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Current Oncology (Toronto, Ont.) Apr 2023Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. Although patients... (Review)
Review
Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. Although patients with MM have a moderate life expectancy, it remains a heterogeneous disease that often requires multiple lines of chemotherapy for durable control and long-term survival. This review outlines current management strategies for both transplant-eligible and transplant-ineligible patients as well as for relapsed and refractory disease. Advances in drug therapies have widened management options and improved survival. In this paper, we also discuss implications for special populations and survivorship care.
Topics: Adult; Humans; Multiple Myeloma; General Practitioners; Hematologic Neoplasms
PubMed: 37232792
DOI: 10.3390/curroncol30050334 -
International Journal of Molecular... May 2021Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response... (Review)
Review
Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton's Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones' interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.
Topics: Agammaglobulinaemia Tyrosine Kinase; Biomarkers, Tumor; Bone Marrow; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Multiple Myeloma; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship; Tumor Microenvironment
PubMed: 34071917
DOI: 10.3390/ijms22115707 -
Journal of Oncology Pharmacy Practice :... Jun 2022Multiple myeloma, a plasma cell neoplasm is the second most common hematological malignancy in the United States. Despite significant advances in treatment armamentarium... (Review)
Review
OBJECTIVE
Multiple myeloma, a plasma cell neoplasm is the second most common hematological malignancy in the United States. Despite significant advances in treatment armamentarium over the last decade, multiple myeloma remains an incurable malignancy. B-cell maturation antigen (BCMA) is an antigen expressed on the surface on plasma cells that can be targeted by novel mechanisms of action including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapy. This review summarizes the clinical application and development of approved and investigational immunotherapies targeting BCMA.
DATA SOURCES
A search of the PubMed database was conducted using the following search terms: BCMA, CAR T, myeloma, belantamab mafodotin, and bispecific. Ongoing clinical trials, as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents targeting BCMA were evaluated. Prescribing information was also reviewed.
DATA SUMMARY
Since the discovery of BCMA as a target for myeloma, researchers have developed antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies as novel treatment modalities for myeloma patients. Belantamab mafodotin and idecabtagene vicleucel represent currently available therapies and ongoing trials have demonstrated the efficacy and safety of bispecifics and other BCMA targeting therapies.
CONCLUSION
BCMA targeting antibody drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies have demonstrated clinical activity in myeloma patients and represent novel therapies in multiple myeloma treatment paradigm.
Topics: Antibodies, Bispecific; B-Cell Maturation Antigen; Humans; Immunoconjugates; Immunotherapy; Multiple Myeloma; Receptors, Chimeric Antigen
PubMed: 35006032
DOI: 10.1177/10781552211073517 -
Veterinary Pathology Sep 2022Three dogs under 12 months old were diagnosed with atypical multiple myeloma (MM), having an aggressive multifocal anaplastic round cell sarcoma in bone marrow, viscera,...
Three dogs under 12 months old were diagnosed with atypical multiple myeloma (MM), having an aggressive multifocal anaplastic round cell sarcoma in bone marrow, viscera, and/or peripheral blood, which were confirmed by cytology and immunohistochemistry to be of plasma cell origin. The intramedullary sarcomas caused myelophthisis, osteolysis, and hypercalcemia. Complete or free light chain monoclonal gammopathy in the serum and/or urine was demonstrated by protein electrophoresis and immunofixation. The polymerase chain reaction for antigen receptor rearrangement assay performed on 2 cases identified a clonally rearranged immunoglobulin gene. Neoplastic cells lacked expression of CD45, CD3, CD18, CD21, CD34, and MHCII by flow cytometry. Immunohistochemistry revealed MUM1 immunoreactivity of the neoplastic cells. Combining all data, the diagnosis was MM. An aggressive form of MM in young dogs should be a differential diagnosis for patients with an immunoglobulin-productive, B cell-clonal, CD45-negative, MUM1-positive discrete cell neoplasm arising from the bone marrow.
Topics: Animals; B-Lymphocytes; Bone Marrow; Dog Diseases; Dogs; Flow Cytometry; Multiple Myeloma; Plasma Cells
PubMed: 35400242
DOI: 10.1177/03009858221087637 -
Pathology Feb 2022Plasma cell neoplasms are notorious for having diverse morphological presentations, and less frequently, unusual immunophenotypical profiles. This unexpected... (Review)
Review
Plasma cell neoplasms are notorious for having diverse morphological presentations, and less frequently, unusual immunophenotypical profiles. This unexpected immunomorphological variability could lead to erroneous impressions upon initial assessment, potentially delaying the generation of a final accurate diagnosis. In this review, we present a concise, yet comprehensive summary of both morphological and immunophenotypical variants of plasma cell neoplasms from the archives of MD Anderson Hematopathology Department, with emphasis on possible diagnostic pitfalls precluding a timely and accurate assessment.
Topics: Diagnosis, Differential; Humans; Immunophenotyping; Multiple Myeloma; Neoplasms, Plasma Cell; Plasma Cells; Plasmacytoma
PubMed: 34887091
DOI: 10.1016/j.pathol.2021.09.011 -
International Journal of Molecular... Jan 2020Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of... (Review)
Review
Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a "permissive" environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The "activated phenotype" of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Mesenchymal Stem Cells; Multiple Myeloma; Tumor Microenvironment
PubMed: 31963513
DOI: 10.3390/ijms21020613 -
Haematologica Dec 2023Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in...
Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of MM and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% penetrance that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the IL6Myc tumors resemble aggressive MM by RNA and protein expression. We also found that IL6Myc tumors accumulated fusions and missense mutations in genes that overlap significantly with human myeloma, indicating that the mouse is good model for studying disease etiology. Lastly, we derived cell lines from IL6Myc tumors that express cell surface markers typical of MM and readily engraft into mice, home to the bone marrow, and induce osteolytic disease. The cell lines may be useful in developing immunotherapies directed against BAFF-R and TACI, though not BCMA, and may also be a good model for studying dexamethasone resistance. These data indicate that the IL6Myc model is useful for studying development of aggressive MM and for developing new treatments against such forms of the disease.
Topics: Mice; Humans; Animals; Multiple Myeloma; Bone Marrow
PubMed: 37439384
DOI: 10.3324/haematol.2022.282538 -
Haematologica Jul 2024Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. MM is a heterogeneous disease, featured by various molecular... (Review)
Review
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. MM is a heterogeneous disease, featured by various molecular subtypes with different outcomes. With the advent of very efficient therapies including monoclonal antibodies, bispecific T-cell engagers and chimeric antigen receptor T cells (CAR T cells), most MM patients now have a prolonged survival. However, the disease remains incurable, and a subgroup of high-risk patients continue to have early relapse and short survival. Novel and highly sensitive methods have been developed allowing the detection of minimal residual disease (MRD) during or after treatment. Achievement of MRD negativity is a strong and independent prognostic factor in both prospective randomized clinical trials and in the real-world setting. While MRD assessment is now a validated endpoint in clinical trials, its incorporation in clinical practice is not yet established and its potential impact on guiding therapy remains under in-depth evaluation. Here we discuss the different methods available for MRD assessment and the role of MRD evaluation in MM management.
Topics: Neoplasm, Residual; Multiple Myeloma; Humans; Prognosis; Disease Management; Biomarkers, Tumor
PubMed: 38328864
DOI: 10.3324/haematol.2023.284662 -
Clinical Advances in Hematology &... Sep 2023Multiple myeloma (MM) is a clonal plasma cell dyscrasia and the most common form of primary bone marrow cancer. Nearly 35,000 new cases of MM are diagnosed in the United... (Review)
Review
Multiple myeloma (MM) is a clonal plasma cell dyscrasia and the most common form of primary bone marrow cancer. Nearly 35,000 new cases of MM are diagnosed in the United States each year. MM is a slowly progressive illness that remains incurable. The median survival for patients with MM is approximately 7 years, during which these patients suffer substantial morbidity. Despite the introduction of new drugs and immune-based therapies, many patients unfortunately relapse and require further therapies. Therefore, it is becoming increasingly important to be able to accurately and quickly determine changes in a patient's clinical status. Assessments of monoclonal protein and serum free light chain levels are the most common tests now available for monitoring patients with MM; however, these assays have several drawbacks. Modern radiologic techniques such as positron emission tomography and computed tomography are better than standard radiographs but are costly and cumbersome. Serum B-cell maturation antigen is a new biomarker for both the diagnosis and prognosis of MM. Assessment of measurable residual disease is becoming an important endpoint. The creation of better ways to predict outcomes and promptly and accurately monitor changes for patients with MM should lead to improved quality of life and longer survival.
Topics: Humans; Multiple Myeloma; Quality of Life; Antibodies, Monoclonal; B-Cell Maturation Antigen; Neoplasm, Residual
PubMed: 37647495
DOI: No ID Found -
Cytokine Dec 2020Cytokines play a crucial role in the growth, survival and dissemination of malignant plasma cells in patients of multiple myeloma (MM). We estimated concentrations of...
BACKGROUND
Cytokines play a crucial role in the growth, survival and dissemination of malignant plasma cells in patients of multiple myeloma (MM). We estimated concentrations of five key cytokines: Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Tumor Necrosis Factor- alpha (TNF- α), B-cell activating factor (BAFF), and Receptor Activator of Nuclear Factor-κB ligand (RANKL) in newly diagnosed and relapsed/refractory MM (RRMM).
METHODS
The study groups include 68 newly diagnosed and 21 relapsed/refractory (RR) MM patients. 32 out of 68 newly diagnosed MM patients were evaluated for serum cytokine concentrations after their treatment. For survival analysis, the various parameters were studied in relation to both progression free survival (PFS) and overall survival (OS).
RESULTS
The median serum levels of VEGF, IL-6, BAFF and RANKL were higher in RRMM compared with newly diagnosed patients. However, the difference was significant for BAFF levels (p = 0.04). The median serum levels of VEGF, IL-6, TNF-α, BAFF and RANKL were significantly higher in newly diagnosed and RRMM patients, compared to controls. We also observed lower plasma levels of VEGF (p=<0.0001) and BAFF (p=<0.0001) in BM compartment compared to the levels in serum from peripheral blood of newly diagnosed patients. Significant reduction in the median levels of IL-6, TNF-α, BAFF and RANKL was seen after 4-6 cycles of induction treatment in responders but not in non-responders. On survival analysis, RRMM patients had inferior median OS and PFS compared to that in newly diagnosed MM patients and found to be significantly associated with low haemoglobin representing the more aggressive disease biology in recurrent myeloma. The mean levels of IL-6 were significantly different in patients who died as compared to patients who were alive.
CONCLUSIONS
The present study demonstrates that the serum levels of VEGF, IL-6, TNF, BAFF and RANKL are significantly elevated and decrease significantly after treatment. The concentrations of circulating cytokines will reflect those of the bone marrow and could be used for subsequent analyses.
Topics: Adult; Aged; Cytokines; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins
PubMed: 32916474
DOI: 10.1016/j.cyto.2020.155271