ABSTRACT
INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8â g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.
Subject(s)
Multiple Myeloma , Osteosclerosis , Humans , Middle Aged , Female , Osteosclerosis/diagnostic imaging , Osteosclerosis/etiology , Osteosclerosis/pathology , Multiple Myeloma/complications , Multiple Myeloma/pathology , Multiple Myeloma/diagnostic imaging , Positron Emission Tomography Computed Tomography , Paraproteinemias/complications , Paraproteinemias/pathologyABSTRACT
Paraproteinemias are a group of complex diseases associated with an overproduction of a monoclonal immunoglobulin that can cause a diversity of kidney disorders and end-organ damage. In this review, we focus on paraprotein-mediated glomerular diseases. Kidney biopsy plays a crucial role in diagnosing these disorders, enabling the identification of specific histological patterns. These lesions are categorized into organized (such as amyloidosis, immunotactoid glomerulopathy, fibrillary glomerulonephritis, cryoglobulinemic glomerulonephritis, and monoclonal crystalline glomerulopathies) and nonorganized deposits (such as monoclonal Ig deposition disease and proliferative glomerulonephritis with monoclonal Ig deposits) based on the characteristics of immunofluorescence findings and the ultrastructural appearance of deposits on electron microscopy. This review aims to provide an update, highlight, and discuss clinicopathological aspects such as definition, epidemiology, clinical manifestations, mechanisms of kidney injury, histological features, and diagnostic procedures.
Subject(s)
Glomerulonephritis , Kidney Glomerulus , Paraproteinemias , Humans , Paraproteinemias/pathology , Paraproteinemias/diagnosis , Paraproteinemias/metabolism , Glomerulonephritis/pathology , Glomerulonephritis/metabolism , Glomerulonephritis/diagnosis , Kidney Glomerulus/pathology , Kidney Glomerulus/metabolism , Paraproteins/metabolism , Kidney Diseases/pathology , Kidney Diseases/metabolism , Biopsy , Amyloidosis/pathology , Amyloidosis/metabolism , Amyloidosis/diagnosisABSTRACT
Monoclonal Ig crystalline nephropathies are rare lesions resulting from precipitation of monoclonal Igs in the kidney as crystalline inclusions. They can be categorized into lesions with predominant intracellular crystals (light chain [LC] proximal tubulopathy, LC crystal-storing histiocytosis, and LC crystalline podocytopathy) and lesions with predominant extracellular crystals (crystalglobulin-induced nephropathy and crystalline variant of LC cast nephropathy). The majority of these lesions are associated with low tumor burden lymphoproliferative disorders, with the exception of crystalline variant of LC cast nephropathy. Extrarenal involvement (e.g., skin and cornea) is frequent. Kidney biopsy is the cornerstone for diagnosis, which often requires electron microscopy and antigen retrieval. A thorough hematologic workup and evaluation of extrarenal involvement is mandatory for management. Treatment of these lesions is with clone-directed therapy, with the goal of achieving hematologic very good partial response or complete response, which preserves or improves kidney function. In vitro and in vivo studies, animal models, and novel sequencing techniques have been invaluable tools to understand the pathogenesis of LC proximal tubulopathy and can be used to increase our limited knowledge of the pathogenesis of the other monoclonal Ig crystalline nephropathies. This review provides an update on the pathology, renal and hematologic characteristics, extrarenal manifestations, prognosis, treatment, and pathogenesis of monoclonal Ig crystalline nephropathies.
