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The Neuroradiology Journal Jun 2017Radiology provides a crucial clinical adjunct in patients with plasma cell disorders, in particular multiple myeloma, and its uses are evolving and expanding. This... (Review)
Review
Radiology provides a crucial clinical adjunct in patients with plasma cell disorders, in particular multiple myeloma, and its uses are evolving and expanding. This pictorial review illustrates the role of imaging throughout the patient's clinical course, with specific reference to recently updated international diagnostic criteria. At presentation, imaging optimises characterisation and staging of the plasma-cell disorder, while later in the course of the disease, its roles include the monitoring of disease progression, assessment of post-treatment response and the investigation of clinical deterioration.
Topics: Disease Progression; Humans; Multiple Myeloma; Spinal Neoplasms
PubMed: 28423980
DOI: 10.1177/1971400917699426 -
Frontiers in Immunology 2023Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic... (Review)
Review
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.
Topics: Humans; Multiple Myeloma; Plasma Cells; Bone Marrow; Hematologic Neoplasms; Clonal Evolution; Tumor Microenvironment
PubMed: 37744361
DOI: 10.3389/fimmu.2023.1243997 -
Leukemia Oct 2017Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of...
Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾10 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.
Topics: Adult; Aged; Aged, 80 and over; Antibody Specificity; Cell Count; Equipment Design; Female; Flow Cytometry; Humans; Immunophenotyping; Male; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Plasma Cells; Sensitivity and Specificity; Software; Specimen Handling; Treatment Outcome
PubMed: 28104919
DOI: 10.1038/leu.2017.29 -
International Journal of Molecular... Apr 2018Cancer is known for its cellular changes contributing to tumour growth and cell proliferation. As part of these changes, metabolic rearrangements are identified in... (Review)
Review
Cancer is known for its cellular changes contributing to tumour growth and cell proliferation. As part of these changes, metabolic rearrangements are identified in several cancers, including multiple myeloma (MM), which is a condition whereby malignant plasma cells accumulate in the bone marrow (BM). These metabolic changes consist of generation, inhibition and accumulation of metabolites and metabolic shifts in MM cells. Changes in the BM micro-environment could be the reason for such adjustments. Enhancement of glycolysis and glutaminolysis is found in MM cells compared to healthy cells. Metabolites and enzymes can be upregulated or downregulated and play a crucial role in drug resistance. Therefore, this review will focus on changes in glucose and glutamine metabolism linked with the emergence of drug resistance. Moreover, metabolites do not only affect other metabolic components to benefit cancer development; they also interfere with transcription factors involved in proliferation and apoptotic regulation.
Topics: Animals; Antineoplastic Agents; Bone Marrow; Drug Resistance, Neoplasm; Glucose; Glutamic Acid; Humans; Metabolic Networks and Pathways; Multiple Myeloma; Tumor Microenvironment
PubMed: 29662010
DOI: 10.3390/ijms19041200 -
Journal of Clinical Oncology : Official... Nov 2022ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study...
A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.
PURPOSE
ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study.
METHODS
Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion.
RESULTS
As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively.
CONCLUSION
ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.
Topics: Humans; Aged; Multiple Myeloma; B-Cell Maturation Antigen; Neoplasm Recurrence, Local; Antineoplastic Agents; T-Lymphocytes
PubMed: 36029527
DOI: 10.1200/JCO.22.01504 -
Leukemia & Lymphoma Jun 2018Multiple myeloma (MM) is a plasma cell neoplasm that affects elderly individuals with two-thirds of patients over 65 years at diagnosis. However, data available are... (Review)
Review
Multiple myeloma (MM) is a plasma cell neoplasm that affects elderly individuals with two-thirds of patients over 65 years at diagnosis. However, data available are derived from clinical trials conducted in younger patients. Fewer studies investigated treatment options in the elderly. This review summarizes the clinical outcomes and toxicities associated with therapeutic regimens in older patients including doublet, triplet and high dose therapyin newly diagnosed patients and relapsed patients with MM. We highlight the importance of an approach tailored to individuals, incorporates the geriatric frailty assessment, considers comorbiditiess and commits to early recognition and management of toxicities ranging from myelosuppression to polypharmacy. To date, no trial has prospectively investigated a tailored treatment paradigm in older patients based on frailty and/or comorbidities. As the population ages, the proportion of MM patients with advanced age will grow. Studies are indicated to determine optimal treatment approaches in this increasingly heterogeneous geriatric population.
