Cryoglobulinemic Vasculitis in Disguise: Cryofibrinogenemia as Variant of Monoclonal Gammopathy of Renal Significance.

Monoclonal gammopathy with cryoactivity (ie, cryoglobulins) that causes glomerulonephritis is considered within the spectrum of monoclonal gammopathy of renal significance. Cryofibrinogenemia (cryoactivity of coagulation factors) is very rarely associated with glomerulonephritis. We present a 39-year-old woman with a relapsing nephrotic syndrome. Laboratory investigation detected cryofibrinogen; the precipitate consisted of fibrinogen and a monoclonal immunoglobulin (M-protein; IgG-λ), and the latter was also detected in serum (4g/L). Initial conventional immunosuppressive therapy resulted in temporary renal remission. In view of the M-protein, subsequent therapy consisted of bortezomib/dexamethasone and high-dose melphalan followed by autologous hematopoietic stem cell transplantation, and resulted in a very good partial hematological response and temporary renal remission. However, after hematological and renal relapse, we performed unique experiments to clarify the role of the M-protein. Mixing patient serum with donor plasma resulted in cryoactivity, composed of M-protein+fibrinogen. Patient plasma deprived of M-protein did not have cryoactivity. Therefore, cryoactivity was dependent on the M-protein. We started lenalidomide, which resulted in very good partial hematological and renal remission. Thus, cryofibrinogenemia can be the consequence of an M-protein, which we suggest should be defined as monoclonal gammopathy of renal significance.

[Classification and Management of MGRS Related Diseases].

Monoclonal Gammopathies of Renal Significance (MGRS) are a complex group of disorders characterized by the production of aberrant monoclonal proteins that interact with kidney structures, causing tissue damage. Unlike neoplastic forms, kidney damage in MGRS does not correlate with clone mass or circulating monoclonal protein levels, conferring unique pre-neoplastic or non-neoplastic properties to the responsible clones. This manuscript explores the heterogeneity of monoclonal proteins involved, varying from full immunoglobulins to free light chains (FLC), and how they result in a spectrum of kidney lesions with differing prognoses. We also elaborate on diagnostic challenges, emphasizing the indispensable role of kidney biopsy, including advanced techniques like laser microdissection and mass spectrometry (LMD/MS) for deposit characterization, particularly in ambiguous or complex cases. Clinical management and treatment considerations, including the necessity for clone identification, are also discussed.

Paraproteinemic Neuropathies.

OBJECTIVE: Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical, electrophysiologic, and hematologic phenotypes of the paraproteinemic neuropathies and the diagnostic and treatment strategies for each. LATEST DEVELOPMENTS: Advances in our understanding of the underlying pathophysiology of various paraproteinemic neuropathies and their corresponding phenotypes have identified potential new therapeutic targets. Therapeutic strategies to diminish anti-myelin-associated glycoprotein (MAG) IgM antibodies have shown partial and inconsistent efficacy; however, antigen-specific immune therapy is being investigated as a novel treatment to remove the presumably pathogenic anti-MAG antibody. Advances in genetic and cell signaling studies have resulted in the approval of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Monoclonal antibodies are being investigated for the treatment of light chain amyloidosis. ESSENTIAL POINTS: Early recognition and treatment of underlying plasma cell disorders improves clinical outcomes in patients with paraproteinemic neuropathy. Despite significant progress, our knowledge regarding underlying mechanisms for paraproteinemic neuropathy is still limited. Clinicians' awareness of clinical phenotypes, electrophysiologic hallmarks, and hematologic findings of the different paraproteinemic neuropathies is crucial to promptly identify and treat patients and to avert misdiagnosis. Multidisciplinary collaboration among specialists, including neurologists and hematologists, is paramount for the optimal treatment of these patients with overlapping conditions.

Resolution of dysglycaemia after treatment of monoclonal gammopathy of endocrine significance.

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 × 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.

Gammapatía monoclonal de significado incierto / Monoclonal gammopathy of uncertain significance

La gammapatía monoclonal de significado incierto es una neoplasia de células plasmáticas premaligna, con una elevada prevalencia en la población mayor de 50 años, y un riesgo anual de progresión del 1%. Numerosos estudios recientes han permitido un avance en la compresión de la patogenia de estos trastornos y su riesgo de progresión a otras enfermedades. Los pacientes requieren un seguimiento de por vida, siendo fundamental un enfoque multidisciplinar y adaptado al riesgo. En los últimos años, cada vez se reconocen más entidades asociadas a la presencia de una paraproteína, conocidas como gammapatías monoclonales de significado clínico (AU)

Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1%. Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases. Patients require lifelong follow-up, and a multidisciplinary and risk-adapted approach is essential. In recent years, an increasing number of entities associated with a paraprotein, known as clinically significant monoclonal gammopathies, have been recognized (AU)

Recommendations for the study of monoclonal gammopathies in the clinical laboratory. A consensus of the Spanish Society of Laboratory Medicine and the Spanish Society of Hematology and Hemotherapy. Part I: Update on laboratory tests for the study of monoclonal gammopathies.