Subject(s)
Crystallization , Kidney Diseases , Humans , Animals , Kidney Diseases/pathology , Kidney Diseases/diagnosis , Kidney/pathology , Kidney/drug effects , Antibodies, Monoclonal/therapeutic use , Biopsy , Immunoglobulin Light Chains/metabolism , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Paraproteinemias/drug therapy , Paraproteinemias/complicationsSubject(s)
Inclusion Bodies , Paraproteinemias , Proteinuria , Aged , Humans , Male , Middle Aged , Histiocytes/pathology , Inclusion Bodies/pathology , Kidney/pathology , Kidney Diseases/pathology , Paraproteinemias/pathology , Paraproteinemias/complications , Proteinuria/pathology , Proteinuria/etiologySubject(s)
Paraproteinemias , Humans , Female , Paraproteinemias/complications , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Facies , Middle Aged , AgedABSTRACT
Multiple myeloma (MM) is associated with the secretion of a unique monoclonal protein (M-protein) due to overproduction of immunoglobulin (Ig) by a clone of abnormally proliferating plasma cells. However, in 4% of the cases more than one M-protein can be found. This category of gammopathies is called "double monoclonal gammopathies." Here, we present a rare case of MM with double monoclonal gammopathy, where the presence of both M-proteins was observed in the single sharp peak on capillary zone electrophoresis (CZE). Further the interference of Hook effect is also discussed. Double monoclonal gammopathies need to be identified to increase diagnostic accuracy and reliability, and to get a better understanding of the disease pathogenesis and progression.
Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Paraproteinemias , Humans , Multiple Myeloma/complications , Multiple Myeloma/diagnosis , Multiple Myeloma/pathology , Reproducibility of Results , Paraproteinemias/complications , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Monoclonal Gammopathy of Undetermined Significance/complications , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Antibodies, MonoclonalABSTRACT
BACKGROUND: As the second most prevalent hematologic malignancy, multiple myeloma (MM) affects plasma cells and is characterized by chromosomal abnormalities, particularly involving the immunoglobulin heavy chain switch region. MM represents a biologically and clinically heterogeneous hematological malignancy that serves as a clonal evolution model, exhibiting clonal heterogeneity throughout all stages from monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM. Although significant progress has been made in the treatment of MM, leading to improved patient outcomes, concerns are arising regarding disease relapse due to the presence and selection of pre-existing resistant clones or selective pressure during therapy. CASE PRESENTATION: We present a case of multiple myeloma (MM) in a female patient, who underwent an 8-year course of treatment, including chemotherapy, immunomodulators, hematopoietic stem cell transplantation, CD38 monoclonal antibody, and chimeric antigen receptor T-cell (CAR-T), and was recently diagnosed with concurrent progressive MM and acute myeloid leukemia (AML). This patient has witnessed the evolution of MM treatment paradigms. CONCLUSION: In this course, disease relapses occurred twice, one of which was manifested by a light chain escape (LCE). Moreover, through the course of the disease in this patient, we review the process of clonal evolution that may be relevant.
Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Paraproteinemias , Humans , Female , Middle Aged , Multiple Myeloma/drug therapy , Paraproteinemias/pathology , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Monoclonal Gammopathy of Undetermined Significance/pathology , Leukemia, Myeloid, Acute/drug therapy , ImmunotherapyABSTRACT
BACKGROUND AND OBJECTIVES: TEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonaryshunting) syndrome is a rare multisystemic disease classified as a monoclonal gammopathy of cutaneous significance. The pathogenesis and etiology of TEMPIare not well known because of the rarity of this disorder. Although telangiectasias are the hallmark of this syndrome, skin biopsies are rarely performed. We aim to further characterize TEMPI syndrome through the evaluationof a skin biopsy. METHODS: We reviewed the histopathology and immunophenotypic profile of a skin biopsy from a 53-year-oldwoman diagnosed with TEMPI syndrome. Other components of her syndromic complex included an IgA myeloma, elevated vascular endothelial growth factor (VEGF), and erythrocytosis. RESULTS: A biopsy showed prominent vascular ectasia with some degree of microvascular basement membranezone thickening. Our patient had a reduction in neoplastic plasma cell burdenand clearing of her telangiectasias following myeloma directed treatment. CONCLUSIONS: TEMPI can beviewed as a reactive vascular paraneoplastic syndrome in the setting of a plasma cell dyscrasia. Elaboration of VEGF from neoplastic plasma cells is likely pathogenetically implicated and appears to be a common link that explains other vascular lesions associated with monoclonal gammopathy syndromes.
