Search Results (368)

Introduction: The concomitant occurrence of myeloproliferative neoplasms (MPNs) and plasma cell dyscrasias is rare and presents significant diagnostic challenges. Accurate distinction between overlapping features is essential, particularly when bone marrow fibrosis (BMF) is present. Case Description: We report a 57-year-old female, with a 10-year history of thrombocytosis managed with antiplatelet therapy, who presented with anemia and severe lumbar pain. Bone marrow biopsy revealed marked fibrosis, and imaging revealed multiple vertebral lesions. Diagnostic workup identified features consistent with myelofibrosis (MF) and coexisting IgG-Kappa multiple myeloma (MM). Although the patient initially fulfilled WHO criteria for MF, the rapid resolution of fibrosis following first-line plasma-cell-directed therapy suggested a secondary, cytokine-mediated process rather than a true concomitant MPN. Conclusions: This case highlights the importance of an integrated diagnostic approach in patients with overlapping features of hematologic malignancies. Differentiating between MM-associated fibrosis and true concurrent MPN and MM is critical, as misclassification may alter both prognosis and therapeutic strategy. In triple-negative cases, the histologic response to plasma-cell-directed therapy can serve as a key discriminating criterion. Awareness of the potential association between MM with fibrosis and extramedullary disease is also essential for clinical management. This case underscores the importance of an integrated diagnostic approach in patients with overlapping hematologic features. Full article

Multiple myeloma (MM) develops through asymptomatic precursor stages characterized by progressive remodeling of the bone marrow (BM) immune microenvironment and disruption of bone homeostasis. To delineate changes in natural killer (NK) cell states during disease evolution, we investigated coordinated immune-tumor remodeling by integrating NK cell functional states with plasma cell-intrinsic susceptibility programs derived from CRISPR-based screens across healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed MM patients. The integration of NK cell state-associated gene signatures with plasma cell transcriptional programs revealed stage-specific co-variation between immune and tumor compartments. Public single-cell RNA sequencing datasets were interrogated to resolve NK cell heterogeneity, identifying cytotoxic CD56^dim and regulatory CD56^bright subsets. NK cell dynamics displayed stage-dependent changes, with early expansion followed by the contraction of CD56^dim cells in BM, whereas CD56^bright cells showed predominantly compositional remodeling. Within the CD56^bright subset, transcriptional changes included an increased expression of KLRC1 (encoding NKG2A), subsequently validated by multiparametric flow cytometry. In parallel, plasma cell programs associated with NK sensitivity progressively decreased along disease stages, supporting tumor adaptation to immune pressure. The NKG2A ligand HLA-E displayed selective expression within CD16⁺ monocytes and followed a distinct variable pattern across disease stages, highlighting a microenvironmental contribution to NK cell regulation. Collectively, these findings indicate a coordinated process of immune-tumor co-evolution, characterized by dynamic remodeling of NK cell states and plasma cell susceptibility, with the NKG2A–HLA-E axis emerging as a central interface during MM progression. Full article

Background/Objectives: Multiple myeloma (MM) is a genetically complex hematological neoplasm driven by accumulating genomic events. Despite therapeutic advances, MM remains an incurable disease with a complex molecular picture. Characterizing copy number alterations (CNAs) represents a promising strategy to identify dysregulated biological pathways and reveal novel therapeutic targets. This study aimed to characterize the CNA profile across pre-malignant gammopathies, MM, and plasma cell leukemia, identifying the key molecular pathways involved in disease progression. Methods: Genomic analysis via array comparative genomic hybridization (aCGH) was performed on bone marrow samples from 21 patients representing all disease stages. Data were analyzed in CytoGenomics software version 5.3.0.14 utilizing the GRCh38/hg38 human genome. CNAs were identified with the ADM-2 algorithm, followed by functional enrichment analysis to determine significantly overrepresented pathways. Results: Pre-malignant evaluation suggested a potential functional switch from innate immunity and olfactory signaling in Monoclonal Gammopathy of Undetermined Significance (MGUS) to DNA repair mechanisms in Smoldering Multiple Myeloma (SMM), marking early genomic instability. In active MM, 280 CNAs were detected. Low-risk (ISS-I) patients retained cell adhesion signatures, whereas high-risk (ISS-III) profiles exhibited extensive genomic instability affecting tissue remodeling and cytokine signaling. Conclusions: In summary, our descriptive findings suggest that early alterations in immune response and olfactory signaling pathways may emerge as potential triggers driving pre-malignant dyscrasias and active MM development. Full article

