ABSTRACT
INTRODUÇÃO: O mieloma múltiplo (MM) é uma neoplasia hematológica maligna caracterizada pela proliferação descontrolada de plasmócitos alterados na medula óssea, resultando na produção aumentada de imunoglobulinas não funcional (proteína monoclonal). O acúmulo destas imunoglobulinas e a interação dos plasmócitos com outras células da medula óssea resultam em anemia, lesões ósseas, infecções, hipercalcemia, injúria renal, fadiga e dor. A incidência mundial informada pelo Globocan é de 2,2 novos casos por 100.000 habitantes em homens e 1,5/100.000 em mulheres, com ocorrência, a nível mundial, de 176 mil novos casos e 117 mil mortes em 2020. Carfilzomibe é um agente antineoplásico, inibidor de proteassoma que se liga seletiva e irreversivelmente nos sítios ativos. Tem atividade antiproliferativa e próapoptóticas. PERGUNTA: Kyprolis® (carfilzomibe) em combinação com dexametasona é eficaz e seguro no tratamento de pacientes com mieloma múltiplo recidivado ou refratário que receberam uma terapia prévia quando em comparação a bortezomibe, ciclofosfamida, dexametasona, cisplatina, doxorrubicina, doxorrubicina li
Subject(s)
Humans , Proteasome Inhibitors/therapeutic use , Multiple Myeloma/prevention & control , Multiple Myeloma/drug therapy , Unified Health System , Brazil , Cost-Benefit Analysis/economicsABSTRACT
Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
Subject(s)
Monoclonal Gammopathy of Undetermined Significance/diagnosis , Multiple Myeloma/diagnosis , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Follow-Up Studies , Humans , Iceland/epidemiology , Male , Middle Aged , Monoclonal Gammopathy of Undetermined Significance/epidemiology , Multiple Myeloma/epidemiology , Multiple Myeloma/prevention & control , Risk FactorsABSTRACT
Multiple myeloma (MM), a malignant neoplasm of plasma cells that reside in the bone marrow (BM), is universally preceded by a precursor state termed monoclonal gammopathy of undetermined significance (MGUS). Many individuals with MGUS never progress to MM or progress over many years. Therefore, MGUS provides a unique opportunity to surveil changes in the BM tumor microenvironment throughout disease progression. It is increasingly appreciated that MGUS cells carry many of the genetic changes found in MM. Prior studies have also shown that MGUS cells can be recognized by the immune system, leading to early changes in the BM immune environment compared to that of healthy individuals, including alterations in both innate and adaptive immunity. Progression to clinical MM is associated with attrition of T cells with stem memory-like features and instead accumulation of T cells with more terminally differentiated features. Recent clinical studies have suggested that early application of immune-modulatory drugs, which are known to activate both innate and adaptive immunity, can delay the progression to clinical MM. Understanding the biology of how the immune response and tumors coevolve over time is needed to develop novel immune-based approaches to achieve durable and effective prevention of clinical malignancy.