Subject(s)
Multiple Myeloma , Paraproteinemias , Polycythemia , Telangiectasis , Female , Humans , Middle Aged , Multiple Myeloma/complications , Paraproteinemias/complications , Paraproteinemias/pathology , Polycythemia/pathology , Polycythemia/therapy , Telangiectasis/pathology , Vascular Endothelial Growth Factor AABSTRACT
Diagnosis of plasma cell proliferative disorders (PCPDs) is primarily based on the demonstration of monoclonal protein (M-Protein) in blood and/ or urine which often precedes clinical manifestations of the disease. The basic pathophysiology behind the M-protein presence is the proliferation of clonal plasma cells (PCs) in bone marrow or extramedullary sites and is assessed using cytomorphology and immunophenotyping. The role of multiparametric flow cytometry (MFC) for PC identification is technically the most valuable tool in this context as it characterizes as well as quantifies the clonal PCs based on differential expression of various immunophenotypic (IPT) markers. From a diagnostic perspective, MFC is critical in the definite identification of the clonal PCs and delineates benign and borderline entities at one end of the spectrum (MGUS, SMM) with lower clonal PC% and, malignant diseases at the other end (MM and PCL) with higher clonal PC fraction. The role of MFC in assessment of measurable residual disease (MRD) and monitoring of progression in MM and various PCPDs has been validated in multiple clinical studies and is probably one of the most promising tools for predicting treatment outcomes. Furthermore, MFC also plays a crucial role in disease prognostication based on specific IPT profiles. An additional role of MFC in the current clinical scenario is the evaluation of tumor microenvironment based on immune cell repertoire, which is reflecting encouraging results across. Thus, in the current review we concisely describe the role of MFC as a reliable and essential modality in PCPDs, from diagnosis to prediction of treatment outcome and disease monitoring.
Subject(s)
Multiple Myeloma , Paraproteinemias , Humans , Plasma Cells/pathology , Multiple Myeloma/pathology , Flow Cytometry/methods , Paraproteinemias/pathology , Bone Marrow/pathology , Immunophenotyping , Neoplasm, Residual/pathology , Tumor MicroenvironmentABSTRACT
Necrobiotic xanthogranuloma is a rare disease that is part of the non-Langerhans cell histiocytoses. It is characterized by yellowish skin lesions, which are typically periorbitally localized. Extracutaneous manifestations of all organs are possible and can cause potentially life-threatening complications. The disease also belongs to the facultative paraneoplasias and is often associated with paraproteinemia. These aspects should be considered regarding further diagnostics. Due to the rarity of the disease, there are no standardized guidelines for therapy so far. The combination of prednisolone and chlorambucil as well as intravenous immunoglobulins seem to be effective therapeutic options. We present four cases from our clinic as well as the current results of the literature in this mini-review and would like to highlight the therapeutic challenge as well as the need for the development of guidelines.
Subject(s)
Histiocytosis, Non-Langerhans-Cell , Necrobiotic Xanthogranuloma , Paraproteinemias , Skin Diseases , Humans , Necrobiotic Xanthogranuloma/diagnosis , Necrobiotic Xanthogranuloma/therapy , Paraproteinemias/complications , Paraproteinemias/pathology , Skin Diseases/pathology , ChlorambucilABSTRACT
Amyloid-like IgM deposition neuropathy is a distinct entity in the setting of IgM monoclonal gammopathy in which endoneurial perivascular entire IgM-particle accumulation leads to a painful sensory followed by motor peripheral neuropathy. We report a 77-year-old man presenting with progressive multiple mononeuropathies starting with painless right foot drop. Electrodiagnostic studies showed severe axonal sensory-motor neuropathy superimposed by multiple mononeuropathies. Laboratory investigations were remarkable for biclonal gammopathy of IgM kappa, IgA lambda and severe sudomotor and mild cardiovagal autonomic dysfunction. A right sural nerve biopsy showed multifocal axonal neuropathy, prominent microvasculitis, and prominent large endoneurial deposits of Congo-red negative amorphous material. Laser dissected mass spectrometry-based proteomics identified IgM kappa deposit without serum amyloid-P protein. This case has several distinctive features, including motor preceding sensory involvement, prominent IgM-kappa proteinaceous deposits replacing most of the endoneurium, a prominent inflammatory component, and improvement of motor strength after immunotherapy.
