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Leukemia Apr 2022Interrogation of cell-free DNA (cfDNA) represents an emerging approach to non-invasively estimate disease burden in multiple myeloma (MM). Here, we examined low-pass...
Interrogation of cell-free DNA (cfDNA) represents an emerging approach to non-invasively estimate disease burden in multiple myeloma (MM). Here, we examined low-pass whole genome sequencing (LPWGS) of cfDNA for its predictive value in relapsed/ refractory MM (RRMM). We observed that cfDNA positivity, defined as ≥10% tumor fraction by LPWGS, was associated with significantly shorter progression-free survival (PFS) in an exploratory test cohort of 16 patients who were actively treated on diverse regimens. We prospectively determined the predictive value of cfDNA in 86 samples from 45 RRMM patients treated with elotuzumab, pomalidomide, bortezomib, and dexamethasone in a phase II clinical trial (NCT02718833). PFS in patients with tumor-positive and -negative cfDNA after two cycles of treatment was 1.6 and 17.6 months, respectively (HR 7.6, P < 0.0001). Multivariate hazard modelling confirmed cfDNA as independent risk factor (HR 96.6, P = 6.92e-05). While correlating with serum-free light chains and bone marrow, cfDNA additionally discriminated patients with poor PFS among those with the same response by IMWG criteria. In summary, detectability of MM-derived cfDNA, as a measure of substantial tumor burden with therapy, independently predicts poor PFS and may provide refinement for standard-of-care response parameters to identify patients with poor response to treatment earlier than is currently feasible.
Topics: Cell-Free Nucleic Acids; Humans; Multiple Myeloma; Treatment Failure
PubMed: 35027656
DOI: 10.1038/s41375-021-01492-y -
American Society of Clinical Oncology... May 2018A national conversation regarding the price and affordability of drugs exists, where concern for value and benefits of medications is challenged by the increasing price... (Review)
Review
A national conversation regarding the price and affordability of drugs exists, where concern for value and benefits of medications is challenged by the increasing price of both injectable and oral medications, including the cost of care of myeloma. At the same time, we have seen unprecedented improvements in the overall survival of patients with myeloma, mostly because of the availability of these new drugs. Here, we present data to assert that these medications and associated expenses are of direct benefit to patients and society. The entrepreneurial reward for drug development in the United States has fueled vigorous drug development efforts that have culminated in the approval of 11 new drugs for the treatment of myeloma by the U.S. Food and Drug Administration (FDA) since 1999. These patented drugs are available to patients in the United States usually at a higher price than in the rest of the world. Nevertheless, the majority of patients, via direct copay assistance or through indirect support via third parties, have access to these drugs irrespective of their socioeconomic status. One of the major regulatory hurdles that prevents access to these drugs is the legal impossibility that pharmaceutical companies have in directly supporting copay assistance for patients with government-funded health care. Moreover, assessments of value should include formal pharmacoeconomic analyses performed by experts. Interference with market forces and coercive action, such as price controls, or exercising eminent domain in the quest for cheaper medications will stymie innovation and rob us of the cures of the future.
Topics: Humans; Multiple Myeloma
PubMed: 30231366
DOI: 10.1200/EDBK_200869 -
British Journal of Haematology Sep 2019Treatment response assessment in multiple myeloma (MM) relies on the detection of paraprotein in serum and/or urine, bone marrow morphology and immunohistochemistry.... (Review)
Review
Treatment response assessment in multiple myeloma (MM) relies on the detection of paraprotein in serum and/or urine, bone marrow morphology and immunohistochemistry. With remarkable advances in therapy, particularly in the newly diagnosed setting, achievement of complete remission became frequent, creating the need to identify smaller amounts of residual disease and understand their prognostic and therapeutic implications. Measurable residual disease (MRD) can be assessed primarily by flow cytometry and next generation sequencing and state-of-the-art assays have sensitivity approaching 1 in 10 cells. This review discusses the existing challenges in utilizing MRD to inform management of MM and highlights open research questions and opportunities as MRD is more routinely incorporated into clinical practice for patients with MM.
Topics: Flow Cytometry; High-Throughput Nucleotide Sequencing; Humans; Multiple Myeloma; Neoplasm, Residual
PubMed: 31364160
DOI: 10.1111/bjh.16130 -
South African Family Practice :... Jun 2023Multiple myeloma (MM) is a plasma cell malignancy associated with morbidity and mortality worldwide, and most patients are referred for specialist care very late with...