Subject(s)
Multiple Myeloma/immunology , Multiple Myeloma/prevention & control , Adaptive Immunity , Bone Marrow/immunology , Humans , Immune Checkpoint Proteins/immunology , Immunity, Innate , Immunologic Surveillance , Immunomodulation , Monoclonal Gammopathy of Undetermined Significance/genetics , Monoclonal Gammopathy of Undetermined Significance/immunology , Multiple Myeloma/genetics , Tumor MicroenvironmentSubject(s)
Dendritic Cells/immunology , Killer Cells, Natural/immunology , Multiple Myeloma/immunology , T-Lymphocytes, Cytotoxic/immunology , Ubiquitin-Specific Peptidase 7/metabolism , Humans , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Multiple Myeloma/prevention & control , Tumor Cells, Cultured , Ubiquitin-Specific Peptidase 7/geneticsABSTRACT
The development of next-generation sequencing technology has dramatically improved our understanding of the genetic landscape of multiple myeloma. Several new drivers and recurrent events have been reported and linked to a potential driver role. This complex landscape is enhanced by intraclonal mutational heterogeneity and variability introduced through the dimensions of time and space. The evolutionary history of multiple myeloma is driven by both the accumulation of different genomic drivers and by the activity of different mutational processes active overtime. In this review, we describe how these new findings and sequencing technologies have been progressively allowed to understand and reshape our knowledge of the complexity of multiple myeloma at each of its developmental stages: premalignant, at diagnosis, and in relapsed/refractory states. We discuss how these evolutionary concepts can be utilized in the clinic to alter evolutionary trajectories providing a framework for therapeutic intervention at early-disease stages.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Medical Oncology/methods , Multiple Myeloma/prevention & control , Precancerous Conditions/drug therapy , Precision Medicine/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytogenetic Analysis , DNA Mutational Analysis , Disease Progression , High-Throughput Nucleotide Sequencing , Humans , Multiple Myeloma/genetics , Mutation , Precancerous Conditions/geneticsABSTRACT
Circular RNAs (circRNAs) possess important regulatory effects on multiple myeloma (MM) progression. Here, we aimed at exploring the function of circ_0007841 in MM and the underlying molecular mechanism. Expression of circ_0007841, microRNA (miR)-129-5p and Jagged1 (JAG1) was determined via qRT-PCR or western blot assay. Methyl thiazolyl tetrazolium (MTT) assay was applied to examine cell viability and IC50 value of MM cells to bortezomib (BTZ). Colony formation assay was performed to analyze cell proliferation. Moreover, cell apoptosis was assessed by flow cytometry and western blot analysis. Cell metastasis was evaluated by wound healing assay and Transwell assay. Function of circ_0007841 in vivo was determined by xenograft tumor assay. Target relationship between miR-129-5p and circ_0007841 or JAG1 was confirmed via dual-luciferase reporter, RNA immunoprecipitation (RIP) and pull-down assays. The up-regulation of circ_0007841 and JAG1, and the down-regulation of miR-129-5p were detected in MM bone marrow aspirates and cells. Circ_0007841 knockdown significantly repressed cell proliferation, chemoresistance, and metastasis, while contributed to apoptosis of MM cells in vitro, and reduced tumor growth in vivo. Circ_0007841 targeted miR-129-5p, and miR-129-5p inhibition reversed impact of silencing of circ_0007841 on MM cells. JAG1 was a mRNA target of miR-129-5p, whose overexpression could undermine the miR-129-5p-mediated effects on MM cells. Circ_0007841 positively regulated JAG1 expression via absorbing miR-129-5p. Circ_0007841 knockdown inhibited MM cell proliferation, metastasis and chemoresistance through modulating miR-129-5p/JAG1 axis, suggesting that circ_0007841 might serve as a potential therapeutic target of MM.
Subject(s)
Bortezomib/pharmacology , Drug Resistance, Neoplasm/drug effects , Jagged-1 Protein/biosynthesis , MicroRNAs/biosynthesis , Multiple Myeloma/metabolism , RNA, Circular/antagonists & inhibitors , Aged , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bortezomib/therapeutic use , Drug Resistance, Neoplasm/physiology , Female , Humans , Jagged-1 Protein/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Middle Aged , Multiple Myeloma/genetics , Multiple Myeloma/prevention & control , RNA, Circular/genetics , RNA, Small Interfering/administration & dosage , Xenograft Model Antitumor Assays/methodsABSTRACT
Lifestyle factors such as diet, physical activity and exposure to noxious agents are modifiable factors that have a significant impact on the state of health and life expectancy of humans. The following article is intended to provide an overview of current knowledge on the influence of these lifestyle factors on the development and progression of multiple myeloma and is dedicated to the question of the extent to which prevention strategies can be usefully applied.
