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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 -
International Journal of Molecular... May 2024CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently...
CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition. Tackling both points of improvement in the present study, we used previously characterized VHHs that specifically target the idiotype of murine 5T33 MM cells. This idiotype represents one of the most promising yet challenging MM target antigens, as it is highly cancer- but also patient-specific. These VHHs were incorporated into VHH-based CAR modules, the format of which has advantages compared to scFv-based CARs. This allowed a side-by-side comparison of the influence of the targeting domain on T cell activation. Surprisingly, VHHs previously selected as lead compounds for targeted MM radiotherapy are not the best (CAR-) T cell activators. Moreover, the majority of the evaluated VHHs are incapable of inducing any T cell activation. As such, we highlight the importance of specific VHH selection, depending on its intended use, and thereby raise an important shortcoming of current common CAR development approaches.
Topics: Multiple Myeloma; Humans; Animals; Immunotherapy, Adoptive; Mice; T-Lymphocytes; Cell Line, Tumor; Antibodies, Anti-Idiotypic; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Immunoglobulin Heavy Chains; Single-Chain Antibodies; Single-Domain Antibodies; Lymphocyte Activation
PubMed: 38891821
DOI: 10.3390/ijms25115634 -
Molecular Diagnosis & Therapy Jul 2024Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by... (Review)
Review
Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by CARsgen for the treatment of multiple myeloma. Zevorcabtagene autoleucel is an autologous CAR T cell comprising a fully human BCMA-specific scFv (25C2), a CD8α hinge region and transmembrane domain, a 4-1BB costimulatory domain and a CD3-ζ T cell activation domain. Zevorcabtagene autoleucel recognizes and induces selective toxicity against BCMA-expressing tumour cells leading to their elimination. In February 2024, zevorcabtagene autoleucel received its first approval in China for the treatment of adults with relapsed or refractory multiple myeloma who have progressed after ≥ 3 prior lines of therapy (including ≥ 1 proteasome inhibitor and an immunomodulatory agent). Clinical studies of zevorcabtagene autoleucel are underway in Canada and the US. This article summarizes the milestones in the development of zevorcabtagene autoleucel leading to this first approval for relapsed or refractory multiple myeloma.
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Clinical Trials as Topic; Drug Approval; Treatment Outcome
PubMed: 38888762
DOI: 10.1007/s40291-024-00723-z -
Supportive Care in Cancer : Official... Jun 2024
Topics: Humans; Multiple Myeloma; Vitamin D Deficiency; Japan; Prognosis; Male; Female; Aged; Middle Aged; Vitamin D; East Asian People
PubMed: 38888661
DOI: 10.1007/s00520-024-08640-x -
Journal of Investigational Allergology... Jun 2024
Successful Desensitization to Isatuximab in a Patient With Refractory Multiple Myeloma and Indolent Systemic Mastocytosis. Reply to: Anaphylactic Shock due to Isatuximab and Successful Desensitization.
Topics: Humans; Multiple Myeloma; Anaphylaxis; Mastocytosis, Systemic; Desensitization, Immunologic; Antibodies, Monoclonal, Humanized; Drug Hypersensitivity
PubMed: 38888584
DOI: 10.18176/jiaci.0990 -
Nature Communications Jun 2024Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. It arises from mutational changes in immunoglobulin light chains. To...
Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. It arises from mutational changes in immunoglobulin light chains. To explore whether these mutations may affect the structure of the formed fibrils, we determine and compare the fibril structures from several patients with cardiac AL amyloidosis. All patients are affected by light chains that contain an IGLV3-19 gene segment, and the deposited fibrils differ by the mutations within this common germ line background. Using cryo-electron microscopy, we here find different fibril structures in each patient. These data establish that the mutations of amyloidogenic light chains contribute to defining the fibril architecture and hence the structure of the pathogenic agent.
Topics: Humans; Cryoelectron Microscopy; Immunoglobulin Light-chain Amyloidosis; Immunoglobulin Light Chains; Mutation; Amyloid; Male; Female; Middle Aged
PubMed: 38879609
DOI: 10.1038/s41467-024-49520-6