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Frontiers in Immunology 2024Infections are common in plasma cell cancer multiple myeloma (MM) due to disease-related immune deficiencies and cancer treatment. Myeloma cells express Toll-like...
Toll-like receptor signaling in multiple myeloma cells promotes the expression of pro-survival genes B-cell lymphoma 2 and MYC and modulates the expression of B-cell maturation antigen.
Infections are common in plasma cell cancer multiple myeloma (MM) due to disease-related immune deficiencies and cancer treatment. Myeloma cells express Toll-like receptors (TLRs), and TLR activation has been shown to induce proliferative and pro-survival signals in cancer cells. MM is a complex and heterogeneous disease, and expression levels of TLRs as well as downstream signaling components are likely to differ between patients. Here, we show that in a large cohort of patients, TLR1, TLR4, TLR6, TLR9, and TLR10 are the most highly expressed in primary CD138 cells. Using an MM cell line expressing TLR4 and TLR9 as a model, we demonstrate that TLR4 and TLR9 activation promoted the expression of well-established pro-survival and oncogenes in MM such as , , , and . TLR4 and TLR9 activation inhibited the efficacy of proteasome inhibitors bortezomib and carfilzomib, drugs used in the treatment of MM. Inhibiting the autophagosome-lysosome protein degradation pathway by hydroxychloroquine (HCQ) diminished the protective effect of TLR activation on proteasome inhibitor-induced cytotoxicity. We also found that TLR signaling downregulated the expression of , the gene encoding for B-cell maturation antigen (BCMA). , , and were upregulated in approximately 50% of primary cells, while the response to TLR signaling in terms of expression was dichotomous, as an equal fraction of patients showed upregulation and downregulation of the gene. While proteasome inhibitors are part of first-line MM treatment, several of the new anti-MM immune therapeutic drugs target BCMA. Thus, TLR activation may render MM cells less responsive to commonly used anti-myeloma drugs.
Topics: Humans; Multiple Myeloma; Signal Transduction; B-Cell Maturation Antigen; Cell Line, Tumor; Toll-Like Receptors; Proto-Oncogene Proteins c-myc; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins c-bcl-2; Bortezomib; Male
PubMed: 38911853
DOI: 10.3389/fimmu.2024.1393906 -
Journal of Radiology Case Reports 2024Multiple myeloma is a plasma cell neoplasm, which may present as a solitary plasmacytoma and, uncommonly, as an extramedullary plasmacytoma. Intracranial plasmacytomas...
Multiple myeloma is a plasma cell neoplasm, which may present as a solitary plasmacytoma and, uncommonly, as an extramedullary plasmacytoma. Intracranial plasmacytomas may manifest in central nervous system involvement as cranial nerve palsies. Cranial nerve six palsy is the most common in cases of malignancy. However, isolated abducens palsy presenting as multiple myeloma recurrence is very uncommon. Here, we detail two cases in which intracranial plasmacytoma lesions were present within the region of the Dorello canal, resulting in acute isolated unilateral diplopia from disease recurrence in the absence of systemic marrow involvement.
Topics: Humans; Abducens Nerve Diseases; Multiple Myeloma; Neoplasm Recurrence, Local; Male; Magnetic Resonance Imaging; Middle Aged; Aged; Diagnosis, Differential; Plasmacytoma; Female; Diplopia; Brain Neoplasms
PubMed: 38910589
DOI: 10.3941/jrcr.v18i1.5240 -
Oncology (Williston Park, N.Y.) Jun 2024The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.
The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.
Topics: Multiple Myeloma; Humans; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Chromosomes, Human, Pair 14; Antineoplastic Agents; Translocation, Genetic; Chromosomes, Human, Pair 11; Clinical Trials as Topic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38899981
DOI: 10.46883/2024.25921023 -
BMC Medical Genomics Jun 2024Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis...
BACKGROUND
Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis was used to construct the risk model and evaluate the prognostic value of ubiquitination-related genes in MM.