BACKGROUND
Multiple myeloma (MM) is a plasma cell malignancy associated with morbidity and mortality worldwide, and most patients are referred for specialist care very late with complications. The low index of suspicion among medical practitioners is among the reasons for the delay in MM diagnosis and management. This study aimed to determine the level of awareness and knowledge of MM among medical practitioners working in public hospitals of Tshwane Municipality, Gauteng Province, South Africa.
METHODS
A cross-sectional descriptive study on 74 doctors working in three district, one regional and one central hospital using a convenience sampling.
RESULTS
Seventy-four medical practitioners participated in this study. Their median age was 37 years with an interquartile range of 43-30 years. The majority (85%) of the respondents were aware of MM, while 74% were knowledgeable regarding MM presentations and diagnostic investigations.
CONCLUSION
The findings highlighted a high level of awareness and knowledge of MM among the study population, but almost all of the participants requested an educational information brochure on MM.Contribution: Medical practitioners have a high level of awareness of multiple myeloma; however, there is a discrepancy between this level of awareness and the delayed presentation of patients at the public hospitals. As primary healthcare in South Africa is nurse-driven, the study indicates that not all primary healthcare providers may be aware of this disease. Future awareness campaigns should target other primary healthcare providers, including nurses and private general practitioners.
Topics: Humans; South Africa; Multiple Myeloma; Cross-Sectional Studies; Surveys and Questionnaires; Health Personnel; Hospitals, Public
PubMed: 37427777
DOI: 10.4102/safp.v65i1.5644 -
Leukemia Jul 2018Multiple myeloma (MM) is a malignant plasma cell (PC) disorder, characterized by a complex interactive network of tumour cells and the bone marrow (BM) stromal... (Review)
Review
Multiple myeloma (MM) is a malignant plasma cell (PC) disorder, characterized by a complex interactive network of tumour cells and the bone marrow (BM) stromal microenvironment, contributing to MM cell survival, proliferation and chemoresistance. Mesenchymal stem cells (MSCs) represent the predominant stem cell population of the bone marrow stroma, capable of differentiating into multiple cell lineages, including fibroblasts, adipocytes, chondrocytes and osteoblasts. MSCs can migrate towards primary tumours and metastatic sites, implying that these cells might modulate tumour growth and metastasis. However, this issue remains controversial and is not well understood. Interestingly, several recent studies have shown functional abnormalities of MM patient-derived MSCs indicating that MSCs are not just by-standers in the BM microenvironment but rather active players in the pathophysiology of this disease. It appears that the complex interaction of MSCs and MM cells is critical for MM development and disease outcome. This review will focus on the current understanding of the biological role of MSCs in MM as well as the potential utility of MSC-based therapies in this malignancy.
Topics: Animals; Antineoplastic Agents; Biomarkers; Bone Diseases; Cell Communication; Cell- and Tissue-Based Therapy; Humans; Immunophenotyping; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Molecular Targeted Therapy; Multiple Myeloma; Signal Transduction; Tumor Microenvironment
PubMed: 29535427
DOI: 10.1038/s41375-018-0061-9 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor... (Review)
Review
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.
Topics: Humans; Multiple Myeloma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Immunization, Passive; Antibodies
PubMed: 37353432
DOI: 10.1016/j.clml.2023.05.008 -
Blood May 2015Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer... (Review)
Review
Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment.