Monoclonal gammopathies (MG) are characterized by the proliferation of plasma cells that produce identical abnormal immunoglobulins (intact or some of their subunits). This abnormal immunoglobulin component is called monoclonal protein (M-protein), and is considered a biomarker of proliferative activity. The identification, characterization and measurement of M-protein is essential for the management of MG. We conducted a systematic review of the different tests and measurement methods used in the clinical laboratory for the study of M-protein in serum and urine, the biochemistry and hematology tests necessary for clinical evaluation, and studies in bone marrow, peripheral blood and other tissues. This review included literature published between 2009 and 2022. The paper discusses the main methodological characteristics and limitations, as well as the purpose and clinical value of the different tests used in the diagnosis, prognosis, monitoring and assessment of treatment response in MG. Included are methods for the study of M-protein, namely electrophoresis, measurement of immunoglobulin levels, serum free light chains, immunoglobulin heavy chain/light chain pairs, and mass spectrometry, and for the bone marrow examination, morphological analysis, cytogenetics, molecular techniques, and multiparameter flow cytometry.

Monoclonal gammopathies of renal significance.

The term monoclonal gammopathies of renal significance (MGRS) encompasses a group of renal histopathological lesions fulfilling two criteria: (a) they are caused by nephrotoxic monoclonal immunoglobulins and (b) the monoclonal immunoglobulins are produced by small B-cell or plasma cell clones which do not meet the criteria for multiple myeloma or malignant lymphoma. Here, we provide a review of the MGRS definition and related terminology and elaborate on the diagnostic approach and treatment principles from the general physician perspective.

Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance-Like Phenotype in Patients With Monoclonal Gammopathies.

PURPOSE: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated. PATIENTS AND METHODS: An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis. RESULTS: Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival. CONCLUSION: We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

Monoclonal Gammopathy-Related Kidney Diseases.

Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins. The kidneys are often affected by these monoclonal proteins, and, although not mutually exclusive, can involve the glomeruli, tubules, interstitium, and vasculature. The nephrotoxic potential of these monoclonal proteins is dependent on a variety of physicochemical characteristics that are responsible for the diverse clinicopathologic manifestations, including glomerular diseases with organized deposits, glomerular diseases with granular deposits, and other lesions, such as C3 glomerulopathy and thrombotic microangiopathy with unique pathophysiologic features. The diseases that involve primarily the tubulointerstitial and vascular compartments are light chain cast nephropathy, light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulin-induced nephropathy with distinct acute and chronic clinicopathologic features. The diagnosis of a monoclonal gammopathy-related kidney disease is established by identification of an underlying active or more commonly, low-grade hematologic malignancy, serologic evidence of a monoclonal gammopathy when detectable, and most importantly, monoclonal protein-induced pathologic lesions seen in a kidney biopsy, confirming the association with the monoclonal protein. Establishing a diagnosis may be challenging at times, particularly in the absence of an overt hematologic malignancy, with or without monoclonal gammopathy, such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Overall, the treatment is directed against the underlying hematologic disorder and the potential source of the monoclonal protein.

TEMPI Syndrome: Update on Clinical Features, Management, and Pathogenesis.

TEMPI (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) syndrome is a rare and newly defined multisystemic disease, which belongs to "monoclonal gammopathy of clinical significances". Due to its rarity, the etiology, pathogenesis, and clinical features of this disease remain largely unknown. Owing to its hidden and diverse clinical manifestations, missed diagnosis and misdiagnosis are common. In recent years, as more patients (including three fatal cases) were identified, some special clinical manifestations other than the typical pentad of TEMPI syndrome have been reported. Meanwhile, several studies attempting to identify the pathogenesis of TEMPI syndrome were conducted. In this review, we summarize the reported clinical characteristics of TEMPI syndrome and discuss the current and potential treatment options for patients with TEMPI syndrome, including those with relapsed/refractory disease. Furthermore, we provide an overview of current knowledge on the pathophysiology of TEMPI syndrome.

IgM monoclonal gammopathies of clinical significance: diagnosis and management.

IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.

The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches.

Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cytokine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the relapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell impairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunotherapeutic approaches in these settings.

When a Monoclonal Gammopathy Is Not Multiple Myeloma.