METHODS AND RESULTS
The data on ubiquitination-related genes and MM samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The consistent cluster analysis and ESTIMATE algorithm were used to create distinct clusters. The MM prognostic risk model was constructed through single-factor and multiple-factor analysis. The ROC curve was plotted to compare the survival difference between high- and low-risk groups. The nomogram was used to validate the predictive capability of the risk model. A total of 87 ubiquitination-related genes were obtained, with 47 genes showing high expression in the MM group. According to the consistent cluster analysis, 4 clusters were determined. The immune infiltration, survival, and prognosis differed significantly among the 4 clusters. The tumor purity was higher in clusters 1 and 3 than in clusters 2 and 4, while the immune score and stromal score were lower in clusters 1 and 3. The proportion of B cells memory, plasma cells, and T cells CD4 naïve was the lowest in cluster 4. The model genes KLHL24, HERC6, USP3, TNIP1, and CISH were highly expressed in the high-risk group. AICAr and BMS.754,807 exhibited higher drug sensitivity in the low-risk group, whereas Bleomycin showed higher drug sensitivity in the high-risk group. The nomogram of the risk model demonstrated good efficacy in predicting the survival of MM patients using TCGA and GEO datasets.
CONCLUSIONS
The risk model constructed by ubiquitination-related genes can be effectively used to predict the prognosis of MM patients. KLHL24, HERC6, USP3, TNIP1, and CISH genes in MM warrant further investigation as therapeutic targets and to combat drug resistance.
Topics: Humans; Multiple Myeloma; Computational Biology; Prognosis; Ubiquitination; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Nomograms; Cluster Analysis
PubMed: 38898455
DOI: 10.1186/s12920-024-01937-0 -
BMC Ophthalmology Jun 2024Paraproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with...
BACKGROUND
Paraproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with diffuse or patchy pseudo lipid deposits. We present an atypical case of paraproteinemic keratopathy which lead to an initial misdiagnosis of infectious crystalline keratopathy.
CASE PRESENTATION
a 69-year-old woman with an asymptomatic keratopathy detected during a cataract intervention. Slit-lamp examination revealed several hyper refringent subepithelial foci with fern-shaped branches, resembling crystalline keratopathy, in her left eye. Anterior segment optical coherence tomography revealed exclusively subepithelial hyperreflective lesions limited to the anterior stroma. The progressive bilateralization and progression of the condition prompted us to include other entities with crystalline corneal deposits in our differential diagnosis. Hematological analysis showed a high number of free Kappa light chains. Despite the typical clinical appearance of crystalline keratopathy, the atypical evolution and test results led us to consider that monoclonal gammopathy could be the cause of this entity.
CONCLUSIONS
Paraproteinemic keratopathy may present in its early stages as a unilateral subepithelial crystalline keratopathy. Thus, it must always be taken into account in the differential diagnosis of any crystalline keratopathy, particularly when there are no predisposing factors for an infectious crystalline keratopathy. Early recognition of this rare entity is important to address the associated potentially serious systemic disease.
Topics: Humans; Aged; Female; Diagnosis, Differential; Corneal Diseases; Paraproteinemias; Tomography, Optical Coherence
PubMed: 38898421
DOI: 10.1186/s12886-024-03487-6 -
Nature Communications Jun 2024GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for...
GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, including monoclonal antibodies, CAR-T cells, and T-cell engagers. Despite its therapeutic potential, the insufficient understanding regarding of the receptor's structure and antibody recognition mechanism has impeded the progress of effective therapeutic development. Here, we present the structure of GPRC5D in complex with a preclinical-stage single-chain antibody (scFv). Our structural analysis reveals that the GPRC5D presents a close resemblance to the typical Class C GPCRs in the transmembrane region. We identify a distinct head-to-head homodimer arrangement and interface mainly involving TM4, setting it apart from other Class C homo- or hetero-dimers. Furthermore, we elucidate the binding site engaging a sizable extracellular domain on GPRC5D for scFv recognition. These insights not only unveil the distinctive dimer organization of this unconventional Class C GPCR but also hold the potential to advance drug development targeting GPRC5D for the treatment of multiple myeloma.
Topics: Humans; Multiple Myeloma; Receptors, G-Protein-Coupled; Single-Chain Antibodies; Protein Multimerization; Protein Binding; Binding Sites; Antibodies, Monoclonal
PubMed: 38898050
DOI: 10.1038/s41467-024-49625-y -
EJHaem Jun 2024Multiple myeloma (MM) is a disease, that at times poses diagnostic and monitoring challenges. Over the last decades laboratory methods have been expanded with serum free...