Topics: Age Factors; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease Management; Geriatric Assessment; Humans; Multiple Myeloma; Prognosis; Recurrence; Treatment Outcome
PubMed: 28847191
DOI: 10.1080/10428194.2017.1365859 -
Annals of Oncology : Official Journal... Jul 2017
Topics: Follow-Up Studies; Humans; Medical Oncology; Multiple Myeloma; Neoplasm Staging; Risk Assessment
PubMed: 28453614
DOI: 10.1093/annonc/mdx096 -
International Journal of Molecular... Mar 2021Multiple myeloma (MM) is a plasma cell neoplasm characterized by an abnormal proliferation of clonal, terminally differentiated B lymphocytes. Current approaches for the... (Review)
Review
Multiple myeloma (MM) is a plasma cell neoplasm characterized by an abnormal proliferation of clonal, terminally differentiated B lymphocytes. Current approaches for the treatment of MM focus on developing new diagnostic techniques; however, the search for prognostic markers is also crucial. This enables the classification of patients into risk groups and, thus, the selection of the most optimal treatment method. Particular attention should be paid to the possible use of immune factors, as the immune system plays a key role in the formation and course of MM. In this review, we focus on characterizing the components of the immune system that are of prognostic value in MM patients, in order to facilitate the development of new diagnostic and therapeutic directions.
Topics: Biomarkers, Tumor; Chemokines; Cytokines; Humans; Immunologic Factors; Intercellular Signaling Peptides and Proteins; Interferon-gamma; Multiple Myeloma; Prognosis; Tumor Necrosis Factors
PubMed: 33808304
DOI: 10.3390/ijms22073587 -
Blood Advances Jul 2023The use of bispecific antibodies (BsAbs) in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily... (Meta-Analysis)
Meta-Analysis
The use of bispecific antibodies (BsAbs) in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily pretreated patients. Infectious complications related to the use of BsAbs are not well described. We conducted a pooled analysis that included all single-agent BsAbs used in MM with no prior use of different BsAbs. A total of 1185 patients with MM were treated with a BsAb in the studied period (71.6% of the patients treated with an agent targeting B-cell maturation antigen (BCMA). Pooled median follow-up was short at 6.1 months (7.5 vs 5.2 months for BCMA vs non-BCMA BsAbs, respectively). Adverse events of interest included all grade neutropenia in 38.6%, all grade infections in 50% (n = 542/1083), all grade cytokine release syndrome in 59.6% (n = 706/1185), grade III/IV neutropenia in 34.8% (n = 372/1068), grade III/IV infections in 24.5% (n = 272/1110), grade III/IV pneumonia in 10% (n = 52.4/506), and grade III/IV coronavirus disease 2019 in 11.4% (n = 45.4/395) of the patients. Non-BCMA-targeted BsAbs were associated with lower grade III/IV neutropenia (25.3% vs 39.2%) and lower grade III/IV infections (11.9% vs 30%) when compared with BCMA-targeted BsAbs. Hypogammaglobulinemia was reported in 4 studies, with a prevalence of 75.3% (n = 256/340) of the patients, with IV immunoglobulin used in 48% (n = 123/256) of them. Death was reported in 110 patients, of which 28 (25.5%) were reported to be secondary to infections. Certain precautions should be used when using BsAbs to mitigate the risk and/or identify and treat infections promptly.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; COVID-19; Neoplasms, Plasma Cell; Neutropenia
PubMed: 36857755
DOI: 10.1182/bloodadvances.2022009435 -
Haematologica Oct 2022
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Plasma Cell; Thalidomide
PubMed: 35734925
DOI: 10.3324/haematol.2022.280660