Monoclonal Gammopathy Of Clinical Significance Research Articles

Ethnic diversity in presentation and outcome of Waldenström macroglobulinemia and IgM monoclonal gammopathy of clinical significance in the United Kingdom.

Not available.

Therapy of disorders with organ dysfunctions related to "Monoclonal Gammopathy of Clinical Significance" - MGCS

Therapy of disorders with organ dysfunctions related to "Monoclonal Gammopathy of Clinical Significance" - MGCS

Long Term Outcomes and Renal Response Following Autologous Stem Cell Transplantation for Light Chain Deposition Disease:a Retrospective Study on Behalf of the Cmwp of the EBMT

Background: There is a paucity of data concerning long-term outcomes following autologous stem cell transplantation (ASCT) for light chain deposition disease (LCDD). The goal of this retrospective study was to analyze the outcomes following ASCT in LCDD patients in terms of toxicity and efficacy with both hematological and renal responses. Methods: Adult patients who underwent a first ASCT for renal biopsy-proven LCDD (AL amyloidosis excluded) between the years 1995 and 2021 were selected from the EBMT registry. The probability of overall survival (OS) and progression-free survival (PFS) was estimated based on the Kaplan-Meier method and differences analyzed using the log-rank test. Engraftment with death as competing event and relapse and non-relapse mortality (NRM) were modeled using the crude cumulative incidence estimator and compared between groups with Gray's test. eGFR, measured at auto-HCT and 3 6, and 12 months was longitudinally modeled using linear mixed effects models. Results: There were 51 patients in 24 centres. 63% were male. The median year of diagnosis was 2011 (IQR: 2008-2015). The underlying plasma cell disorder was either myeloma (47%) or Monoclonal Gammopathy of Clinical Significance (MGCS, 50%), with 3% missing. The median bone marrow aspirate plasmacytosis was 10% (IQR: 7.8-20) and the immunoglobulin isotypes were as follows: Light Chain only 69% (Kappa 82%, Lambda 18%), IgG 24%, IgA 2%, IgD 2% and non-secretory 2%. Of 17 patients with cytogenetic data, 3 were t(11;14) and one del 17p. All 40 patients with data on disease involvement had renal involvement, and, of these, 3 had cardiac and 2 hepatic involvement. At diagnosis, the median serum creatinine was 233 µmol/L (IQR:159-467), median proteinuria was 1,813 mg/24h (IQR:445-5974) and 16% had bone lesions. 42 of 44 patients with available data had received an induction regimen (93% bortezomib-based) and the hematological responses prior to transplant were as follows: CR 12%, VGPR 29%, PR 31%, MR/SD 16%, and relapse/progression 6% (missing: 6%). A total of 59% were transplanted in or after 2012. The median age at transplant was 55 years (IQR:49-61). The median time from diagnosis to transplant was 7.4 months (IQR:5.5-13.0) and 42% were on dialysis at the time of transplant. The Karnofsky Performance Score (KPS) was >80 in 79%. The Melphalan conditioning dose (mg/m 2) was 100 (23%), 140 (55%) or 200 (21%). The median number of infused CD34+ cells x 10 6/kg was 3.4 (IQR:2.5-4.6) and 33% received G-CSF post-ASCT. A total of 13% received consolidation and 8% maintenance treatment post-ASCT. The median follow-up post-ASCT was 84 months (IQR:46-122). The median time to neutrophil engraftment was 12 days (IQR:11-13) and to platelet engraftment 13 days (11-16). The best hematological response at Day +100 post-ASCT (33% missing) was as follows: CR 44%, VGPR 26% and PR 29%. Mean eGFR at auto-HCT was 48.8 mL/min/1.73m 2 (95% CI 36.8-60.8) in those not on dialysis and 15.2 mL/min/1.73m 2 (95% CI 1.9-28.8) in those on dialysis (difference 33.6 mL/min/1.73m 2, p<0.0001). In both groups there were no significant changes in eGFR after auto-HCT (p=0.99 and p=0.80, respectively). The box-plot figure shows eGFR at auto-HCT, and at 3, 6 and 12 months. At 6 years post-ASCT, OS was 88% (95% CI: 78-98%) and PFS was 44% (95% CI 28-60%). The median OS was not reached. The median PFS was 65 months (95% CI: 45-103). The 2-year cumulative relapse incidence was 17% (95% CI: 6-27%) and the 2-year cumulative incidence of NRM was 2% (95% CI: 0-6%). In univariate analysis, transplant from 2012 onwards was associated with a significantly superior OS (6-year OS 100 vs. 75%; log-rank p=0.05). There was a trend to superior OS in females (6-year OS 100 vs 82%, p=0.05). There was no significant association between KPS, Age, Disease Status at ASCT (VGPR or better vs. Other) or Dialysis Status at ASCT with any outcomes in this small cohort evaluation. Conclusions: ASCT is a feasible option for patients with LCDD even though 42% were on dialysis at the time of transplantation. Overall outcomes are favourable with a low NRM and good long-term OS. There was no improvement in renal function.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Investigation and management of the monoclonal gammopathy of undetermined significance: A British Society for Haematology Good Practice Paper.