Subject(s)
Multiple Myeloma/prevention & control , Diet , Humans , Life Style , Primary Prevention , Secondary PreventionABSTRACT
BACKGROUND: Studies on receipt of statins and risk of multiple myeloma (MM) yielded conflicting results. This systematic review and meta-analysis was conducted in order to comprehensively investigate the relationship between receipt of statins and risk of MM. PATIENTS AND METHODS: Potentially eligible studies that compared the risk of MM between statin recipients and those who did not receive statins were identified from Medline and Embase databases from inception to August 2019 using a search strategy that comprised terms for "statin" and "multiple myeloma." To be eligible, cohort studies must have recruited 2 groups of participants, statin recipients and nonrecipients, and followed their participants for incident MM. Eligible case-control studies must have recruited cases of MM and controls without MM, and must have explored the history of receipt of statins. Relative risk, hazard risk ratio, standardized incidence ratio, or odds ratio (OR) of this association must be reported. Relative risk and standard error from each study were extracted and combined using random-effect generic inverse variance. Relative risk of cohort study was used as an estimate for OR to calculate the pooled effect estimate along with the OR of the case-control studies. RESULTS: A total of 1744 articles were identified using the search strategy, and 10 studies were included in the meta-analysis. The odds of MM were significantly lower among statin recipients than nonrecipients, with a pooled OR of 0.80 (95% confidence interval, 0.68-0.93; I2 72%). The funnel plot was relatively symmetrical and did not suggest publication bias. CONCLUSION: Receipt of statins is associated with a significant 20% reduction in the odds of MM.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Multiple Myeloma/prevention & control , Aged , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacologyABSTRACT
OBJECTIVE: To investigate the outcomes of radiotherapy with or without surgery during treatment of patients with solitary plasmacytoma of bone (SBP) of the spine. METHODS: Patients diagnosed with SBP of the spine treated with radiotherapy with or without surgery were identified and extracted from the SEER database. Propensity score matched (PSM) analysis was performed to balance patient characteristics between radiotherapy alone and radiotherapy with surgery groups. Patients in different age-groups were stratified and analyzed. RESULTS: A total of 1275 patients with SBP of the spine treated with radiotherapy with or without surgery were extracted from the SEER database. Before PSM, the unadjusted Kaplan-Meier curve showed that the radiotherapy with surgery group had worse overall survival than did the radiotherapy without surgery group (both P < 0.05), whereas the difference of overall survival was attenuated after PSM. Stratified analysis found that the radiotherapy with surgery group had less progression to multiple myeloma for young patients (age <45 years) with SBP of the spine than did the radiotherapy without surgery group. CONCLUSIONS: The results of our study suggest that radiotherapy with surgery may show less progression to multiple myeloma for younger patients with SBP of the spine.
Subject(s)
Multiple Myeloma/prevention & control , Plasmacytoma/radiotherapy , Spinal Neoplasms/radiotherapy , Adult , Aged , Combined Modality Therapy , Disease Progression , Female , Humans , Male , Middle Aged , Neurosurgical Procedures , Plasmacytoma/surgery , Propensity Score , Proportional Hazards Models , SEER Program , Spinal Neoplasms/surgery , Survival RateABSTRACT
Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.
Subject(s)
Multiple Myeloma , Animals , Antineoplastic Agents , Bone Diseases , Bone and Bones , Multiple Myeloma/prevention & control , Multiple Myeloma/therapy , Signal TransductionABSTRACT
PURPOSE: Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. METHODS: We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. RESULTS: Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. CONCLUSIONS: The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.
Subject(s)
Acute Kidney Injury/blood , Acute Kidney Injury/chemically induced , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/blood , Vancomycin/adverse effects , Vancomycin/blood , Adult , Aged , Aged, 80 and over , Amphotericin B/administration & dosage , Amphotericin B/adverse effects , Drug Interactions , Female , Humans , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/therapy , Lymphoma/blood , Lymphoma/therapy , Male , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/prevention & control , Multiple Myeloma/therapy , Piperacillin, Tazobactam Drug Combination/administration & dosage , Piperacillin, Tazobactam Drug Combination/adverse effects , Retrospective Studies , Surveys and QuestionnairesABSTRACT
Multiple myeloma (MM) is a B-cell malignancy characterized by the abnormal proliferation of clonal plasma cells in the bone marrow leading to end-organ manifestations. Despite the advancement in the therapy and care of patients with MM, relapse and resistance to standard therapy remain significant. The development of immunotherapy as a treatment modality for many types of cancers has led investigators to explore its use in MM in order to elicit myeloma-targeted immune responses, especially given that immune dysregulation is an underlying feature in the pathogenesis and progression of MM. In this concise review, we discuss the different advances in the immune-based therapy of MM, from immunomodulation, vaccines, to monoclonal antibodies, checkpoint inhibitors, adoptive T-cell therapies, and future promising therapies under investigation.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Cancer Vaccines/therapeutic use , Immunotherapy/methods , Multiple Myeloma/immunology , Multiple Myeloma/prevention & control , Humans , PrognosisABSTRACT
Relapse is now the major cause of treatment failure after allogeneic HSCT (alloHSCT). Many novel strategies to address this critical issue are now being developed and tested. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg, Germany in November 2016, international experts presented and discussed recent developments in the field. Some approaches may be applicable to a wide range of patients after transplant, whereas some may be very disease-specific. We present a report from the session dedicated to issues related to prevention and treatment of relapse of lymphoid malignancies after alloHSCT. This session included detailed reviews as well as forward-looking commentaries that focused on Hodgkin lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma, diffuse large cell and follicular lymphoma, and multiple myeloma.