Subject(s)
Mononeuropathies , Paraproteinemias , Peripheral Nervous System Diseases , Male , Humans , Aged , Peripheral Nervous System Diseases/diagnosis , Peripheral Nerves/pathology , Paraproteinemias/complications , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Immunoglobulin MABSTRACT
BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described. METHODS: We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021. RESULTS: The median age was 69.5 years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months. CONCLUSIONS: The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.
Subject(s)
Kidney Diseases , Multiple Myeloma , Paraproteinemias , Renal Insufficiency, Chronic , Humans , Middle Aged , Aged , Aged, 80 and over , Retrospective Studies , Kidney Diseases/pathology , Kidney/pathology , Multiple Myeloma/diagnosis , Multiple Myeloma/complications , Immunoglobulin Light Chains/analysis , Renal Insufficiency, Chronic/complications , Paraproteinemias/diagnosis , Paraproteinemias/complications , Paraproteinemias/pathologyABSTRACT
TEMPI syndrome is a new and poorly understood disease that is currently considered a type of plasma cell neoplasm with paraneoplastic manifestations. The TEMPI acronym defines the hallmarks of the syndrome: T for telangiectasia; E for erythrocytosis with elevated erythropoietin; M, monoclonal gammopathy; P, perinephric collections; and I, intrapulmonary shunting. Due to the marked erythrocytosis as the most common presenting feature, TEMPI is often misdiagnosed as polycythemia vera. However, unlike polycythemia vera, TEMPI is not associated with a JAK2 mutation. The pathogenesis of TEMPI syndrome is unknown, although a few hypothetical disease mechanisms have been previously discussed. Here we present a new case of TEMPI syndrome, discuss results of a next-generation sequencing (NGS) panel covering 1,425 known cancer-related genes, and review the current literature with focus on an update of the genetics of TEMPI syndrome. This is the first report of TEMPI that includes results of comprehensive NGS testing.
Subject(s)
Paraproteinemias , Polycythemia Vera , Polycythemia , Telangiectasis , Humans , Polycythemia/diagnosis , Polycythemia/genetics , Polycythemia Vera/genetics , Paraproteinemias/pathology , Telangiectasis/diagnosis , Telangiectasis/pathology , High-Throughput Nucleotide SequencingABSTRACT
Light chain deposition disease (LCDD) is a rare manifestation of monoclonal gammopathy, which can lead to renal failure. We previously reported a detailed recurrence process in a case of LCDD after renal transplantation. To the best of our knowledge, no report has described the long-term clinical course and renal pathology findings of recurrent LCDD in patients after renal transplantation. In this case report, we describe the long-term clinical presentation and changes in renal pathology of the same patient after early LCDD relapse in a renal allograft. A 54-year-old woman with recurrent immunoglobulin A λ-type LCDD in an allograft was admitted 1 year post-transplant for bortezomib and dexamethasone therapy. At 2 years post-transplantation, a graft biopsy performed after complete remission was achieved, showing some glomeruli with residual nodular lesions similar to the pre-treatment renal biopsy findings. However, the enlarged subendothelial space disappeared. She remained in complete remission serologically for 6 years. Subsequently, the ratio of serum κ/λ-free light chains decreased gradually. She underwent a transplant biopsy approximately 12 years after renal transplantation due to increased proteinuria and decreased renal function. Compared with the previous graft biopsy, almost all glomeruli showed advanced nodule formation and subendothelial expansion. Because the LCDD case relapsed after long-term remission following renal transplantation, protocol biopsy monitoring might be necessary.