This Good Practice Paper provides recommendations for the diagnosis, risk stratification and management of the monoclonal gammopathy of undetermined significance (MGUS). It describes the recently recognised entity of the monoclonal gammopathy of clinical significance (MGCS), and recommends how it should be managed. The potential for targeted population screening for MGUS is also discussed.

Ibrutinib response in a patient with refractory mixed essential cryoglobulinemia.

A 74-year-old male presented with fatigue, parasthesiae, Raynaud's phenomena, visual disturbances, and recurrent lower extremity rash (left). Investigations revealed an elevated serum cryoglobulin, rheumatoid factor >1320 IU/ml (ref. <15 IU/mL), undetectable C4, and C3 of 25 mg/dL (ref. 87–200 mg/dL). A small amount of IgM kappa monoclonal protein (M spike of 2.5%) and polyclonal IgG were identified by immunofixation. A diagnosis of mixed (Type II) cryoglobulinemia was made. Testing for Hepatitis B and C was negative. Positron emission/computed tomography (PET-CT) showed no evidence of lymphoma. Although the bone marrow appearance raised suspicion for Waldenstrom macroglobulinemia (WM), testing for MYD88 L265P mutation, which is commonly associated with this disorder, was negative. Of note, scattered CD20-positive B-cells comprised only ∼5% of bone marrow cellularity. The patient's rash gradually evolved into large ulcers over bilateral medial malleoli. Despite treatment with immunosuppression, rituximab, and plasmapheresis, they expanded to 9.3 × 8.9 × 0.3 cm on the left and 8.6 × 5.6 × 0.4 cm on the right (middle), requiring extensive use of opioids and significantly interfering with patient's mobility. A second bone marrow biopsy was again suggestive of WM. However, the frequency of abnormal B-cells was even lower (1.7%), likely reflecting prior therapy. Therefore, B-cells were purified by flow sorting using antibodies against CD19, CD20, and CD38 prior to molecular testing. Critically, this approach revealed the presence of MYD88 L265P mutation, supporting the diagnosis of WM and justifying therapy with Ibrutinib, a Bruton kinase inhibitor which is highly effective in this disease. Starting Ibrutinib 420 mg daily was a clear turning point in the patient's clinical course. After just a few days, he reported a drastic improvement in fatigue and leg ulcer pain. Within the following 2 months, he became pain-free and no longer required narcotics. By the end of the 9 months of therapy, the ulcers were completely healed (right) and quantitative IgM went down from 1058 to 325 mg/dL after the first 3 months. Nearly 2 years since starting the treatment, the patient is asymptomatic except for mild parasthesiae. He continues on Ibrutinib at a lower dose (280 mg daily). Cryoglobulinemia (CG) is a rare multisystem disorder which is caused by immunoglobulins with a capacity to aggregate at lower temperatures (cryoglobulins). Notably, even a small amount of cryoglobulin in the serum is sufficient to cause disease. Hence, a low-burden lymphoproliferative disorder that serves as the source of monoclonal cryoglobulin may be difficult to diagnose, precluding the use of targeted therapies. In agreement with a single prior report [1], our case shows that Ibrutinib can be remarkably effective in refractory CG due to WM. Unexpectedly, we found that despite a near-complete resolution of symptoms with Ibrutinib, the patient's cryoglobulins/IgM paraprotein persisted. In addition, the rheumatoid factor was still elevated, and C4 complement remained undetectable. This suggests that the therapeutic benefit of Ibrutinib may be explained not only by anti-tumor effect but also anti-inflammatory properties, as demonstrated by its efficacy in COVID [2], graft-versus-host disease [3], and autoimmune conditions [4]. Finally, our case shows that enriching for B-cells prior to molecular analysis may aid the diagnosis of occult lymphoproliferative disorder in other patients, for example those with IgM monoclonal gammopathy of clinical significance, who may also benefit from a trial of targeted therapy. H. Jamali wrote the manuscript. D. Wu performed cell sorting and molecular analysis. L. Soma performed morphological assessment of the bone marrow. M. Linenberger contributed to clinical management of the patient (plasma exchange). M. Wener provided rheumatology expertise and co-managed the patient with LS. L. Silberstein provided haematology expertise, co-managed the patient with MW, and wrote the manuscript. The authors have nothing to report. The authors received no specific funding for this work. None of the authors received financial compensation from an external source in return for writing or publishing this paper. The patient consented to the use of their clinical data and photographs for this correspondence.