Multiple myeloma profoundly remodels the bone marrow microenvironment, causing osteolytic bone disease through a persistent uncoupling of bone resorption and formation. Beyond the canonical roles of the receptor activator of nuclear factor kappa-B ligand/receptor activator of nuclear factor kappa-B/osteoprotegerin triad and Wnt antagonism, three interdependent stress programs orchestrate the osteolytic niche. These include oxidative stress driven by mitochondrial and nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species; sterile inflammation sustained by damage-associated molecular patterns, pattern-recognition receptors, and pro-inflammatory cytokines; and autophagy–lysosomal remodeling governed by transcription factor EB and the coordinated lysosomal expression and regulation network. These axes intersect with iron handling and lipid peroxidation to regulate sensitivity to ferroptotic cell death, thereby shaping osteoclast priming, osteoblast suppression, and matrix turnover. Building on these mechanistic insights, we outline a translational framework that aligns standardized bone turnover markers of formation and resorption with composite panels of oxidative and nitrosative stress. This framework also integrates modern imaging to capture structural injury and metabolically active marrow disease. We further propose a therapeutic roadmap layered on antiresorptive foundations that targets selective inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4 and calibrated modulation of nuclear factor erythroid 2–related factor 2, disrupts damage-associated molecular pattern and cytokine circuits, and applies lineage- and timing-specific tuning of autophagy together with restoration of ferroportin-1 or iron chelation. This integrated strategy is designed to recouple bone remodeling and improve clinically meaningful skeletal outcomes in multiple myeloma. Full article

Multiple myeloma (MM) is a malignancy of plasma cells that is characterized by a complex and spatially heterogeneous genomic landscape. Despite this complexity, clinical monitoring remains largely dependent on localized bone marrow (BM) assessments. This dependence creates a significant diagnostic gap, as the primary monitoring tools fail to account for the spatial and temporal heterogeneity that drives tumor relapse. Liquid biopsy can serve as an adjunctive approach in assessing the pan-clonal landscape in MM through the molecular profiling of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). In this review, we examine the clinical utility of liquid biopsy components in capturing mutational profiles, clonal evolution, treatment resistance mechanisms, and minimal residual disease (MRD), including early detection of relapse and extramedullary progression. We will further discuss current limitations, including variability in assay sensitivity, lack of standardization, and the need for prospective validation. Full article

Background and Clinical Significance: Chromothripsis represents a catastrophic genomic event in plasma cell myeloma (PCM) associated with poor prognosis. We report a case of newly diagnosed PCM with complex cytogenetic abnormalities indicative of genomic instability. Case Presentation: A 67-year-old man presented with acute dyspnea and was found to have severe acute kidney injury, anemia, hypercalcemia, and IgG lambda monoclonal gammopathy. Bone marrow biopsy revealed plasma cell infiltration. Comprehensive FISH analysis demonstrated a complex pattern with gain of 1q, monosomy 13, and multiple numeric and structural abnormalities affecting chromosomes 5, 9, and 15, suggestive of a chromothripsis-like pattern. Despite requiring hemodialysis, the patient achieved complete renal recovery and >99% reduction in serum-free light chains after one cycle of CyBorD plus daratumumab, which was continued for four cycles. Follow-up bone marrow evaluation at three months confirmed complete histologic, flow cytometric, and cytogenetic remission, allowing for preparation for autologous stem cell transplantation. Conclusions: This case demonstrates that exceptional clinical responses can be achieved in high-risk disease with contemporary quadruplet regimens. While the long-term durability of such responses in genomically unstable cases remains uncertain, this case highlights the importance of comprehensive cytogenetic characterization to identify and monitor genomic instability in PCM. Full article