Our knowledge of monoclonal gammopathies is continuously evolving. Once accepted as a possible precursor condition to multiple myeloma, monoclonal gammopathies as an entity are now associated with many renal, neurologic, and dermatologic disorders of clinical significance. This change has created a challenge for patients and clinicians, as a monoclonal gammopathy may be a harbinger not of multiple myeloma but of other lymphoproliferative disorders such as light-chain amyloidosis and Waldenström macroglobulinemia. Early recognition of monoclonal gammopathies along with a careful workup are essential in determining the next steps in the care of a given patient. Recognition has become all the more important as we understand how to triage the 4% to 9% of patients with monoclonal gammopathies depending on age, with the goal of limiting overdiagnosis and misdiagnosis. In this review, we focus on treatment strategies for patients with monoclonal gammopathies that are not multiple myeloma, including smoldering multiple myeloma, light-chain amyloidosis, and Waldenström macroglobulinemia.

Successful treatment of acquired von Willebrand syndrome associated with monoclonal gammopathy : Breaking a dangerous bond.

Acquired von Willebrand syndrome is exceedingly rare and accounts for only 1-3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since.The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients.

RNA-based immunoglobulin repertoire sequencing is a new tool for the management of monoclonal gammopathy of renal (kidney) significance.

The diagnostic approach of monoclonal gammopathy of renal significance is based on the detection of a monoclonal immunoglobulin in the blood and urine, and the identification of the underlying clone through bone marrow and/or peripheral blood cytologic and flow cytometry analysis. However, the monoclonal component and its corresponding clone may be undetectable using these routine techniques. Since clone identification is the cornerstone for guiding therapy and assessing disease response, more sensitive methods are required. We recently developed a high-throughput sequencing assay from bone marrow mRNA encoding immunoglobulins (RACE-RepSeq). This technique provides both full-length V(D)J region (variable, diversity and joining genes that generate unique receptors as antigen receptors) of the monoclonal immunoglobulin and the dominant immunoglobulin repertoire. This allows analysis of mutational patterns, immunoglobulin variable gene frequencies and diversity due to somatic hypermutation. Here, we evaluated the diagnostic performance of RACE-RepSeq in 16 patients with monoclonal-associated kidney lesions, and low serum monoclonal immunoglobulin and free light chain levels at diagnosis. Bone marrow immunohistochemical analysis was negative in all 11 patients so tested and 7 of 12 patients had no detectable clone matching the kidney deposits using flow cytometry analysis. By contrast, RACE-RepSeq detected a dominant clonal light chain sequence of matched isotype with respect to kidney deposits in all patients. Thus, high throughput mRNA sequencing appears highly sensitive to detect subtle clonal disorders in monoclonal gammopathy of renal significance and suggest this novel approach could help improve the management of this kidney disease.

Monoclonal gammopathy of ocular significance (MGOS) - a short survey of corneal manifestations and treatment outcomes.

Monoclonal gammopathy of ocular significance (MGOS) is a rare subset of monoclonal gammopathy of clinical significance occurring secondary to plasma cell disorders and causing ocular manifestations. We identified 23 patients with paraproteinemic keratopathy (PPK) in the setting of monoclonal gammopathy of unknown significance (MGUS, 10), smoldering multiple myeloma (SMM, 3) or multiple myeloma (MM, 10). Many of these patients with PPK (11/23) presented decreased vision. All patients with MM and 40% of those with other diagnoses such as SMM and MGUS received systemic therapy with or without autologous stem cell transplantation. Four eyes of four patients were treated by penetrating keratoplasty. In most cases, neither ocular nor hematologic treatment afforded a durable improvement in the visual acuity (recurrence after a median of 11 months), despite initial responses. Further studies will be required to determine the optimal strategy to treat and prevent the relapse of ocular symptoms in patients with PPK.

Paraproteinemia and neuropathy.

Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin in the myelin, represented by anti-myelin-associated glycoprotein (MAG) neuropathy; deposition of immunoglobulin or its fragment in the interstitium, represented by immunoglobulin light chain amyloidosis (AL amyloidosis); and paraneoplastic mechanisms that cannot be solely attributed to the deposition of immunoglobulin or its fragment, represented by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome. Patients with anti-MAG neuropathy and POEMS syndrome present with slowing of nerve conduction parameters. This characteristic fulfills the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) defined by the European Academy of Neurology and Peripheral Nerve Society (EAN/PNS). Although direct damage caused by the deposition of amyloid can induce axonal damage in AL amyloidosis, some patients with this condition have features fulfilling the EAN/PNS electrodiagnostic criteria for CIDP. Conventional immunotherapies for CIDP, such as steroids, intravenous immunoglobulin, and plasma exchange, offer no or only minimal-to-modest benefit. Although rituximab can reduce the level of circulating autoantibodies, it may only be effective in some patients with anti-MAG neuropathy. Drugs including melphalan, thalidomide, lenalidomide, and bortezomib for POEMS syndrome and those including melphalan, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, and daratumumab for AL amyloidosis are considered. Since there will be more therapeutic options in the future, thereby enabling appropriate treatments for individual neuropathies, there is an increasing need for early diagnosis.