Monoclonal Gammopathies of Clinical Significance

Monoclonal Gammopathies of Clinical Significance: History

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Subjects: Hematology

Contributor:

Rafael Ríos-Tamayo

Bruno Paiva

Juan José Lahuerta

Joaquín Martínez López

Rafael F. Duarte

Monoclonal gammopathy of clinical significance (MGCS) refers to a recently coined term describing a complex and heterogeneous group of nonmalignant monoclonal gammopathies. These patients are characterized by the presence of a commonly small clone and the occurrence of symptoms that may be associated with the clone or with the monoclonal protein through diverse mechanisms. This is an evolving, challenging, and rapidly changing field. Patients are classified according to the key organ or system involved, with kidneys, skin, nerves, and eyes being the most frequently affected. However, multiorgan involvement may be the most relevant clinical feature at the presentation or during the course.

monoclonal gammopathy of clinical significance
diagnosis
prognosis
treatment

1. Introduction

Monoclonal gammopathies (MGs) are a wide and heterogeneous group of conditions characterized by the presence of a monoclonal (M) protein in the peripheral blood and/or in the urine. The synthesis and release into the plasma of the M-protein, in most cases, is an expression of an underlying plasma cell (PC) neoplasm (PCN).

PCNs are clonal B-cell tumors that range from asymptomatic and stable disorders to diseases with extensive end-organ damage. This great heterogeneity translates to clinical decisions that range from periodic observation to the urgent initiation of anti-clonal therapy. The World Health Organization (WHO) classification of lymphoid tumors periodically provides a global reference for the diagnosis of lymphoid neoplasms. The fifth edition (WHO-HAEM5) has just been released [1]. Remarkably, its definitions have not only been adopted for clinical and research use, but they have also been incorporated into the International Classification of Diseases. Therefore, it correspondingly serves as a universal position for epidemiological analysis and monitoring across international health policy organizations on five continents. The updated WHO-HAEM5 classification of PCNs, now called PCNs, and other diseases with paraproteins is shown in Table 1.

Table 1. Plasma cell neoplasms and other diseases with paraproteins.

Monoclonal Gammopathies
▪ Cold agglutinin disease *
▪ IgM monoclonal gammopathy of undetermined significance
▪ Non-IgM monoclonal gammopathy of undetermined significance
▪ Monoclonal gammopathy of renal significance *
Diseases with monoclonal immunoglobulin deposition
▪ Immunoglobulin-related (AL) amyloidosis
▪ Monoclonal immunoglobulin deposition disease
Heavy chain diseases
▪ Mu heavy chain disease
▪ Gamma heavy chain disease
▪ Alpha heavy chain disease
Plasma cell neoplasms
▪ Plasmacytoma
▪ Plasma cell myeloma
▪ Plasma cell neoplasms with associated paraneoplastic syndrome
◊ POEMS
◊ TEMPI
◊ AESOP *

Adapted from Alaggio et al. [1]. * Not previously included. POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities; TEMPI: telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting; AESOP: adenopathy and extensive skin patch overlying a plasmacytoma.

On the other hand, the International Consensus Classification of Mature Lymphoid Neoplasms has also just been revised [2]. The definition, work-up recommended tests, and diagnostic criteria for these entities have been upgraded. Table 2 shows the International Consensus Classification of Mature B-cell Neoplasms.

Table 2. International Consensus Classification of Mature B-cell Neoplasms.

IgM Monoclonal Gammopathy of Undetermined Significance (MGUS)
▪ IgM MGUS, plasma cell type *
▪ IgM MGUS, NOS *
Primary cold agglutinin disease *
Heavy chain diseases
▪ Mu heavy chain disease
▪ Gamma heavy chain disease
▪ Alpha heavy chain disease
Plasma cell neoplasms
▪ Non-IgM monoclonal gammopathy of undetermined significance
▪ Multiple myeloma (Plasma cell myeloma) *
◊ Multiple myeloma NOS
◊ Multiple myeloma with recurrent genetic abnormality
- Multiple myeloma with CCND family translocation
- Multiple myeloma with MAF family translocation
- Multiple myeloma with NSD2 translocation
- Multiple myeloma with hyperdiploidy
▪ Solitary plasmacytoma of bone
▪ Extraosseous plasmacytoma
Monoclonal immunoglobulin deposition diseases
▪ Immunoglobulin light chain amyloidosis (AL) *
▪ Localized AL amyloidosis *
▪ Light chain and heavy chain deposition disease

Adapted from Campo, E. et al. [2]. * Changes from the 2016 WHO classification; NOS: not otherwise specified; CCND: cyclin D; MAF: musculoaponeurotic fibrosarcoma; NSD2: nuclear receptor SET domain-containing.

