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Current Oncology (Toronto, Ont.) Apr 2023Multiple myeloma (MM) is malignant disease characterized by the clonal proliferation of plasma cells in the bone marrow, leading to anemia, immunosuppression, and other... (Review)
Review
Multiple myeloma (MM) is malignant disease characterized by the clonal proliferation of plasma cells in the bone marrow, leading to anemia, immunosuppression, and other symptoms, that is generally hard to treat. In MM, the immune system is likely exposed to neoplasia-associated neoantigens for several years before the tumor onset. Different types of neoantigens have been identified. Public or shared neoantigens derive from tumor-specific modifications often reported in several patients or across diverse tumors. They are intriguing therapeutic targets because they are frequently observed, and they have an oncogenic effect. Only a small number of public neoantigens have been recognized. Most of the neoantigens that have been identified are patient-specific or "private", necessitating a personalized approach for adaptive cell treatment. It was demonstrated that the targeting of a single greatly immunogenic neoantigen may be appropriate for tumor control. The purpose of this review was to analyze the neoantigens present in patients with MM, and to evaluate the possibility of using their presence as a prognostic factor or as a therapeutic target. We reviewed the most recent literature on neoantigen treatment strategies and on the use of bispecific, trispecific, and conjugated antibodies for the treatment of MM. Finally, a section was dedicated to the use of CAR-T in relapsed and refractory patients.
Topics: Humans; Multiple Myeloma; Antigens, Neoplasm; Immunotherapy
PubMed: 37232806
DOI: 10.3390/curroncol30050348 -
International Journal of Molecular... Jul 2018Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction... (Review)
Review
Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. This article summarizes the more recent literature data concerning the employment of anti-angiogenic therapeutic agents actually used in preclinical models and clinical settings for the treatment of multiple myeloma.
Topics: Angiogenesis Inhibitors; Animals; Bone Marrow; Humans; Multiple Myeloma; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 30002349
DOI: 10.3390/ijms19072031 -
Annals of Oncology : Official Journal... Feb 2017Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients... (Review)
Review
BACKGROUND
Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians.
DESIGN
A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review.
RESULTS
Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide.
CONCLUSION
In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.
Topics: Humans; Incidence; Multiple Myeloma; Neoplasms, Second Primary; Risk Factors
PubMed: 27864218
DOI: 10.1093/annonc/mdw606 -
International Journal of Molecular... Dec 2022Over the past two decades, the natural history of multiple myeloma (MM) has evolved dramatically, owing primarily to novel agents targeting MM in the bone marrow... (Review)
Review
Over the past two decades, the natural history of multiple myeloma (MM) has evolved dramatically, owing primarily to novel agents targeting MM in the bone marrow microenvironment (BMM) pathways. However, the mechanisms of resistance acquisition remain a mystery and are poorly understood. Autophagy and apoptosis are tightly controlled processes and play a critical role in the cell growth, development, and survival of MM. Genetic instability and abnormalities are two hallmarks of MM. During MM progression, plasma malignant cells become genetically unstable and activate various signaling pathways, resulting in the overexpression of abnormal proteins that disrupt autophagy and apoptosis biological processes. Thus, achieving a better understanding of the autophagy and apoptosis processes and the proteins that crosslinked both pathways, could provide new insights for the MM treatment and improve the development of novel therapeutic strategies to overcome resistance. This review presents a sufficient overview of the roles of autophagy and apoptosis and how they crosslink and control MM progression and drug resistance. Potential combination targeting of both pathways for improving outcomes in MM patients also has been addressed.
Topics: Humans; Multiple Myeloma; Bone Marrow; Drug Resistance, Neoplasm; Apoptosis; Autophagy; Tumor Microenvironment
PubMed: 36614089
DOI: 10.3390/ijms24010644 -
Hematology. American Society of... Dec 2017Considerable progress has been made in the treatment of multiple myeloma in the past decade with median survival for the disease improving significantly. This has come... (Review)
Review
Considerable progress has been made in the treatment of multiple myeloma in the past decade with median survival for the disease improving significantly. This has come through a combination of better understanding of the disease biology and coordinated research into new treatment approaches including better supportive care. However, patients eventually become refractory to available treatments and succumb to the disease, highlighting the need to develop new treatment approaches. The genetic heterogeneity in the disease and clonal evolution under treatment pressure underlie the development of resistance, underscoring the need to develop more effective therapies that can eradicate the disease at initial treatment as well as the need for new classes of drugs with varying mechanisms of action. To this end, there has been intense focus on exploring novel approaches to therapy including small-molecule inhibitors targeting specific abnormalities, immune therapies including monoclonal antibodies and adaptive T-cell therapy, as well as epigenetic approaches. Although many of these drugs are in the early stages of clinical development, the early data appear to be very promising. Many of these drugs can be safely and effectively combined with the current treatment classes such as proteasome inhibitors and immunomodulatory drugs, further enhancing the treatment options for myeloma.