Manifestations rares des gammapathies monoclonales : à propos de 2 cas et revue de la littérature

IntroductionMonoclonal gammopathies are common over the age of 50. Patients are usually asymptomatic. However, some patients present with secondary clinical manifestations, which are now grouped under the entity « Monoclonal Gammopathy of Clinical Significance » (MGCS). Case reportHere, we report two rare cases of MGCS: an acquired von Willebrand syndrome (AvWS) and an acquired angioedema (AAE). ConclusionThe discovery of a decrease in von Willebrand activity (vWF:RCo) or angioedema in a patient over 50 years of age, in the absence of a family history, should prompt a search for a hemopathy and in particular, a monoclonal gammopathy.

An update on proliferative glomerulonephritis with monoclonal immunoglobulin deposits in pediatric patients

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) was first described by Nasr et al. in 2004 with a subsequent study composed of a larger patient cohort a few years later [1,2]. Although more commonly occurring in older adults, PGNMID has since been reported in a wide range of age groups including children [3-5]. PGNMID is categorized as a monoclonal gammopathy of renal significance (MGRS), and is additionally included in the recently expanded concept of monoclonal gammopathy of clinical significance (MGCS), which encompasses disorders of any organ system related to underlying plasma cell or B-cell clones [6]; however, most patients with PGNMID do not show evidence of a circulating monoclonal protein or clonal plasma cell proliferation, and monoclonal gammopathy has not been reported in any pediatric patients with the disease. Herein we briefly discuss the clinical and histopathologic features of PGNMID, as well as advances in our understanding of the pathogenesis and clinical course of the disease.

Monoclonal gammopathies of clinical significance (MGCS): In pursuit of optimal treatment.

Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal gammopathy of undetermined significance (MGUS). The establishment of MGCS expands our current understanding of the pathophysiology of a range of diseases, in which the M protein is often found. Aside from the kidney, the three main organ systems most affected by monoclonal gammopathy include the peripheral nervous system, skin, and eye. The optimal management of these MGUS-related conditions is not known yet due to the paucity of clinical data, the rarity of some syndromes, and limited awareness among healthcare professionals. Currently, two main treatment approaches exist. The first one resembles the now-established therapeutic strategy for monoclonal gammopathy of renal significance (MGRS), in which chemotherapy with anti-myeloma agents is used to target clonal lesion that is thought to be the culprit of the complex clinical presentation. The second approach includes various systemic immunomodulatory or immunosuppressive options, including intravenous immunoglobulins, corticosteroids, or biological agents. Although some conditions of the MGCS spectrum can be effectively managed with therapies aiming at the etiology or pathogenesis of the disease, evidence regarding other pathologies is severely limited to individual patient data from case reports or series. Future research should pursue filling the gap in knowledge and finding the optimal treatment for this novel clinical category.

Prevalence of Monoclonal Gammopathy of Clinical Significance (MGCS) Among Patients with Monoclonal Gammopathies: Report from a Referral Center