Multiple myeloma (MM) is a disease, that at times poses diagnostic and monitoring challenges. Over the last decades laboratory methods have been expanded with serum free light chain (FLC) analysis. Alerted by two index cases with clinical impact due to failure of the FLC analysis to indicate a disease progression, we aimed to identify any clinical consequences due to known differences between FLC analysis methods. We applied two FLC analysis methods (Freelite Binding Site [FBS] and N-Latex Siemens [NLS]) on all patients with MM and monoclonal gammopathy of uncertain significance diagnosed/followed up at Södra Älvsborg Hematology Unit, from April to December 2022. From a total of 123 patients with malignant plasma cell disorder, we identified five cases (4.1%) where solely the FBS method, as opposed to NLS, urine and serum electrophoresis, could support diagnosis or detect progression. The consequences of this discrepancy included not only change of diagnosis or delayed therapy but also change of treatment. Our findings indicate that a stronger awareness of the potential weaknesses of different FLC methods is needed, which calls for a closer collaboration between clinical chemists and hematologists.
PubMed: 38895087
DOI: 10.1002/jha2.886 -
Sensors (Basel, Switzerland) May 2024Multiple myeloma (MM) patients complain of pain and stiffness limiting motility. To determine if patients can benefit from vertebroplasty, we assessed muscle activation...
Instrumental Evaluation of the Effects of Vertebral Consolidation Surgery on Trunk Muscle Activations and Co-Activations in Patients with Multiple Myeloma: Preliminary Results.
Multiple myeloma (MM) patients complain of pain and stiffness limiting motility. To determine if patients can benefit from vertebroplasty, we assessed muscle activation and co-activation before and after surgery. Five patients with MM and five healthy controls performed sitting-to-standing and lifting tasks. Patients performed the task before and one month after surgery. Surface electromyography (sEMG) was recorded bilaterally over the erector spinae longissimus and rectus abdominis superior muscles to evaluate the trunk muscle activation and co-activation and their mean, maximum, and full width at half maximum were evaluated. Statistical analyses were performed to compare MM patients before and after the surgery, MM and healthy controls and to investigate any correlations between the muscle's parameters and the severity of pain in patients. The results reveal increased activations and co-activations after vertebroplasty as well as in comparison with healthy controls suggesting how MM patients try to control the trunk before and after vertebroplasty surgery. The findings confirm the beneficial effects of vertebral consolidation on the pain experienced by the patient, despite an overall increase in trunk muscle activation and co-activation. Therefore, it is important to provide patients with rehabilitation treatment early after surgery to facilitate the CNS to correctly stabilize the spine without overloading it with excessive co-activations.
Topics: Humans; Multiple Myeloma; Male; Female; Electromyography; Middle Aged; Aged; Vertebroplasty; Muscle, Skeletal; Spine; Torso
PubMed: 38894318
DOI: 10.3390/s24113527 -
International Journal of Molecular... Jun 2024Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites.... (Review)
Review
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.
Topics: Humans; Multiple Myeloma; Molecular Targeted Therapy; Antineoplastic Agents; Animals
PubMed: 38892379
DOI: 10.3390/ijms25116192 -
International Journal of Molecular... May 2024MicroRNAs (miRNAs), particularly miR-16 and miR-21, play a crucial role in multiple myeloma (MM) pathogenesis by regulating gene expression. This study evaluated the...
MicroRNAs (miRNAs), particularly miR-16 and miR-21, play a crucial role in multiple myeloma (MM) pathogenesis by regulating gene expression. This study evaluated the prognostic significance of circulating miR-16 and miR-21 expression levels in 48 patients with MM at diagnosis treated with lenalidomide-dexamethasone (LD) compared with 15 healthy individuals (HI). All patients were treated with LD, 13 at first line and 35 at relapse, of whom 21 were tested twice at diagnosis and before LD initiation. The results revealed significantly lower levels of miR-16 and miR-21 in patients than in HIs, both at diagnosis and relapse, with decreased miR-16 levels at diagnosis, indicating improved overall survival (OS) ( value 0.024). Furthermore, miR-16 and miR-21 levels were associated with disease markers, while both correlated with the depth of response and mir-16 with sustained response to LD treatment. Ratios of both miR-16 and miR-21 expression levels (prior to LD treatment/diagnosis) below two predicted a shorter time to response ( = 0.027) and a longer time to next treatment ( = 0.042), respectively. These findings suggested a prognostic value for serum miR-16 and miR-21 levels in MM, as their expression levels correlated with disease variables and treatment outcomes.
Topics: Humans; Multiple Myeloma; MicroRNAs; Lenalidomide; Male; Female; Aged; Middle Aged; Prognosis; Thalidomide; Biomarkers, Tumor; Dexamethasone; Aged, 80 and over; Adult; Gene Expression Regulation, Neoplastic; Circulating MicroRNA; Treatment Outcome
PubMed: 38892251
DOI: 10.3390/ijms25116065