Monoclonal Gammopathy Of Clinical Significance Research Articles

From light chain deposition to multiple myeloma – Case report and literature review

Monoclonal gammopathies consist of a broad spectrum of diseases, ranging from asymptomatic monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Multiple myeloma is a malignant plasma cell disorder and accounts for 10% of all hematological malignancies and 1% of all malignancies. Differential diagnosis may be challenging, considering the variety of clinical entities with similar behavior. About 15­‑20% of MM only secretes monoclonal light chains, called light chain MM, which is associated with poorer outcome. Two intermediate concepts were recently introduced, monoclonal gammopathy of renal significance (MGRS) and a wider concept of monoclonal gammopathy of clinical significance (MGCS). The former behaves as a clonal proliferative disorder with associated nephrotoxicity, but does not have the hematological criteria for MM, while MGCS expands this concept to other organs. A subtype of MGCS is monoclonal immunoglobulin deposition disease, a multisystemic disorder characterized by light or heavy chain deposition of monoclonal immunoglobulin in various organs and encompasses three clinical entities: Light­‑Chain, Light­‑ and Heavy­‑Chain, and Heavy­‑Chain Deposition Disease (LCDD, LHCDD and HCDD, respectively). We describe an unusual case of LCDD in which MM was subsequently considered although the proposed criteria are not met. We demonstrate the variability of clinical­‑pathological presentation of LCDD, requiring a rapid decision­‑making, particularly in terms of kidney and survival outcomes.

Monoclonal gammopathy of clinical significance (MGCS): when monoclonal gammopathy of undetermined significance (MGUS) is no longer undetermined

Monoclonal gammopathy of undetermined significance (MGUS) is a condition characterized by the presence of a monoclonal immunoglobulin (mIg) without its organ- or tissue-damaging effect. In recent years, attention has been paid to patients who show a MGUS-like condition, but at the same time present damage to the kidneys, peripheral nerves, or skin, resulting from the deposit of mIg. These disorders do not meet the criteria for smoldering myeloma or multiple myeloma. In 2018, the term ‘monoclonal gammopathy of clinical significance’ (MGCS) was introduced for this group of patients. The dysfunction associated with MGCS is the result of the toxic activity of a monoclonal protein produced by dangerous, small clones of B cells and plasmocytes. Taking this into account, the term ‘MGUS’ should be limited to those cases where no association with mIg organ or tissue damage can be demonstrated, whereas the term ‘MGCS’ (monoclonal gammopathy of clinical significance) should be used in patients in whom the monoclonal protein plays a direct role in damage, especially to the kidneys, skin, and nervous system. This article summarizes the current state of knowledge of the main syndromes and symptoms of MGCS.

Monoclonal gammopathy of clinical importance.

Monoclonal gammopathy is a frequent finding and may be associated with severe cancer such as myelomatosis and other B-cell lymphoproliferative disorders. However, the monoclonal component can also be the direct cause of serious disease, namely monoclonal gammopathy of clinical significance (MGCS). MGCS is most likely significantly underdiagnosed and is consequently also undertreated. In order to achieve a good therapeutic outcome, it is crucial that the condition is recognised at an early stage, so that treatment can be initiated before the patient has developed irreversible organ damage. Increased awareness of MCGS is therefore essential.

Severe Cryoglobulinemic Vasculopathy and Underlying Monoclonal Gammopathy: The Importance of Identifying and Targeting the Underlying Plasma Cell Clone in Diagnosis and Treatment

Cryoglobulinemia often occurs secondary to an underlying monoclonal gammopathy (MG). MG is a common finding in the elderly population with a prevalence of 5% in persons aged 70 years and older and can range from asymptomatic monoclonal gammopathy of unknown significance (MGUS) to symptomatic multiple myeloma (MM) for which treatment is clearly indicated. However, rare forms of MG lead to clinical symptoms and are summarized as monoclonal gammopathy of clinical significance (MGCS). Here, no clear treatment recommendations exist, treatment ranges from symptomatic treatment of paraneoplasia to causal treatment of the underlying plasma cell clone. Here, we report an exemplary case of a 74-year-old female with MG and cryoglobulinemic vasculopathy seriously affecting skin and peripheral nervous system accompanied by severe pain. First- and second-line treatments with conventional immunosuppressive agents and B cell depleting therapy did not lead to sustained remission. After identifying MG as the potential underlying cause MGCS was considered. As symptoms were markedly affecting quality of life, myeloma-derived treatment with anti-CD38 antibody daratumumab, lenalidomide and dexamethasone was initiated and subsequently clinical symptoms and laboratory cryoglobulinemia resolved. In conclusion, this case report shows for the first time that daratumumab-based treatment of MGCS can be effective and is well-tolerated.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell–targeted therapies

AbstractCANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

A colonic mass revealing a disseminated crystal storing histiocytosis secondary to indolent multiple myeloma: a case report with literature review