Monoclonal gammopathies (MG) may be associated with a variety of syndromes due to the properties of the monoclonal protein, ectopic production of cytokines or other mechanisms. These syndromes may involve the kidneys, peripheral nerve, skin, eyes or other non-organ confined systemic syndromes. These disorders are usually associated with a nonmalignant or premalignant B-cell or plasma cell clone that does not fulfill the typical criteria of symptomatic myeloma or Waldenström's macroglobulinemia. These heterogeneous syndromes have attracted increasing attention and have been termed as "Monoclonal Gammopathy of Clinical Significance" (MGCS), however, their diagnosis remains challenging, requiring a high degree of suspicion or invasive target organ biopsies. Because of the difficulties in their recognition, it is not known how common these syndromes are among patients with monoclonal gammopathies. On the other hand, MG is a frequent finding: a recent prospective study in Iceland reported a prevalence of ~5% among subjects over the age of 40. Thus, the prevalence of MGCS may be significantly underestimated due to the heterogeneous phenotype, the difficulties in establishing the diagnosis and low degree of suspicion. In order to provide an estimate of the prevalence of MGCS among patients with known MG, we analyzed the database of a plasma cell dyscrasia referral center, in Athens, Greece. This is a prospectively maintained database which includes all patients with monoclonal gammopathies who are referred to our center for evaluation or treatment. Since AL amyloidosis is associated with a more aggressive clinical phenotype and requires prompt initiation of therapy, we evaluated these patients separately in our analysis. Because of an increasing interest in MGCS after 2010, and subsequent rising awareness and diagnostic sensitivity, we excluded earlier referrals and focused only on patients who were referred after 1/1/2010. The analysis included all patients who were referred for evaluation because of MG with or without concomitant symptoms or laboratory abnormalities. From 1/1/2010 to 31/12/2021, 3138 patients were referred for evaluation. The final diagnosis was MGUS or asymptomatic myeloma or asymptomatic WM in 1437 patients, symptomatic MM in 1145 patients, AL amyloidosis in 320 patients, symptomatic WM in 108 patients and a MGCS-related syndrome was diagnosed in 128 patients (4.1%). Among those with MGCS, the majority had either MGRS (n=51) or IgM-related neuropathy (n=58); other specific diagnoses included POEMS syndrome, Schnitzler's syndrome, necrobiotic xanthogranuloma or scleromyxedema, and other rare syndromes (TEMPI syndrome, IgM retinopathy, Clarkson's syndrome). Peripheral neuropathy with a concomitant MG was the most common co-existing condition among non-AL amyloidosis patients: 73% had IgM and 37% a non-IgM MG. A causal relationship between MG and neuropathy was established for 42% of those with non-IgM neuropathy (mainly due to POEMS syndrome). The median age of the MGCS patients was 64, not significantly different in clinical terms from that of patients with SMM/MGUS, AL amyloidosis, symptomatic MM and symptomatic WM (which was 65, 65, 67 and 70 years respectively). The baseline level of monoclonal immunoglobulin among MGCS patients was low (median 0.4 gr/dl) and significantly lower than in patients with MGUS/SMM/aWM (median 1.04 gr/dl). The median BM infiltration by clonal cells in patients with MGCS was 10%, and was 7% in the MGUS/SMM group, 15% in patients with AL amyloidosis, 50% in patients with symptomatic MM and 40% for patients with symptomatic WM. Most patients with MGCS received anticlonal therapy; other non-clone targeting therapies were used in patients with Schnitzler's syndrome and Clarkson's disease. A significant proportion of patients with IgM-related neuropathy received only supportive therapy. In conclusion, MGCS was found in ~4% of patients with MG in a plasma cell dyscrasia referral center. The establishment of MGCS diagnosis requires high degree of clinical suspicion due to their rarity and highly heterogeneous clinical presentation. Despite the bias associated with the analysis from a referral center, given the frequency of MG in the general population, there is probably a significant number of patients with MGCS who remain underdiagnosed and may suffer from complications associated with an otherwise non-malignant plasma cell dyscrasia.

34811 Treatment of underlying monoclonal gammopathy of clinical significance (MGCS) with lenalidomide for IVIG-resistant scleromyxedema

34811 Treatment of underlying monoclonal gammopathy of clinical significance (MGCS) with lenalidomide for IVIG-resistant scleromyxedema

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.

Immunoglobulin M Monoclonal Gammopathies of Clinical Significance.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler’s syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.

Diagnosis and management of monoclonal gammopathy of clinical significance.

The term “monoclonal gammopathy of clinical significance” (MGCS) refers to any plasma cell or B-cell clonal disorder that does not meet the current criteria for malignant disorders but produces a monoclonal protein that directly or indirectly results in organ damage. The most commonly affected organs are the kidneys, nerves, and skin. This review summarizes the current classification of MGCS and its diagnostic and treatment approaches.

Treatment in AL Amyloidosis: Moving towards Individualized and Clone-Directed Therapy

Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell non-Hodgkin’s lymphoma (e.g., Waldenstrom’s disease or marginal zone lymphoma) with secretory activity. It is crucial to characterize the underlying disease very precisely as the treatment of AL amyloidosis is directed against the (often small) B cell clone. Finally, the detection of cytogenetic aberrations of the plasma cell clone will likely play an important role for choosing an effective drug in the near future.

