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American Society of Clinical Oncology... Jun 2024Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in... (Review)
Review
Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell-directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.
Topics: Humans; Multiple Myeloma; Immunotherapy; Immunotherapy, Adoptive; Antibodies, Bispecific; Combined Modality Therapy; Treatment Outcome; Receptors, Chimeric Antigen
PubMed: 38875506
DOI: 10.1200/EDBK_432204 -
Medicine Jun 2024Pleural effusion, especially bilateral bloody pleural effusion, is a rare complication of Waldenström macroglobulinemia (WM). Pleural effusion in patients with WM has...
RATIONALE
Pleural effusion, especially bilateral bloody pleural effusion, is a rare complication of Waldenström macroglobulinemia (WM). Pleural effusion in patients with WM has many causes, such as infection, tumor invasion of the pleura, and rupture of the thoracic duct or its branches. Patients with WM presenting to the respiratory department with chest tightness and shortness of breath need more differential diagnosis by respiratory physicians, which is helpful for effective treatment. Herein, we present a case of MV diagnosis in a patient with bilateral bloody pleural effusion.
PATIENT CONCERN
Our patient is a 59-year-old man with WM presenting as having bilateral bloody pleural effusion.
INTERVENTIONS
The patient was treated with pleural effusion drainage. After confirming the diagnosis, the patient was treated with rituximab, cyclophosphamide, and dexamethasone.
OUTCOMES
Following these treatments, the patient's symptoms improved, and ultrasound showed a decrease in pleural effusion.
LESSONS
Despite its favorable prognosis, the cause of pleural effusion in a patient with WM can be challenging to diagnose. The cause of pleural effusion should be considered a differential diagnosis when diagnosing patients diagnosed with WM.
Topics: Humans; Waldenstrom Macroglobulinemia; Male; Middle Aged; Pleural Effusion; Diagnosis, Differential; Rituximab; Cyclophosphamide; Dexamethasone
PubMed: 38875392
DOI: 10.1097/MD.0000000000038406 -
Cancer Medicine Jun 2024Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a...
BACKGROUND
Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a portion of MM patients do not respond to CAR-T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR-34a on the immunosuppressive polarization of macrophages obtained from MM patients.
METHODS
The levels of miR-34a and TLR9 (Toll-like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co-culture experiments were conducted to evaluate the immunomodulatory impact of MM-associated macrophages on CAR-T cells.
RESULTS
There was an observed suppressed activation of macrophages and CD4 T lymphocytes in the blood samples of MM patients. Overexpression of miR-34a in MM-associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co-culture system and an animal model, MM-associated macrophages suppressed the activity and tumoricidal effect of CAR-T cells in a miR-34a-dependent manner.
CONCLUSION
The findings imply that targeting the macrophage miR-34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR-T therapy in MM patients.
Topics: Multiple Myeloma; MicroRNAs; Toll-Like Receptor 9; Humans; Animals; Mice; Signal Transduction; Coculture Techniques; Tumor-Associated Macrophages; Macrophages; Immunotherapy, Adoptive; Male; Female; Macrophage Activation; Cell Line, Tumor
PubMed: 38864479
DOI: 10.1002/cam4.7387 -
Cell Communication and Signaling : CCS Jun 2024Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable... (Review)
Review
Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. Intense protein synthesis is a distinctive trait of MM cells, supporting the massive production of clonal immunoglobulins or free light chains. The mammalian target of rapamycin (mTOR) kinase is appreciated as a master regulator of vital cellular processes, including regulation of metabolism and protein synthesis, and can be found in two multiprotein complexes, mTORC1 and mTORC2. Dysregulation of these complexes is implicated in several types of cancer, including MM. Since mTOR has been shown to be aberrantly activated in a large portion of MM patients and to play a role in stimulating MM cell survival and resistance to several existing therapies, understanding the regulation and functions of the mTOR complexes is vital for the development of more effective therapeutic strategies. This review provides a general overview of the mTOR pathway, discussing key discoveries and recent insights related to the structure and regulation of mTOR complexes. Additionally, we highlight findings on the mechanisms by which mTOR is involved in protein synthesis and delve into mTOR-mediated processes occurring in MM. Finally, we summarize the progress and current challenges of drugs targeting mTOR complexes in MM.
Topics: Humans; Multiple Myeloma; TOR Serine-Threonine Kinases; Signal Transduction; Animals; Molecular Targeted Therapy; MTOR Inhibitors; Mechanistic Target of Rapamycin Complex 2
PubMed: 38862983
DOI: 10.1186/s12964-024-01699-3 -
Blood Cancer Journal Jun 2024
Topics: Humans; Multiple Myeloma; Neoplasm Staging; Female; Male; Middle Aged; Aged; Adult; Aged, 80 and over; Cohort Studies
PubMed: 38862493
DOI: 10.1038/s41408-024-01076-w -
Journal of Korean Medical Science Jun 2024Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone....
BACKGROUND
Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited.
METHODS
We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018.
RESULTS
Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use.
CONCLUSION
This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.
