56 nm), with high stability and reduction-triggered DM1 release. DPDC potently inhibited the proliferation of CD38-overexpressed LP-1 and MM.1S MM cells with IC values of 2.7 and 1.2 ng DM1 equiv. per mL, about 4-fold stronger than non-targeted PDC. Moreover, DPDC effectively and safely depleted LP-1-Luc MM cells in an orthotopic mouse model at a low DM1 dosage of 0.2 mg kg, thus alleviating osteolytic bone lesion and extending the median survival by 2.8-3.5-fold compared to all controls. This CD38-selective DPDC provides a safe and potent treatment strategy for MM.
Topics: Mice; Animals; Multiple Myeloma; ADP-ribosyl Cyclase 1; Hematologic Neoplasms; Cell Line, Tumor
PubMed: 37334506
DOI: 10.1039/d3bm00470h -
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