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.

Monoclonal Gammopathy of Ocular Significance (MGOS) - a Series of Corneal Manifestations and Treatment Outcomes

IntroductionMonoclonal gammopathy of ocular significance (MGOS) is a rare subset of monoclonal gammopathy of clinical significance (MGCS) occurring secondary to plasma cell dyscrasia resulting in ocular manifestations. Given the rarity of these conditions, optimal management strategies are not defined; the approach is dependent upon the underlying cause of the monoclonal gammopathy and whether or not the patient's vision is affected. We report our review of 23 cases with MGOS, more specifically on paraproteinemic keratopathy (PPK) the most common form, to obtain a better understanding of the patient characteristics, diagnosis and treatments.MethodsWe report an international retrospective series of patients with MGOS. Data was collected on patients with MGOS:there were no other inclusion criteria besides monoclonal gammopathy with an ophthalmologic manifestation; however, this report focuses only on patients with PPK. Efficacy outcomes were the hematologic and the ocular responses in patients with PPK. Hematologic responses were reported according to the IMWG response criteria. The ophthalmologic response to treatment was assessed by each contributing physician and reported as either complete, partial or no sight recovery.ResultsWe identified 23 patients with PPK in the setting of monoclonal gammopathy of unknown significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM) diagnosed between 2006 and 2019 in 7 countries. Table 1 summarizes the patients' characteristics. The ocular diagnosis was typically made at the same time or after the hematologic diagnosis. Eleven of 23 patients presented decreased vision. Four were treated by penetrating keratoplasty with or without systemic therapy, including chemotherapy with new generation anti-MM agents with or without autologous stem cell transplantation (ASCT). All patients with MM and 40% of those with other diagnoses such as SMM or MGUS received systemic therapy. In most cases, neither ocular nor hematologic treatment, even when ASCT was performed, afforded a durable improvement in the visual acuity despite initial responses. MGOS typically relapsed within one year of the initial response (Table 2).ConclusionTo date, this is the largest retrospective study focusing on MGOS patients with monoclonal immunoglobulin deposits accumulating in the cornea and resulting in visual impairment. Further studies will be required to determine the optimal strategy to treat and prevent the relapse of ocular symptoms in patients with PPK and specifically to address the timing of keratoplasty and systemic chemotherapy and the role of maintenance therapy. Patients with corneal manifestation of unknown origin should undergo a hematologic check-up and patients with paraproteinemia should have a periodic ocular health assessment. [Display omitted] DisclosuresGarderet: Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Munder: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; GSK: Consultancy; Incyte: Research Funding. Gozzetti: AbbVie: Honoraria; Janssen: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau.

Treatment of Patients with Monoclonal Gammopathy of Clinical Significance

Simple SummaryMonoclonal gammopathy of clinical significance (MGCS) is a recently recognized clinical-pathological entity. Symptoms are caused by the presence of a monoclonal protein leading to high comorbidity. The affected organs vary according to the target antigen However, as most of the knowledge relies on case reports or short series; there is a lack of consensus regarding treatment approach. Here, we discuss MGCS other than renal (skin, ocular, neurologic, and bleeding disorders). We provide insights into the pathophysiology, diagnosis, treatment, and follow-up based on clinical cases. Finally, we discuss future directions in this field, such as potential novel therapeutic targets and prognosis of patients with MGCS. Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a monoclonal protein (M-protein) produced by a small amount of plasma cells. The majority of patients remain asymptomatic; however, a fraction of them develop clinical manifestations related to the monoclonal gammopathy despite not fulfilling criteria of multiple myeloma or other lymphoproliferative disorder. These patients constitute an emerging clinical issue coined as monoclonal gammopathy of clinical significance (MGCS). The mechanisms involved are poorly understood, and literature is scarce regarding management. The clinical spectrum involves symptoms related to renal, neurologic, skin, ocular, or bleeding manifestations, requiring a multidisciplinary approach. Treatment strategies rely on the basis of symptomatic disease and the M-protein isotype. In this review, we focus on MGCS other than renal, as the latter was earliest recognized and better known. We review the literature and discuss management from diagnosis to treatment based on illustrative cases from daily practice.

What is the best treatment approach for sporadic late‐onset nemaline myopathy associated with “monoclonal gammopathy of neurological significance”?

What is the best treatment approach for sporadic late‐onset nemaline myopathy associated with “monoclonal gammopathy of neurological significance”?

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.