Topics: Humans; Multiple Myeloma; Female; Male; Retrospective Studies; Middle Aged; Aged; Diphosphonates; Risk Factors; Databases, Factual; Republic of Korea; Bone Density Conservation Agents; Odds Ratio; Fractures, Spontaneous; Spinal Cord Compression; Adult; Logistic Models
PubMed: 38859738
DOI: 10.3346/jkms.2024.39.e175 -
Journal of Cancer Research and Clinical... Jun 2024Microvesicles are membraned particles produced by different types of cells recently investigated for anticancer purposes. The current study aimed to investigate the...
BACKGROUND
Microvesicles are membraned particles produced by different types of cells recently investigated for anticancer purposes. The current study aimed to investigate the effects of human bone marrow mesenchymal stem cell-derived microvesicles (BMSC-MVs) on the multiple myeloma cell line U266. BMSC-MVs were isolated from BMSCs via ultracentrifugation and characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). U266 cells were treated with 15, 30, 60, and 120 µg/mL BMSC-MVs for three and seven days and the effects of treatment in terms of viability, cytotoxicity, and DNA damage were investigated via the MTT assay, lactate dehydrogenase (LDH) assay, and 8‑hydroxy-2'-deoxyguanosine (8‑OHdG) measurement, respectively. Moreover, the apoptosis rate of the U266 cells treated with 60 µg/mL BMSC-MVs was also assessed seven days following treatment via flow cytometry. Ultimately, the expression level of BCL2, BAX, and CCND1 by the U266 cells was examined seven days following treatment with 60 µg/mL BMSC-MVs using qRT-PCR.
RESULTS
BMSC-MVs had an average size of ~ 410 nm. According to the MTT and LDH assays, BMSC-MV treatment reduced the U266 cell viability and mediated cytotoxic effects against them, respectively. Moreover, elevated 8‑OHdG levels following BMSC-MV treatment demonstrated a dose-dependent increase of DNA damage in the treated cells. BMSC-MV-treated U266 cells also exhibited an increased apoptosis rate after seven days of treatment. The expression level of BCL2 and CCND1 decreased in the treated cells whereas the BAX expression demonstrated an incremental pattern.
CONCLUSIONS
Our findings accentuate the therapeutic benefit of BMSC-MVs against the multiple myeloma cell line U266 and demonstrate how microvesicles could be of therapeutic advantage. Future in vivo studies could further corroborate these findings.
Topics: Humans; Multiple Myeloma; Apoptosis; Mesenchymal Stem Cells; Cell Line, Tumor; Cell-Derived Microparticles; Cell Survival; DNA Damage
PubMed: 38850382
DOI: 10.1007/s00432-024-05822-2 -
Cancer Medicine Jun 2024Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of...
OBJECTIVE
Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of mobilization failure and characterize the risk factors associated with poor mobilization (PM) of MM patients in novel therapies era.
METHODS
We conducted a retrospective study of 211 MM patients who received their first peripheral blood stem cells (PBSC) mobilization at our single center. The following data were collected: age, gender, clinical stage, disease status, complete blood cell count, induction regimen, CD34 cell count in peripheral blood (PB), and PBSC collections.
RESULTS
In addition to conventional drugs, 22 (10.4%) patients received daratumumab containing induction, and 33 (15.6%) patients used plerixafor for poor mobilization (pre-apheresis PB CD34 cells <20/μL). Failure of collection occurred in 24 (11.4%) patients and was correlated with low white blood cell (WBC), ≥3 cycles of lenalidomide treatment before mobilization, steady-state mobilization and nouse of plerixafor are associated with mobilization failure. Daratumumab-based induction treatment ≥2 courses, albumin >41 g/L before mobilization, and steady-state mobilization were risk factors for PM in subgroups of patients treated with lenalidomide for <3 courses. In addition, Hepatitis B virus infection at baseline, thalassemia and measurable residual disease positivity were recognized as predictive factors for PM in subset of chemo-mobilization patients.
CONCLUSION
In addition to some well-recognized risk factors, baseline WBC count and daratumumab exposure ≥2 courses before mobilization were revealed as the predictive factors of mobilization failure, providing consultation for preemptive use of plerixafor.
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Mobilization; Female; Male; Middle Aged; Retrospective Studies; Aged; Adult; Cyclams; Benzylamines; Peripheral Blood Stem Cells; Risk Factors; Antibodies, Monoclonal; Lenalidomide; Heterocyclic Compounds; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous
PubMed: 38850125
DOI: 10.1002/cam4.7356 -
Diagnostic Pathology Jun 2024Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome.... (Review)
Review
BACKGROUND
Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria.
CASE PRESENTATION
We report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone.
CONCLUSIONS
Monoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren't enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.
Topics: Humans; POEMS Syndrome; Male; Middle Aged; Lenalidomide; Thalidomide; Vascular Endothelial Growth Factor A; Dexamethasone; Treatment Outcome; Myeloma Proteins
PubMed: 38849857
DOI: 10.1186/s13000-024-01502-4 -
Journal of Translational Medicine Jun 2024Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can...
Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens.
BACKGROUND
Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance.
METHODS
To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM.
RESULTS
Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated.
CONCLUSION
Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.
Topics: Humans; Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance; Disease Progression; Proteomics; Male; Female; Protein Biosynthesis; Middle Aged; Aged; Cluster Analysis; Plasma Cells; Signal Transduction; Proteome; Quality Control
PubMed: 38849800
DOI: 10.1186/s12967-024-05345-x