2. Definitions

2.1. MGUS

MGUS is a premalignant, clonal PC disorder characterized by the presence of an M-protein produced by a small B-cell/PC clone in persons without features of symptomatic disease related to malignant disorders [32,33,34,35,36,37]. MGUS can be classified into 3 main subtypes, Ig M MGUS, non-IgM MGUS, and LC MGUS, based on a different pattern of progression.

2.1.1. Non-Ig M MGUS

Non-Ig M MGUS is defined by a serum M-protein less than 3 g/dL and less than 10% of clonal bone marrow PC (cBMPC), and the absence of symptoms or end-organ damage attributed to the underlying lymphoplasmacytic disorder.

2.1.2. Ig M MGUS

Ig M MGUS has the same definition as Non-Ig M MGUS, except for the type of bone marrow cells to assess. In this case, less than 10% of cBMPC and a lack of lymphoplasmacytic B-cell aggregates should be demonstrated. In accordance with recent international consensus recommendations, two subtypes of Ig M MGUS should be differentiated: IgM MGUS of PC type, which is considered a precursor of MM, and IgM MGUS, NOS, including all cases with a MYD88 mutation, those with detectable monotypic/monoclonal B-cells but without abnormal lymphoplasmacytic aggregates diagnostic of lymphoplasmacytic lymphoma, and those lacking evidence of other small B-cell neoplasms. Hence, MYD88 mutation should be incorporated into routine workups [2,38,39,40,41].

2.1.3. LC MGUS

LC MGUS patients have an abnormal FLCr, <0.26 or >1.65, with increased level of the involved LC without Ig heavy chain expression on immunofixation, BMPC less than 10%, urinary M-protein less than 500 mg/24 h, and again, the absence of end-organ damage or amyloidosis [42,43].

2.2. MGRS

MGRS is basically defined as a kidney disease related to the presence of an M-protein, diagnosed by demonstration of monoclonal deposits in the kidney biopsy. Monoclonal deposits can consist of monoclonal LC, heavy chain, or intact Igs. Restriction to a single class of LC and/or heavy chain is mandatory [44,45,46,47,48,49].

2.3. MGCS

MGCS is a heterogeneous group of nonmalignant MGs featuring two main characteristics: the presence of a clone, which is commonly associated with the secretion of an M-protein, and symptoms that can be related to the M-protein or to the clone itself by different mechanisms that do not include tumor burden. The MGCSs are best divided into different systems that are affected, the most common of which are kidney, nerve, and skin. However, a systemic and multiorgan presentation is frequent at the time of diagnosis or during the course of the disease [50,51].

3. Historic Note

MGUS is a young concept. The term was coined less than a half century ago [52]. The first studies led by the Mayo Clinic group laid the foundations for an understanding of this entity in terms of epidemiology and clinical impact, but our knowledge about it has been limited until the current century. The first prospective population-based MGUS screening study was published in 2009, showing that MM is consistently preceded by the MGUS precursor stage [29]. MGUS is a heterogeneous disorder associated with a higher risk of other medical problems. Despite the availability of diagnostic criteria, there has been a notable lack of consensus in recent years on key aspects, such as performing a diagnostic bone marrow biopsy and aspirate [35], and this controversy has reached the present day.

MGRS was described for the first time in 2012 [44]. A subgroup of MGUS patients had a condition that was no longer undetermined or insignificant. The term MG of cutaneous or skin significance (MGSS) emerged four years later [53]. These concepts paved the way to the broader and unifying concept of MGCS, which was introduced in 2018 [50]. This term encompasses a wide range of entities, including patients who paradoxically present a small clone and a very low protein level but with significant organ damage that can be life-threatening. In 2019, the term MG of ocular significance (MGOS) was proposed [54]. A schematic timeline representation of the description of relevant MGCS disorders is shown in Figure 1.