Topics: Animals; Cell Transformation, Neoplastic; Cellular Microenvironment; Clonal Evolution; Humans; Multiple Myeloma
PubMed: 25838343
DOI: 10.1182/blood-2014-11-568881 -
Journal of Geriatric Oncology May 2021Multiple myeloma is the second most common hematological malignancy in the USA and Europe. Despite improvements in the 5-year and overall survival rates over the past... (Review)
Review
Multiple myeloma is the second most common hematological malignancy in the USA and Europe. Despite improvements in the 5-year and overall survival rates over the past decade, older adults (aged ≥65 years) with multiple myeloma continue to experience disproportionately worse outcomes than their younger counterparts. These differences in outcomes arise from the increased prevalence of vulnerabilities such as medical comorbidities and frailty seen with advancing age that can influence treatment-delivery and tolerance and impact survival. In general, geriatric assessments can help identify those patients more likely to benefit from enhanced toxicity risk-prediction and aid treatment decision-making. Despite the observed benefits of geriatric assessments and other screening frailty tools, provider and systems-level barriers continue to influence the overall perception of the feasibility of geriatric assessments in clinical practice settings. Clinical trials are underway evaluating the efficacy and safety of various multiple myeloma therapies in less fit/frail older adults, with a minority examining fitness-based/risk-adapted approaches. Thus, significant gaps exist in knowing which myeloma therapies are most appropriate for older and more vulnerable adults with multiple myeloma. The purpose of this Review is to discuss how geriatric assessments can be used to guide the management of transplant-ineligible patients; and to highlight frontline therapies for standard-risk and high-risk cytogenetic abnormalities [i.e., t(4;14), t(14;16), and del(17p)] associated with multiple myeloma. We also discuss the current shortcomings of the existing clinical approaches to care and highlight ongoing clinical trials evaluating newer fitness-based approaches to managing transplant-ineligible patients.
Topics: Aged; Europe; Frail Elderly; Frailty; Geriatric Assessment; Humans; Multiple Myeloma
PubMed: 33342724
DOI: 10.1016/j.jgo.2020.12.001 -
Clinical Journal of Oncology Nursing Oct 2017Oncologic emergencies associated with multiple myeloma include myelosuppression (anemia, neutropenia, and thrombocytopenia), bone-related emergencies, and acute renal... (Review)
Review
BACKGROUND
Oncologic emergencies associated with multiple myeloma include myelosuppression (anemia, neutropenia, and thrombocytopenia), bone-related emergencies, and acute renal failure. .
OBJECTIVES
This article reviews the pathophysiology of these multiple myeloma-associated oncology emergencies and provides a framework for assessment and effective intervention. .
METHODS
A comprehensive review of the levels of evidence, focusing on assessment, diagnosis, comorbidities, treatment, ongoing monitoring, and patient education, are presented to support the plan of care for at-risk patients. .
FINDINGS
Attention to signs and symptoms is the foundation for preventing these emergencies or managing additional escalation of symptoms.
Topics: Acute Kidney Injury; Anemia; Bone Diseases; Bone Marrow; Evidence-Based Medicine; Humans; Multiple Myeloma; Neutropenia; Thrombocytopenia
PubMed: 28945730
DOI: 10.1188/17.CJON.S5.60-76 -
Journal of Hematology & Oncology May 2018Multiple myeloma is the second most frequent hematological malignancy in the western world and remains incurable, predominantly due to acquired drug resistance and... (Review)
Review
Multiple myeloma is the second most frequent hematological malignancy in the western world and remains incurable, predominantly due to acquired drug resistance and disease relapse. The highly conserved Wnt signal transduction pathway, which plays a key role in regulating cellular processes of proliferation, differentiation, migration, and stem cell self-renewal, is associated with multiple aspects of disease. Bone homeostasis is severely disturbed by Wnt antagonists that are secreted by the malignant plasma cells in the bone marrow. In the vast majority of patients, this results in osteolytic bone disease, which is associated with bone pain and pathological fractures and was reported to facilitate disease progression. More recently, cumulative evidence also indicates the importance of intrinsic Wnt signaling in the survival of multiple myeloma cells. However, Wnt pathway-activating gene mutations could not be identified. The search for factors or processes responsible for Wnt pathway activation currently focuses on aberrant ligand levels in the bone marrow microenvironment, increased expression of Wnt transcriptional co-factors and associated micro-RNAs, and disturbed epigenetics and post-translational modification processes. Furthermore, Wnt pathway activation is associated with acquired cell adhesion-mediated resistance of multiple myeloma cells to conventional drug therapies, including doxorubicin and lenalidomide. In this review, we present an overview of the relevance of Wnt signaling in multiple myeloma and highlight the Wnt pathway as a potential therapeutic target for this disease.
Topics: Animals; Bone Diseases; Drug Resistance; Humans; Molecular Targeted Therapy; Multiple Myeloma; Osteolysis; Wnt Signaling Pathway
PubMed: 29776381
DOI: 10.1186/s13045-018-0615-3