Background/Objectives: Serum protein electrophoresis (SPE) is a widely used laboratory test for the detection and monitoring of monoclonal gammopathies, including multiple myeloma (MM). Although SPE is usually recommended in the presence of specific clinical or laboratory abnormalities, monoclonal gammopathies may occasionally develop rapidly and without typical symptoms. This case report aims to emphasize the diagnostic value of SPE in identifying an unexpected and fast-evolving monoclonal gammopathy. Methods: We report the clinical and laboratory eight-month follow-up of a 58-year-old male who initially underwent SPE for unrelated clinical conditions. Serial SPE analyses were performed using capillary zone electrophoresis. When abnormalities emerged, immunotyping and serum free light chain (FLC) assays were conducted. The diagnostic workup was completed with bone marrow aspiration, flow cytometry, and imaging studies according to current international diagnostic criteria. Results: The initial SPE (November 2023) showed a normal protein profile. After eight months, follow-up SPE revealed a prominent monoclonal spike in the gamma region (2.9 g/dL), associated with increased total serum proteins (91 g/L; range 64–82 g/L), elevated IgA levels (20.0 g/L; range 0.4–3.5 g/L), and a markedly abnormal κ/λ FLC ratio (54.00; range 0.31–1.56). Bone marrow analysis demonstrated >18% plasma cell infiltration, confirming the diagnosis of IgA-κ MM. The patient underwent standard therapy followed by autologous stem cell transplantation, achieving disease remission. Conclusions: This case highlights that clinically relevant monoclonal gammopathies may arise rapidly in the absence of classical diagnostic features. Routine SPE represents a cost-effective and accessible screening tool that can identify subtle protein abnormalities, prompting the timely use of more specific and invasive diagnostic procedures for aggressive plasma cell disorders. Full article

Multiple myeloma is a complex hematologic malignancy characterized by significant biological heterogeneity, a relapsing–remission clinical course, and a continuously evolving therapeutic landscape. Accurate and timely laboratory assessment is central to disease management, supporting diagnosis, risk stratification, evaluation of treatment response, and long-term monitoring. Despite major advances in therapy, a critical need remains for laboratory tools that can detect disease with greater sensitivity, capture spatial and clonal tumor heterogeneity, and reflect the true depth of treatment response beyond conventional serological and bone marrow-based criteria. Recent laboratory innovations have the potential to transform myeloma care by enabling earlier detection, more accurate prognostication, and personalized therapeutic strategies. This review focuses specifically on innovative laboratory technologies for the diagnosis of multiple myeloma and the evaluation of treatment response. Within this scope, we examine the current diagnostic approaches and the role of high-throughput technologies for measurable residual disease assessment. We explore the emerging role of liquid biopsy approaches, including circulating tumor cells, cell-free DNA/RNA, and mass spectrometry for ultrasensitive detection of monoclonal proteins. We further discuss novel molecular biomarkers and the integration of artificial intelligence and machine learning tools to enhance data interpretation. The innovations reviewed here represent a shift in the contribution of laboratory medicine to myeloma care, offering a more precise, less invasive, and biologically informative framework for targeted and adaptive clinical decisions. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is the clonal expansion of somatically mutated hematopoietic stem cells (HSCs) in the bone marrow. CHIP mutations are relatively common in multiple myeloma (MM) and have been identified as potential biomarkers for poorer survival outcomes. MM is a hematological malignancy that, despite treatment advances, remains aggressive and incurable for many patients. The potential impact of CHIP mutations on the outcomes of MM treatments has been the topic of several recent studies, yet both the magnitude and the modality by which CHIP exerts its negative effects on treatment and disease progression remain to be fully elucidated. Evidence suggests that CHIP mutations may contribute to inferior survival and treatment tolerances, as well as contribute to greater treatment toxicity and related frailty. In this review, we synthesize and discuss the available literature to provide an updated understanding of the complex role that CHIP plays in altering the MM microenvironment, and the resulting impact on standard MM treatments, autologous stem cell transplant (ASCT) and B-cell maturation antigen (BCMA)-targeted therapy/CAR-T, and the important role of immunomodulatory drug (IMiD) maintenance therapy in clinical outcomes. Full article