Figure 1. Schematic timeline of selected MGCS disorders. Abbreviations: AESOP; adenopathy and extensive skin patch overlying a plasmacytoma, CANOMAD; chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins, anti-disialosyl antibodies MGs; monoclonal gammopathies, MGCS; MG of clinical significance, MGOS; MG of ocular significance, MGNS; MG of neurological significance ^†, MGRS; MG of renal significance, MGSS; MG of skin significance, MGUS; MG of undetermined significance, POEMS; polyradiculoneuropathy (P), organomegaly (O), endocrinopathy(E), monoclonal gammopathy (M), and skin changes (S) syndrome, TEMPI; Telangiectasias, elevated erythropoietin level and Erythrocytosis, Monoclonal gammopathy, Perinephric fluid collections, and Intrapulmonary shunting. ^† MGNS is not a term formally coined in a specific moment of time. Before the term MGCS was coined, the name “paraproteinemic neuropathy” was commonly used to describe the association (not always causal) between MG and neuropathy. Since 2018, MGNS has been an increasingly used term, and some old entities, such as CANOMAD syndrome, have been recognized as belonging to this group.

4. A Practical Classification of MGCS

Despite the increasing knowledge and interest in MGs observed in recent years, MGRS were not included in the last International Classification of Diseases 11th Ed. 2021 or in the previous WHO-HAEM4, except for Monoclonal Ig deposition diseases. MGRS have been most recently included in the 2022 WHO-HAEM5 classification.

As a concept, the key difference between MGUS and MGCS is the presence of disease or organ damage associated with the M-protein or to the clone itself, with therapeutic implications in the last one. Therefore, individuals with MGUS are asymptomatic, without organ damage attributable to the clone or the M-protein, and without the need for treatment, whereas patients with MGCS are symptomatic, organ damage associated with the clone itself or the M-protein can be confirmed, and treatment is needed. Despite recent progress, the link between organ damage and the underlying clone or the M-protein is difficult to prove for some of these entities, for which the pathophysiological mechanism is poorly understood or unknown.

From a practical point of view, MGCS can be divided according to the main organs involved: MGRS, MGSS, MGOS, and MG of neurological significance (MGNS). It remains to be demonstrated whether other groups of MGCS will be unveiled in the coming years.

5. Monoclonal Gammopathies of Renal Significance

Kidney biopsy plays a central role in this diagnosis [55,56,57]. Strikingly, in a study of 6300 patients with MG, only 160 (2.5%) had undergone a kidney biopsy. Of the 160 patients, 64 (40%) had an MGRS lesion, with AL amyloidosis the most common finding, accounting for 43.8% of these lesions. In this study, the decision to perform a kidney biopsy depended on age, the level of proteinuria, and renal function. Despite some limitations, this study showed that the likelihood of performing a kidney biopsy was higher in younger patients with more severe kidney disease in terms of proteinuria and serum creatinine. The probability of reaching a diagnosis of MGRS was associated with the presence of significant proteinuria (≥1.5 g/day), hematuria and an abnormal FLCr. Therefore, a kidney biopsy should be particularly considered in patients with these characteristics [58].

The list of MGRS-associated kidney disorders is still expanding. These conditions can manifest as glomerular diseases, tubulopathies, and vascular involvement, with varying clinical presentations. Therefore, diagnosis is often challenging due to the heterogeneous presentation, the difficulty in establishing a pathogenic link between the presence of the M-protein or serum FLC and kidney disease, and the decision to perform a kidney biopsy. The high incidence of MGUS and other kidney disorders in elderly patients makes the diagnostic process even more difficult. Treatment can potentially reverse kidney disease; hence, early diagnosis is of great value [59,60]. A combined hematologic and nephrologic approach is crucial to establishing the causative role of the M-protein in the pathogenesis of kidney disease. Regarding the risk of progression to MM, MGRS had a significantly higher risk than MGUS (18% vs. 3%; p < 0.001), and this risk was 10% vs. 1% within the first year after diagnosis [61].