Topics: Adoptive Transfer; Antineoplastic Agents, Immunological; Epigenesis, Genetic; Humans; Immunologic Factors; Multiple Myeloma; Proteasome Inhibitors; T-Lymphocytes
PubMed: 29222300
DOI: 10.1182/asheducation-2017.1.518 -
Frontiers in Immunology 2023Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of...
BACKGROUND
Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades.
METHODS
We first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months).
RESULTS
RNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma.
CONCLUSION
RNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.
Topics: Humans; Multiple Myeloma; RNA; Hematopoietic Stem Cell Transplantation; B-Cell Maturation Antigen; Transplantation, Autologous
PubMed: 38035078
DOI: 10.3389/fimmu.2023.1286700 -
Blood May 2015Over the last few decades, significant improvement in outcomes has been observed for myeloma patients, mainly as a result of the use of currently available approved... (Review)
Review
Over the last few decades, significant improvement in outcomes has been observed for myeloma patients, mainly as a result of the use of currently available approved antimyeloma agents, along with combining autologous stem cell transplantation in the treatment of myeloma. With more targeted agents in development, the treatment of a myeloma patient at relapse has become complicated and, as a consequence, results in vast heterogeneity in treatment patterns. Although a consensus on the timing of initiation of treatment, the choice of agents to be used, and the role of transplant is less clear, we describe an evidence-based approach and the factors to consider upon relapse. We describe additional newer agents and targets that are under development, with the goal of achievement of durable remissions for myeloma patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Transplantation, Homologous; Treatment Outcome
PubMed: 25838342
DOI: 10.1182/blood-2014-11-568923 -
Current Opinion in Oncology Nov 2021Multiple myeloma is a disease of elderly adults. Improvement in survival has occurred because of biological insights and novel agents. Therapeutic options involve... (Review)
Review
PURPOSE OF REVIEW
Multiple myeloma is a disease of elderly adults. Improvement in survival has occurred because of biological insights and novel agents. Therapeutic options involve choices today, thus have become more complex. Demographics have led to an increased number of elderly patients and age may be associated with a poorer outcome but is not the only prognostic predictor today.
RECENT FINDINGS
To evaluate patients' health status rather than their chronological age alone, frailty scores and functional geriatric assessments are used to identify prognostic groups, avoid adverse events, compare clinical trials and tailor treatment. As most clinical trials exclude frail elderly patients, those enrolled therein are often younger and healthier than the typical multiple myeloma patient. This represents a challenge for frail cohorts because of their increased risk of adverse events, overtreatment and undertreatment and/or therapy discontinuation, which may lead to poorer survival and quality of life (QoL). Reassessing patients' status via geriatric assessments is also relevant during treatment to adjust interventions appropriately.
SUMMARY
Integrating geriatric assessments may lead to individual treatment decisions, dose adjustments, better clinical outcome and QoL. Prospective clinical trials that enroll elderly multiple myeloma patients with comorbidities, incorporate frailty scores/geriatric assessments and help with prognostication, adverse event avoidance and QoL maintenance, remain warranted.
Topics: Aged; Aged, 80 and over; Frailty; Geriatric Assessment; Humans; Multiple Myeloma; Precision Medicine; Prognosis; Randomized Controlled Trials as Topic
PubMed: 34534141
DOI: 10.1097/CCO.0000000000000792 -
Hematology. American Society of... Dec 2022Novel therapies in multiple myeloma (MM) have increased the rates of conventional complete remission (CR) in patients. However, patients in CR can have highly... (Review)
Review
Novel therapies in multiple myeloma (MM) have increased the rates of conventional complete remission (CR) in patients. However, patients in CR can have highly heterogeneous outcomes. Novel and more sensitive methods of assessing residual disease burden after therapy will help prognosticate this group better and, ideally, allow individualized therapy adjustments based on response depth in the future. Here, we review novel bone marrow, peripheral blood, and imaging methods for assessing myeloma burden and discuss the opportunities and limitations of incorporating these in everyday clinical practice.
Topics: Humans; Multiple Myeloma; Remission Induction; Bone Marrow; Neoplasm, Residual
PubMed: 36485143
DOI: 10.1182/hematology.2022000348 -
Blood Reviews Jul 2019Extramedullary disease of multiple myeloma (EM) remains a treatment challenge even in the era of new drugs. While many reports analyzing various aspects of EM have been... (Review)
Review
Extramedullary disease of multiple myeloma (EM) remains a treatment challenge even in the era of new drugs. While many reports analyzing various aspects of EM have been published, mechanism of EM development has not been clarified yet. This review summarizes current knowledge about this clinical entity, including its history, diagnostics, imaging methods, incidence, prognosis, current treatment options, risk factors and known molecular mechanisms that might be involved in pathogenesis of EM.
Topics: Humans; Multiple Myeloma
PubMed: 31005420
DOI: 10.1016/j.blre.2019.04.002