Subject(s)
Hematologic Neoplasms/prevention & control , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/prevention & control , Lymphoma, Non-Hodgkin/prevention & control , Multiple Myeloma/prevention & control , Congresses as Topic , Germany , Humans , Recurrence , Transplantation, HomologousABSTRACT
Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM.
Subject(s)
Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Multiple Myeloma/prevention & control , Neoplastic Stem Cells/drug effects , Polycomb Repressive Complex 2/antagonists & inhibitors , Wnt Signaling Pathway/drug effects , Xenograft Model Antitumor Assays , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Neoplastic Stem Cells/metabolism , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Side-Population Cells/drug effects , Side-Population Cells/metabolism , Wnt Signaling Pathway/geneticsABSTRACT
Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study.
Subject(s)
Disease Progression , Monoclonal Gammopathy of Undetermined Significance/pathology , Multiple Myeloma/pathology , Multiple Myeloma/prevention & control , Humans , Monoclonal Gammopathy of Undetermined Significance/genetics , Multiple Myeloma/genetics , Multiple Myeloma/therapy , Mutation/genetics , Risk FactorsABSTRACT
Autologous stem cell transplantation (SCT) remains a standard of care for multiple myeloma (MM) patients and prolongs progression-free survival. A small cohort of patients achieve long-term control of disease, but the majority of patients ultimately relapse, and the mechanisms permitting disease progression remain unclear. In this study, we used a preclinical model of autologous SCT for myeloma where the disease either progressed (MM relapsed) or was controlled. In the bone marrow (BM), inhibitory receptor expression on CD8+ T cells correlated strongly with myeloma progression after transplant. In conjunction, the costimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated. Interestingly, DNAM-1- CD8+ T cells in MM-relapsed mice had an exhausted phenotype, characterized by upregulation of multiple inhibitory receptors, including T-cell immunoglobulin and ITIM domains (TIGIT) and programmed cell death protein 1 (PD-1) with decreased T-bet and increased eomesodermin expression. Immune checkpoint blockade using monoclonal antibodies against PD-1 or TIGIT significantly prolonged myeloma control after SCT. Furthermore, CD8+ T cells from MM-relapsed mice exhibited high interleukin-10 (IL-10) secretion that was associated with increased TIGIT and PD-1 expression. However, while donor-derived IL-10 inhibited myeloma control post-SCT, this was independent of IL-10 secretion by or signaling to T cells. Instead, the donor myeloid compartment, including colony-stimulating factor 1 receptor-dependent macrophages and an IL-10-secreting dendritic cell population in the BM, promoted myeloma progression. Our findings highlight PD-1 or TIGIT blockade in conjunction with SCT as a potent combination therapy in the treatment of myeloma.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antigens, Differentiation, T-Lymphocyte/metabolism , CD8-Positive T-Lymphocytes/immunology , Interleukin-10/physiology , Multiple Myeloma/prevention & control , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Receptors, Immunologic/antagonists & inhibitors , Animals , Antigens, Differentiation, T-Lymphocyte/genetics , Cells, Cultured , Hematopoietic Stem Cell Transplantation/adverse effects , Mice , Mice, Knockout , Multiple Myeloma/etiology , Multiple Myeloma/pathology , Programmed Cell Death 1 Receptor/immunology , Receptors, Immunologic/immunologyABSTRACT
Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far, immune checkpoint blockade targeting programmed cell death protein 1 has not proven effective as single agent in this disease. T-cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T-cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8+ T cells. TIGIT+ CD8+ T cells from MM patients exhibited a dysfunctional phenotype characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk*MYC mouse MM cells, TIGIT-deficient mice showed decreased serum monoclonal immunoglobulin protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits antimyeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies increased the effector function of MM patient CD8+ T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT-blocking strategies for the treatment of MM patients.