BackgroundCrystal storing histiocytosis is a rare disorder associated with monoclonal gammopathy. In this disease, monoclonal heavy and light chains accumulate in the lysosome of macrophages, leading to histiocytic reaction in different organs. It is secondary to the presence of a small B-cell clone, responsible for monoclonal immunoglobulin production. Histological diagnosis is a challenge and differential diagnoses include fibroblastic and histiocytic neoplasm. Clinical manifestations depend on the involved organs, rarely including peritoneum or digestive tract.Case presentationWe present a case of a 75-year-old with a medical history of colonic carcinoma. She presented with abdominal pain and inflammatory syndrome revealing a colonic mass. Hemicolectomy was performed. Initial diagnosis was fibroblastic tumour. The patient worsened, and diagnosis of a diffuse crystal storing histiocytosis was finally done. Haematological exploration found an indolent IgG-kappa multiple myeloma. The initial treatment with conventional chemotherapy did not permit an improvement of the patient condition. Immunotherapy with anti-CD38 monoclonal antibody (daratumumab) was proposed with a clinical and biological response.ConclusionThis case report emphasizes the histopathological challenge of histiocytic tumours which may involve digestive track. It focuses on the concept of monoclonal gammopathy of clinical significance, which can have a large spectrum of manifestations.

Immunoglobulin M Paraproteinaemias.

Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15–20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of “monoclonal gammopathy of clinical significance” entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.

Immunglobulin depositions in different organs in monoclonal gammopathy

AbstractMonoclonal immunoglobulins (heavy and/or light chain) can deposit in various organs. The most prominent targeted organs are the kidney, the nerves, the heart, the liver, the gastrointestinal tract but it could also involve the eyes, the skin and it can interact with the hemostasis proteins. This is at the origin of a new concept called monoclonal gammopathy of clinical significance (MGCS). It is challenging to diagnose and even though the B cell clone may be small, it may be important, in some circumstances, to initiate a hematological treatment.

PS1417 TREATMENT OUTCOMES OF PATIENTS WITH MONOCLONAL GAMMOPATHY OF CLINICAL SIGNIFICANCE

Background:Monoclonal gammopathy of clinical significance(MGCS) is defined by the relationship between a small dangerous B‐cell clone and severe organ damage due to the toxicity of the monoclonal immunoglobulin(MIg) or its fragment and their deposition in different organs. The kidney is one of the main targets of the MGCS which may occur in all B cell or plasma cell proliferative disorders that produce a nephrotoxic monoclonal immunoglobulin(MIg). The treatment strategy is based on chemotherapy adapted to the nature of the underlying clone. The rapid suppression of the secretion of nephrotoxic MIg has been shown to impact patient survival and increase the patients’ quality of life.Aims:In our study we evaluated the impact of kidney damage on patient's survival.Methods:Our cohort included 151 consecutive patients with MGCS‐associated organ damage since 2004 to 2019. The most common involved organs were kidney, heart, liver, nerves system and gastrointestinal tract. The diagnosis in most cases was established by organ biopsy, serum and urine protein immunofixation, analyses of serum free light chains, bone marrow aspiration and biopsy with flow cytometry. MGCS‐ associated renal lesions were: AL amyloidosis 88% (n = 126), monoclonal immunoglobulin deposition disease (MIDD) 5,6%(n = 8),proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy 4,2%(n = 6), trombotic microangiopathy 1,4 %(n = 2) and cryoglobulinemic glomerulonephritis type 1 0,7%(n = 1).Results:Median age of the patients was 62 years (38–79). Median follow‐up was 24,2 months (1–117,5 months). Renal involvement(RI) was noted in 92% of patients (n = 142). 21,8% (n = 31) of these patients required dialysis. The median time to dialysis was 2 months (1–70months).71,1% (101 patients) had nephrotic syndrome at the time of diagnosis. Prognostic criteria for RI were assessable in 117 patients. These criteria included a reduction in eGFR<50 ml/min/1.73m2 and proteinuria (PU)>5 g/24 hours. In our cohort, patients with stage I were 16,1% (n = 21), stage II – 46,4% (n = 66), stage III‐30,2%(n = 43). The 5‐years rate of progression to dialysis was significantly higher in patients with stage III (46,5% vs 9,1% vs 0 %, p < 0,0001, for stage III, II, I,respectively) and in patients with nephrotic syndrome (23,8% vs 3,6%,p = 0,0026,for nephrotic syndrome and asymptomatic proteinuria). Stage III of RI was independent predictor of poor overall survival (OS), but did not impact on renal progression‐free survival (PFS). 5‐years overall survival was: 61,9%, 71,2 and 51,2% (p = 0.0052), 5‐years renal PFS was 90%, 67,7% and 60 % (p = 0,35) for I,II,III renal stage,respectively. Treatments included chemotherapy in 73% (n = 106) and stem cell transplantation 12,5% (n = 18). The median time from treatment initiation to first and best renal response was 7 month (1–68months) and 13,5month (1–69months) respectively. We assessed renal response in 61 patients. In our group of patients, the complete renal response (CR) was achieved in 4,9% cases (n = 3), very good partial response (VGPR) – 42,6% (n = 26), partial response – 32,7% (n = 20). 19,6% (n = 12) have not achieved renal response (NR). OS in patients with CR was 100%, VGPR–88,4%, PR–95%, NR–58,3% (p = 0,0031).5‐years renal PFS in patients who achieved renal response was 70,9%.Summary/Conclusion:Renal involvement and the depth of the response is a prognostically significant factor and a predictor of overall survival and renal survival of patients with MGCS. There is a need for early diagnosis of renal involvement, in order to identify and treat these patients before irreversible organ damage occurs.

Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis.

Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.