Multiple myeloma is a hematological malignancy characterized by clonal proliferation of plasma cells, usually confined to the bone marrow. Extramedullary disease (EMD) occurs in 7–18% of patients during the disease course and is associated with poor prognosis. Among extramedullary sites, testicular involvement is extremely rare, with an incidence of less than 2%. We present a rare case of testicular plasmacytoma as the first manifestation of systemic multiple myeloma, highlighting its imaging features and clinical implications. Full article

Circulating tumour DNA (ctDNA) assays are increasingly applied in haematological malignancies for non-invasive genotyping, quantitative response assessment, measurable residual disease (MRD) detection, and relapse surveillance, often complementing bone marrow-based testing and, in selected scenarios, potentially reducing its frequency. Yet, translating ctDNA results into comparable clinical decisions across laboratories, platforms, and time remains challenging because ctDNA measurements are influenced by the definition of the measurand (for example, variant allele fraction versus mutant molecules per mL), pre-analytical variables, end-to-end workflow losses, and lineage-specific confounders such as clonal haematopoiesis of indeterminate potential (CHIP), therapy-related clonal haematopoiesis, and compartmental disease (marrow, plasma, cerebrospinal fluid, extramedullary sites). This review proposes a harmonisation framework for haematological ctDNA based on three linked concepts—metrological traceability, which connects reported values to reference systems with stated uncertainty, commutability, which ensures that reference materials behave like patient specimens across diverse workflows and fit-for-purpose reference materials that support calibration, and quality control, external quality assessment, and cut-off setting for intended uses such as early molecular response in large B-cell lymphoma, molecular MRD in acute myeloid leukaemia, and deep response monitoring in multiple myeloma. This framework is accompanied by harmonised CHIP-aware reporting rules for settings without matched cellular DNA and practical change-control/bridging strategies to preserve clinical decision thresholds when platforms or bioinformatic pipelines evolve. Full article

Background/Objectives: Multiple myeloma (MM) is an incurable plasma cell neoplasm in which diagnosis and prognostication rely on invasive bone marrow examinations that may not capture biological heterogeneity across different disease sites. There is a clinical need for non-invasive biomarkers that can accurately predict treatment outcomes. Methods: We performed a global proteomic profiling of bone marrow-derived extracellular vesicles (EVs) from nine MM patients and ten controls. A total of 8839 proteins were identified, of which 14 met predefined selection criteria. These candidates were quantified in serum-derived EVs using targeted proteomic analysis. Prognostic relevance of selected proteins was evaluated in newly diagnosed MM (NDMM) patients treated with daratumumab-containing frontline regimens (n = 26) and healthy individuals (n = 60). Progression-free survival (PFS) was analyzed using univariable and multivariable models. Results: IL5RA (p = 0.003) and BCMA (p < 0.001) were significantly elevated in serum EVs from MM patients compared with controls. Higher serum EV-IL5RA and EV-BCMA were associated with a trend toward shorter PFS. Combined assessment of these biomarkers enabled clear stratification of MM patients into three prognostic groups, including a cohort with markedly inferior outcomes, with a 20-month PFS of 0 (p = 0.001). In multivariable analysis, the combined serum EV-IL5RA and EV-BCMA signature suggests an independent prognostic potential (HR = 38.49 [95% CI, 1.51–47.79], p = 0.015). Conclusions: Serum EV-IL5RA and EV-BCMA are novel non-invasive biomarkers, measurable through routine blood testing, with strong potential to improve risk stratification in NDMM patients in the era of daratumumab-based frontline therapy. Full article