Subject(s)
Kidney Transplantation , Multiple Myeloma , Paraproteinemias , Female , Humans , Middle Aged , Multiple Myeloma/pathology , Multiple Myeloma/therapy , Kidney/physiology , Kidney/pathology , Paraproteinemias/pathology , Immunoglobulin Light Chains , Allografts/pathologyABSTRACT
Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin (MIg) produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end stage kidney disease (ESKD). The diagnosis is typically made by nephrologists through a kidney biopsy. Many distinct pathologies have been identified and they are classified based on the site or composition of the deposited Mig, or according to histological and ultrastructural findings. Therapy is directed towards the identified underlying clonal population and treatment decisions should be coordinated between hematologists and nephrologists in a multidisciplinary fashion, depend on the type of MGRS, the degree of kidney function impairment and the risk of progression to ESKD.
Subject(s)
Kidney Diseases , Kidney Failure, Chronic , Monoclonal Gammopathy of Undetermined Significance , Paraproteinemias , Humans , Kidney/pathology , Paraproteinemias/pathology , Monoclonal Gammopathy of Undetermined Significance/complications , Monoclonal Gammopathy of Undetermined Significance/pathologyABSTRACT
BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare M-proteinemia-related nephropathy. Non-crystalline LCPT is even rarer. We herein report an unusual case of renal dysfunction and proteinuria due to κ-restricted and non-crystalline LCPT in a context of monoclonal gammopathy of renal significance (MGRS) without Fanconi syndrome (FS). CASE PRESENTATION: A 67-year-old man was admitted for a 2-year history of proteinuria and renal dysfunction. Fanconi syndrome (FS) was not observed. He was noted to have IgG-κ M protein, and the previous bone marrow biopsy revealed that atypical plasma cells accounted for 1.5% of the cells, which did not meet the diagnostic criteria for multiple myeloma. A renal biopsy revealed proximal tubular injury, including increased lysosomes with irregular contours and a mottled appearance without crystalline structure and the accumulation of κ light chains. He was diagnosed with non-crystalline LCPT with MGRS. Concurrently, we reviewed the non-crystalline LCPT cases previously published in the literature. Our patient finally received chemotherapy with a bortezomib and dexamethasone regimen. The patient did not seem to achieve evident nephrological and hematological remission after chemotherapy, but he was in a stable condition. CONCLUSION: Very few similar cases are reported in the literature. It is considered crucial to enhance our knowledge about these cases to establish the definition of the non-crystalline LCPT entity and allow for early diagnosis. Chemotherapy may not be necessary for all patients to maintain good renal function. Future prospective clinical research studies are necessary.
Subject(s)
Fanconi Syndrome , Kidney Diseases , Multiple Myeloma , Paraproteinemias , Male , Humans , Aged , Fanconi Syndrome/complications , Fanconi Syndrome/diagnosis , Paraproteinemias/complications , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Kidney/physiology , Kidney/pathology , Kidney Diseases/etiology , Kidney Diseases/complications , Multiple Myeloma/complications , Multiple Myeloma/diagnosis , ProteinuriaABSTRACT
This review provides current information on myeloma-related disorders, a group of plasma cell or immunoglobulin (Ig) secreting neoplasms including multiple myeloma, extramedullary plasmacytoma (both cutaneous and noncutaneous variants), solitary osseous plasmacytoma, Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, Ig-secretory B-cell lymphoma, plasma cell leukemia, and monoclonal gammopathy of undetermined significance. The diagnostic procedures commonly used to characterize myeloma-related disorders, including cytopathology, histopathology, polymerase chain reaction for antigen receptor rearrangement, flow cytometry, and electrophoretic techniques are outlined and discussed.
