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Technology in Cancer Research &... 20241q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in...
OBJECTIVE
1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp.
METHODS
Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed.
RESULTS
Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% 37.0%, = 0.034), lower disease progression rate (31.8% 70.3%, = 0.002), longer sustained remission (median 49.7 months 18.3 months, = 0.030), and longer PFS (median 61.9 months 22.9 months, = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% 77.8%, = 0.532) or CR (27.3% 13.0%, = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (= 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (= 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (= 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS.
CONCLUSIONS
When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.
Topics: Humans; Bortezomib; Lenalidomide; Multiple Myeloma; Female; Male; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Aged; Chromosomes, Human, Pair 1; Adult; Retrospective Studies; Prognosis; Treatment Outcome; Chromosome Aberrations; Aged, 80 and over; Dexamethasone
PubMed: 38759699
DOI: 10.1177/15330338241252605 -
Biomedicine & Pharmacotherapy =... Jun 2024Despite significant advancements in multiple myeloma (MM) treatment in recent years, most patients will eventually develop resistance or experience relapse. Matrine, a...
Despite significant advancements in multiple myeloma (MM) treatment in recent years, most patients will eventually develop resistance or experience relapse. Matrine, a primary active compound of traditional Chinese medicinal herb Sophora flavescens Ait, has been found to have anti-tumor properties in various types of malignant tumors. Whether autophagy plays a crucial role in the anti-MM effect of matrine remain unknown. Herein, we found that matrine could trigger apoptosis and cell cycle arrest, and meanwhile induce autophagy in MM cells in vitro. We further ascertained the role of autophagy by using ATG5 siRNA or the autophagy inhibitor spautin-1, which partially reversed matrine's inhibitory effect on MM cells. Conversely, the combination of matrine with the autophagy inducer rapamycin enhanced their anti-tumor activity. These findings suggest that autophagy induced by matrine can lead to cell death in MM cells. Further mechanism investigation revealed that matrine treatment increased the levels of reactive oxygen species (ROS) and AMPKα1 phosphorylation and decreased the phosphorylation of mTOR in MM cells. Additionally, co-treatment with AMPKα1 siRNA or the ROS scavenger N-acetyl-1-cysteine weakened the increase in autophagy that was induced by matrine. Finally, we demonstrated a synergistic inhibitory effect of matrine and rapamycin against MM in a xenograft mouse model. Collectively, our findings provided novel insights into the anti-MM efficacy of matrine and suggest that matrine induces autophagy by triggering ROS/AMPK/mTOR axis in MM cells, and combinatorial treatment of matrine and rapamycin may be a promising therapeutic strategy against MM.
Topics: Matrines; Quinolizines; Multiple Myeloma; Alkaloids; Reactive Oxygen Species; Humans; Apoptosis; Animals; TOR Serine-Threonine Kinases; Cell Line, Tumor; AMP-Activated Protein Kinases; Autophagic Cell Death; Signal Transduction; Xenograft Model Antitumor Assays; Mice; Autophagy
PubMed: 38759291
DOI: 10.1016/j.biopha.2024.116738 -
Cancer Immunology, Immunotherapy : CII May 2024Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all...
BACKGROUND
Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab.
OBJECTIVE
We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment.
METHODS
We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment.
RESULTS
Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen.
CONCLUSION
We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.
Topics: Humans; Multiple Myeloma; Female; Male; Thalidomide; Aged; Middle Aged; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Lymphocytes; Monocytes; Antibodies, Monoclonal, Humanized; Adult; Aged, 80 and over; Prognosis
PubMed: 38758239
DOI: 10.1007/s00262-024-03711-8 -
BMC Nephrology May 2024Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can...
BACKGROUND
Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can also affect younger populations, though with a lower incidence.
CASE PRESENTATION
Here, we present the case of a 32-year-old woman diagnosed with IgA lambda MM. She presented with fatigue, nausea, acute kidney injury (AKI) with a rapid increase in creatinine, and anemia. A kidney biopsy was done to rule out a rapidly progressive glomerular disease and a diagnosis was thus reached. A genetic workup revealed t(14;16) translocation and an extra copy of TP53. The patient received aggressive intravenous steroids and intravenous fluid resuscitation, resulting in an improvement in renal function. Treatment with daratumumab in combination with bortezomib, thalidomide, and dexamethasone was initiated and well tolerated. Despite the generally poor prognosis of IgA MM, our case emphasizes the importance of considering MM in young patients with unexplained kidney injury.