Background: Rapidly progressive glomerulonephritis (RPGN) is a severe nephrological emergency, frequently secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. In older adults, the coexistence of comorbidities and monoclonal gammopathy of undetermined significance (MGUS) makes it difficult to distinguish between ANCA vasculitis and monoclonal gammopathy of renal significance (MGRS), which differ in prognosis and treatment. The coexistence of PR3-ANCA-associated vasculitis and MGUS is uncommon and sparsely documented. Case Presentation: A 72-year-old woman with hypertension and type 2 diabetes presented with acute deterioration and rapidly progressive renal failure, requiring hemodialysis. She had subnephrotic proteinuria, hematuria, and an active urinary sediment. The autoimmune workup showed ANCA negativity using immunofluorescence, but PR3-ANCA positivity using ELISA. Hematologic characterization documented an IgG kappa monoclonal spike; no bone lesions, amyloidosis, or criteria for multiple myeloma were found; and the patient was classified as MGUS. Renal biopsy revealed necrotizing extracapillary pauci-immune glomerulonephritis with cellular and fibrocellular crescents and no monoclonal deposits, consistent with PR3-ANCA vasculitis. Induction therapy with methylprednisolone pulses and oral prednisone was initiated; cyclophosphamide was not administered because of catheter-associated Staphylococcus aureus bacteremia and upper gastrointestinal bleeding complicated by disseminated intravascular coagulation. The patient died on day 25 due to infectious and hemorrhagic complications. Conclusions: This case provides additional documentation of an uncommon overlap between PR3-ANCA-associated vasculitis and MGUS in a Latin American patient and highlights the role of renal biopsy in distinguishing MGRS from pauci-immune vasculitis in the presence of paraproteinemia. It also underscores the need to tailor immunosuppression in frail older adults, balancing disease control against the risk of severe infection. Full article

Background/Objectives: FcγRIIIA presents a single nucleotide polymorphism at position 158 (V/F), which affects its binding affinity to the fragment crystallizable (Fc) of antibodies (Abs). In the presence of immune complexes, FcγRIIIA can mediate the inflammatory signaling, severity of bone disease, and osteoclastogenic activity. Based on this functional relevance, we hypothesized that the FcγRIIIA F158V polymorphism may influence the clinical presentation of multiple myeloma (MM). Methods: FcγRIIIA F158V genotyping was performed on genomic DNA extracted from peripheral blood samples of patients affected by MM or asymptomatic conditions named MGUS and SMM. We compared the allele frequency of FcγRIIIA-F158V polymorphism in 72 MM, 42 MGUS and 31 SMM and evaluated the association with clinical features and occurrence of high-risk chromosome abnormalities. Targeted NGS mutation analysis was performed on genomic DNA isolated from purified CD138⁺ bone marrow plasma cells (BMPCs) of 41 patients, to evaluate the association between somatic mutations and the FcγRIIIA F158V genotype. Results: the FcγRIIIA-158 V/V homozygous genotype was associated with high-risk cytogenetics, anemia, high beta-2 microglobulin levels, and more than 10 osteolytic lesions. V/V homozygous genotype was significantly associated with at least one mutation in RAS pathway genes (N-RAS, K-RAS or B-RAF). In the immune microenvironment, patients carrying the V/V homozygous genotype had a higher percentage of CD14⁺CD16⁺⁺ non-conventional inflammatory monocytes than the V/F or FF genotype. Conclusions: Our study contributes to a better understanding of the interactions between genetic variants, tumor microenvironment, and therapeutic response in plasma cell dyscrasias, to identify molecular biomarkers for precision medicine in MM, MGUS and SMM. Full article

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor erythroid 2-related factor 2 (NRF2)- and Heme Oxygenase 1 (HMOX1)-dependent pathways, metabolic reprogramming, and overexpression of ROS-scavenging enzymes such as peroxiredoxin 6 (PRDX6), allowing survival at the threshold of oxidative toxicity. Evidence indicates that biomarkers of oxidative stress—such as lipid and protein oxidation products, antioxidant enzyme activity, and the Oxidative Stress Score—correlate with disease stage, prognosis, and treatment response. Redox-modulating therapeutic strategies, including pharmacological ROS induction, inhibition of antioxidant defenses, and the use of natural pro-oxidant compounds, are emerging as promising adjuncts to standard MM therapies. Recent studies also highlight the gut microbiota as an indirect regulator of oxidative balance, immune modulation, and metabolic homeostasis in MM. This review summarizes current knowledge on oxidative stress in multiple myeloma, emphasizing its role in pathogenesis, drug resistance, biomarker development, and emerging therapeutic and supportive strategies. Full article