Subject(s)
Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/immunology , Multiple Myeloma/prevention & control , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Receptors, Immunologic/antagonists & inhibitors , Animals , CD8-Positive T-Lymphocytes/drug effects , Cells, Cultured , Humans , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Multiple Myeloma/etiology , Multiple Myeloma/pathology , Programmed Cell Death 1 Receptor/immunology , Receptors, Immunologic/metabolism , Receptors, Immunologic/physiologyABSTRACT
BACKGROUND: Extramedullary plasmacytoma is a rare neoplasm characterized by monoclonal proliferation of plasma cells outside bone marrow. It accounts for 4% of all non-epithelial sinonasal tumors. According to the literature, radiotherapy is the standard therapy for extramedullary plasmacytoma. However, the conversion rate of extramedullary plasmacytoma to multiple myeloma is reported to be between 11 and 33% over 10 years. The highest risk of conversion is reported during the first 2 years after diagnosis, but conversion has been noted up to 15 years after diagnosis. Once conversion to multiple myeloma is complete, less than 10% of patients will survive 10 years. CASE PRESENTATION: We present three cases of sinonasal extramedullary plasmacytoma who underwent radiotherapy: a 61-year-old white man, a 60-year-old white man, and a 37-year-old white woman. We found long-term survival with stable disease in all three cases. CONCLUSIONS: The management of solitary extramedullary plasmacytomas of the sinonasal tract is not well established yet. However, the possibility of recurrence and progression to multiple myeloma requires a thorough follow-up protocol. Due to the absence of a standardized protocol for these tumors, we tried to design a tailored long-term follow-up scheme.
Subject(s)
Antineoplastic Agents , Multiple Myeloma/prevention & control , Nasopharyngeal Neoplasms/therapy , Paranasal Sinus Neoplasms/therapy , Plasmacytoma/therapy , Radiotherapy , Adult , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Nasopharyngeal Neoplasms/diagnosis , Neoplasm Recurrence, Local , Paranasal Sinus Neoplasms/diagnosis , Plasmacytoma/diagnosis , Survival Analysis , Treatment OutcomeABSTRACT
Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD.
Subject(s)
Bone Density Conservation Agents/adverse effects , Bone Neoplasms/drug therapy , Diphosphonates/adverse effects , Multiple Myeloma/drug therapy , Practice Guidelines as Topic , Bisphosphonate-Associated Osteonecrosis of the Jaw/etiology , Bone Density Conservation Agents/administration & dosage , Bone Neoplasms/complications , Bone Neoplasms/prevention & control , Bone and Bones , Diphosphonates/administration & dosage , Evidence-Based Medicine , Humans , Kidney Diseases/etiology , Multiple Myeloma/complications , Multiple Myeloma/prevention & control , Radiography , Risk FactorsABSTRACT
The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy. We consider data supporting the addition of the proteasome inhibitors carfilzomib and ixazomib, or the monoclonal antibodies elotuzumab or daratumumab, to a treatment backbone of lenalidomide and dexamethasone. The clinical data set is less well developed for the addition of a third agent to the combination of bortezomib and dexamethasone; nonetheless, data are presented supporting the addition of the histone deacetylase inhibitor panobinostat, or elotuzumab or daratumumab. While acknowledging the lack of head-to-head data on which to base comparisons between the numerous regimens, we collate the latest data in order to provide a basis on which to make clinical decisions in this rapidly advancing field.