CONCLUSION
Early recognition and prompt intervention are essential in managing MM patients, especially in those with high-risk cytogenetic abnormalities. This case serves as a reminder for clinicians to maintain a high index of suspicion for MM, even in younger populations, when presented with unexplained kidney injury.
Topics: Humans; Female; Adult; Multiple Myeloma; Proteinuria; Translocation, Genetic; Acute Kidney Injury; Immunoglobulin A; Immunoglobulin lambda-Chains; Chromosomes, Human, Pair 14
PubMed: 38755555
DOI: 10.1186/s12882-024-03600-3 -
Nature Communications May 2024The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow...
The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.
Topics: Multiple Myeloma; Humans; Chromatin Assembly and Disassembly; Tumor Microenvironment; Cell Line, Tumor; Mesenchymal Stem Cells; Gene Expression Regulation, Neoplastic; Transcription, Genetic; Bone Marrow Cells; Cell Movement; Stromal Cells; Female; Male
PubMed: 38755155
DOI: 10.1038/s41467-024-47793-5 -
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 -
Scientific Reports May 2024Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Diagnosing MM presents considerable...
Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Diagnosing MM presents considerable challenges, involving the identification of plasma cells in cytology examinations on hematological slides. At present, this is still a time-consuming manual task and has high labor costs. These challenges have adverse implications, which rely heavily on medical professionals' expertise and experience. To tackle these challenges, we present an investigation using Artificial Intelligence, specifically a Machine Learning analysis of hematological slides with a Deep Neural Network (DNN), to support specialists during the process of diagnosing MM. In this sense, the contribution of this study is twofold: in addition to the trained model to diagnose MM, we also make available to the community a fully-curated hematological slide dataset with thousands of images of plasma cells. Taken together, the setup we established here is a framework that researchers and hospitals with limited resources can promptly use. Our contributions provide practical results that have been directly applied in the public health system in Brazil. Given the open-source nature of the project, we anticipate it will be used and extended to diagnose other malignancies.
Topics: Humans; Bone Marrow; Brazil; Hematology; Machine Learning; Multiple Myeloma; Neural Networks, Computer; Plasma Cells
PubMed: 38750071
DOI: 10.1038/s41598-024-61420-9 -
Cancer Research Communications Jun 2024Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However,...
UNLABELLED
Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However, tumors subvert the antigen presentation machinery to escape immunosurveillance. We hypothesized that proteasome activation could concomitantly increase antigen abundance and diversity in multiple myeloma cells. High-throughput screens revealed that histone deacetylase 6 (HDAC6) inhibitors activated proteasomes to unmask neoantigens and amplify the tumor-specific antigenic landscape. Treatment of patient CD138+ cells with HDAC6 inhibitors significantly promoted the antimyeloma activity of autologous CD8+ T cells. Pharmacologic blockade and genetic ablation of the HDAC6 ubiquitin-binding domain released HR23B, which shuttles ubiquitinylated cargo to proteasomes, while silencing HDAC6 or HR23B in multiple myeloma cells abolished the effect of HDAC6 inhibitors on proteasomes, antigen presentation, and T-cell cytotoxicity. Taken together, our results demonstrate the paradigm-shifting translational impact of proteasome activators to expand the myeloma immunopeptidome and have revealed novel, actionable antigenic targets for T cell-directed immunotherapy.
SIGNIFICANCE
The elimination of therapy-resistant tumor cells remains a major challenge in the treatment of multiple myeloma. Our study identifies and functionally validates agents that amplify MHC class I-presented antigens and pave the way for the development of proteasome activators as immune adjuvants to enhance immunotherapeutic responses in patients with multiple myeloma.
Topics: Humans; Histone Deacetylase 6; Proteasome Endopeptidase Complex; Multiple Myeloma; Histone Deacetylase Inhibitors; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Antigen Presentation; Antigens, Neoplasm
PubMed: 38747592
DOI: 10.1158/2767-9764.CRC-23-0528 -
Polish Archives of Internal Medicine May 2024
Health-related quality of life in patients with multiple myeloma treated in the phase 3 ATLAS trial of post-transplant maintenance with carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone.
Topics: Humans; Multiple Myeloma; Lenalidomide; Dexamethasone; Oligopeptides; Quality of Life; Male; Female; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Aged; Thalidomide
PubMed: 38747414
DOI: 10.20452/pamw.16749 -
Blood Advances May 2024
Spencer A, Moreau P, Mateos M-V, et al. Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX. Blood Adv. 2024;8(2):388-398.
Topics: Humans; Multiple Myeloma; Antibodies, Monoclonal; Recurrence
PubMed: 38743411
DOI: 10.1182/bloodadvances.2024013112