6. Monoclonal Gammopathies of Skin Significance

Some dermatologic entities are strongly associated with the presence of a MG, and they should be referred to as MGSS. Again, the demonstration of the association between the M-protein or the clone itself with skin damage is key. As expected, a skin biopsy plays a critical role in the diagnostic process. The direct toxicity of M-protein, host immune abnormalities, specific cytokines, and PC infiltration can, among other mechanisms, produce severe skin manifestations.

The presence of unexplained skin lesions in a patient with MG should be assessed primarily by a hematologist and a dermatologist, with the participation of other specialties, such as rheumatology, internal medicine, and ophthalmology, in certain situations. Every patient with MG and a new skin lesion of unknown origin should be investigated. In these cases, a skin biopsy and bone marrow examination, in addition to the standard laboratory evaluation of PC dyscrasia, should be performed [70]. Only two of these disorders will be described to emphasize the complex clinical presentation as a syndrome and the need to fulfil the diagnostic criteria.

POEMS is a rare paraneoplastic syndrome associated with a PCN [1]. Its acronym stands for polyradiculoneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal gammopathy (M), and skin changes (S). The components of this pentad are not always required for diagnosis. This entity is also called osteosclerotic myeloma due to the presence of osteosclerotic bone lesions in most patients. Other features may include lymphadenopathy, and in these patients, a PC variant of Castleman disease may be present.

7. Monoclonal Gammopathies of Ocular Significance

The cornea is normally a transparent structure. Several abnormalities can cause corneal opacities, making vision difficult. Patients with MG should be included in the differential diagnosis of acquired corneal opacities, as this ocular finding could be the initial manifestation of a systemic disease that can potentially be life threatening. MGOS is a rare subset of MGCS that occurs secondary to PC disorders and causes ocular manifestations. The most frequent ocular M-protein–related condition is crystalline keratopathy consisting of Ig deposition, corneal thickening, photophobia, and finally, visual loss. In a recent series of 23 patients with paraproteinemic keratopathy, neither ocular nor hematologic treatment afforded a durable improvement in visual acuity (recurrence after a median of 11 months), despite initial responses. Further studies are required to determine the optimal strategy to treat and prevent the relapse of ocular symptoms in patients with paraproteinemic keratopathy [79].

8. Monoclonal Gammopathies of Neurological Significance

Peripheral neuropathy (PN) is commonly encountered in clinical practice. It is defined as a disease or degenerative state of the peripheral nerves in which motor, sensory, or vasomotor nerve fibers are affected. Patients can refer to muscle weakness, pain, and numbness [80,81]. Several MGs are associated with PN, and in this context, the constellation of neurological symptoms is often referred to as paraproteinemic neuropathy. N

The efficient management of IgM patients with PN confirmed by neurophysiological tests depends on the type of neuropathy: Demyelinating cases with prolonged distal latency must be tested for anti-myelin-associated glycoprotein antibodies to rule out anti-myelin-associated glycoprotein neuropathy; negative cases with chronic ataxia and ophthalmoplegia must be tested for antiganglioside antibodies to exclude CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, Ig M paraprotein, cold agglutinins, and disialosyl antibodies). In double-negative patients, chronic inflammatory demyelinating polyradiculoneuropathy or paraproteinemic PN are the most plausible scenarios. -On the contrary, in patients with axonal or mixed (both axonal and demyelinating characteristics) NP, cryoglobulinemia, and amyloidosis should be considered. Finally, a nerve biopsy should be reserved for atypical or very aggressive cases with an elusive diagnosis. The accurate diagnosis of MGCS commonly depends on demonstrating specific organ damage through a biopsy. Skin and kidney biopsies are relatively safe procedures. However, a nerve biopsy can be associated with permanent disability in terms of sensory or motor deficits and pain. Therefore, nerve biopsy is less desirable as a diagnostic method, and the decision to perform it must be made after a detailed risk and benefit analysis. Without the routine use of definitive methods to establish a relationship between the M-protein and PN, the diagnosis of MGNS would be one of exclusion.