Subject(s)
Multiple Myeloma , Paraproteinemias , Plasmacytoma , Waldenstrom Macroglobulinemia , Animals , Multiple Myeloma/diagnosis , Multiple Myeloma/veterinary , Plasmacytoma/diagnosis , Plasmacytoma/veterinary , Paraproteinemias/diagnosis , Paraproteinemias/pathology , Paraproteinemias/veterinary , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/veterinaryABSTRACT
Clonal hematopoiesis of indeterminate potential (CHIP) is common both in healthy individuals and patients with hematological cancers. Recent studies have showed worse prognosis for patients with multiple myeloma (MM) and non-Hodgkin lymphoma undergoing stem cell transplant, that have concomitant presence of CHIP. Data regarding the clinical and biological role of CHIP in plasma cell dyscrasias (PCDs) is rapidly increasing. However, the prevalence and prognostic implication of CHIP in patients with MM outside of the transplant setting, and in those with other more indolent PCDs remains elusive. Here we explored the prevalence and clinical implications of CHIP detected through next-generation sequencing in 209 patients with PCDs including MM, light chain (AL) amyloidosis (ALA), monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma (SMM). To avoid attributing the mutations to the plasma cell clone, CHIP was defined as the presence of DNMT3A, TET2, or ASXL1 mutations in the peripheral blood or bone marrow (DTA-CH). The prevalence of DTA-CH was 19% in patients with PCDs, with no difference between each PCD. TET2 (23%) and DNMT3A (22%), were the most frequently mutated genes. DTA-CH correlated with older age in MM (Pâ¯=â¯.001) and MGUS/SMM (Pâ¯=â¯0.0007), as well as with coronary artery disease or congestive heart failure in MM (Pâ¯=â¯.03). DTA-CH did not predict worse OS or PFS in either MM or ALA, nor it predict higher risk of progression to MM in patients with MGUS/SMM. Our results overall further elucidate the prevalence and mutational spectrum of CHIP in PCDs, providing more information regarding the clinical relevance of CHIP in this patient population.
Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Paraproteinemias , Smoldering Multiple Myeloma , Humans , Clonal Hematopoiesis , Prevalence , Paraproteinemias/genetics , Paraproteinemias/pathology , MutationABSTRACT
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.
Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Paraproteinemias , Humans , Multiple Myeloma/pathology , Bone Marrow/metabolism , Plasma Cells/metabolism , Paraproteinemias/pathology , Monoclonal Gammopathy of Undetermined Significance/pathology , Tumor MicroenvironmentABSTRACT
BACKGROUND: Next-generation sequencing (NGS) detects somatic mutations in a high proportion of plasma cell dyscrasias (PCD), but is currently not integrated into diagnostic routine. We correlated NGS data with degree of bone marrow (BM) involvement by cytomorphology (BMC), histopathology (BMH), and multiparameter flow cytometry (MFC) in 90 PCD patients. METHODS: Of the 90 patients the diagnoses comprised multiple myeloma (n = 77), MGUS (n = 7), AL-amyloidosis (n = 4) or solitary plasmocytoma (n = 2). The NGS panel included eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3, and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. RESULTS: Mutations were detected in 64/90 (71%) of cases. KRAS (29%), NRAS (16%) and DIS3 (16%) were most frequently mutated. At least one mutation/sample corresponded to a higher degree of BM involvement with a mean of 11% pathologic PC by MFC (range, 0.002-62%), and ~ 50% (3-100%) as defined by both BMC and BMH. CONCLUSIONS: The probability of detecting a mutation by NGS in the BM was highest in samples with > 10% clonal PC by MFC, or > 20% PC by BMC/ BMH. We propose further evaluation of these thresholds as a practical cut-off for processing of samples by NGS at initial PCD diagnosis.