9. MGCS as a Global and Unifying Concept

9.1. Diagnosis

The diagnosis of MGCS is a complex process. The common clinical challenge is trying to demonstrate a causal link between specific organ damage and the presence of an M-protein. Performing a tissue or organ biopsy is needed in most cases in order to achieve this purpose, nowadays still using conventional immunohistological techniques.

A high titer of autoantibody activity is important for the diagnosis of an M-Ig-mediated immune process. Moreover, the specificity of M-Ig should be defined and correlated with clinical data. Other complementary immunological tests can be of help in the final diagnosis of some specific entities, such as complement studies in type II cryoglobulinemia and xanthomatosis. The pathophysiological mechanism of many MGCS still remains unknown. Epidemiology plays an important role in the definition of the entity in these cases. For certain entities, clinical-based evidence is the main available proof supporting the link between organ damage and the M-protein. This is the case with TEMPI syndrome (Telangiectasias, elevated erythropoietin level and Erythrocytosis, Monoclonal gammopathy, Perinephric fluid collections, and Intrapulmonary shunting). The first patient with TEMPI syndrome was described in 2010 [87]. It is an ultrarare novel multisystem disease [88,89,90,91]. Only 22 patients were reported at the end of 2019. The current proposed diagnostic criteria are outlined in Table 9.

Table 9. TEMPI syndrome diagnostic criteria.

Major	Telangiectasias
	Elevated erythropoietin and erythrocytosis
	Monoclonal gammopathy
Minor	Perinephric fluid
Minor	Intrapulmonary shunting
Other	Venous thrombosis

Adapted from Sykes et al. [89].

9.2. Treatment

Treatment of MGCS focuses on the presence of symptoms and disability. Therapy should be based first on a risk-to-benefit assessment. The next step should be the consideration of the isotype of the M-protein involved, provided that non-Ig-M entities are usually managed with anti-MM therapy, whereas Ig-M ones are mainly treated with an anti-CD20 approach. The primary objective is achieving a hematological response, which is necessary to achieve later an organ response. Future directions need to be focused on the pathophysiology of the disease, exploring new therapeutic options through a deep understanding of immune background dysregulation, and trying to predict which patients might develop MGCS.

There are lights and shadows in the MGCS setting. Several ongoing large-scale prospective studies will help to reveal important knowledge gaps. The Iceland Screens Treats and Prevents Multiple Myeloma (iSTOPMM; NCT03327597) study [106] screens individuals who are at least 45 years old for MGUS, followed by the randomization and evaluation of intensive follow-up versus standard follow-up. The Predicting Progression of Developing Myeloma in a High-Risk Screened Population (PROMISE; NCT03689595) study [107] aimed to assess the prevalence of MGUS in a population at high risk of MM, confirming a high prevalence in older adults who were black/African Americans or who had some first-degree relative with hematologic malignancy. This population may benefit from specific screening, allowing early treatment.

10. Conclusions

The field of MGs is continuously evolving. MGs range from transient MGUS to plasma cell leukemia. MGUS is the most frequent MG, with an increasing prevalence with aging. Despite being considered a pre-malignant asymptomatic disorder, people with MGUS have decreased life expectancy due to malignant transformation and non-malignant causes. MGUS is a large and heterogeneous group. MGCS is a young concept encompassing a constellation of diseases associated with a nonmalignant B cells/PCs clone that produces M-protein and a pathology through diverse, ill-defined mechanisms. Therefore, MGCS patients are characterized by the presence of a quiescent and generally small B-cell/PC non-malignant clone and symptoms that are related to the M-protein or to the clone itself by mechanisms other than the tumor burden. A kidney or skin biopsy is needed for MGRS and MGSS, respectively. Other tissue biopsies could eventually be necessary.

Our current knowledge of the epidemiology and pathogenesis of MGCS is limited due to its heterogeneity and relatively low frequency. There are many syndromes among the spectrum of MGCS. The diagnosis of these disorders is based on a set of criteria that are not always present at baseline, making the diagnosis process difficult. New technologies, including mass spectrometry, multi-omics, and a shift to a minimally invasive approach for diagnosis, will help in making an easier and efficient diagnosis. Ongoing large-scale studies will unveil new insights on the topic in the coming years.

This entry is adapted from the peer-reviewed paper 10.3390/cancers14215247

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