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Clinical course and management of monoclonal gammopathy of undetermined significance

Clinical course and management of monoclonal gammopathy of undetermined significance
Literature review current through: Jan 2024.
This topic last updated: Jan 04, 2024.

INTRODUCTION — Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder characterized by the presence of monoclonal immunoglobulins and/or an abnormal ratio of free immunoglobulin light chains in the blood and/or urine.

MGUS occurs in >4 percent of the general population over the age of 50 years and is typically detected as an incidental finding when a protein electrophoresis is performed as part of an evaluation for a wide variety of clinical symptoms and disorders (eg, peripheral neuropathy, autoimmune diseases, anemia, skin rashes, hypercalcemia, or elevated erythrocyte sedimentation rate).

The clinical course and management of individuals with MGUS will be discussed here. The diagnosis of MGUS, laboratory methods for analyzing monoclonal proteins, and the clinical features, laboratory manifestations, and diagnosis of multiple myeloma and other plasma cell dyscrasias are presented separately.

(See "Diagnosis of monoclonal gammopathy of undetermined significance".)

(See "Laboratory methods for analyzing monoclonal proteins".)

(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

(See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

(See "Monoclonal immunoglobulin deposition disease".)

CLINICAL COURSE

Disease progression — There are three distinct clinical types of MGUS, each with a small risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder (table 1). These are described in the following sections.

While only a small fraction of individuals with MGUS will progress to a malignant plasma cell dyscrasia or lymphoproliferative disorder, virtually all malignant plasma cell dyscrasias are preceded by MGUS. In two large longitudinal studies, virtually all individuals diagnosed with multiple myeloma (MM) had a preceding MGUS, with 75 percent having a detectible monoclonal protein (M-protein) ≥8 years prior to the diagnosis of MM [1,2]. Likewise, another large study showed that all individuals with immunoglobulin light chain (AL) amyloidosis had a preceding MGUS, with evidence of a monoclonal gammopathy being present in 80 percent at least four years prior and in 42 percent >11 years prior to the diagnosis of amyloidosis [3]. The evolution from MGUS to MM is described in more detail separately. (See "Multiple myeloma: Pathobiology".)

Non-IgM MGUS — Non-immunoglobulin M (IgM) MGUS is the most common subtype accounting for approximately 78 to 80 percent of cases [4,5]. The M-protein is most commonly immunoglobulin G (IgG) or immunoglobulin A (IgA); immunoglobulin D (IgD) and immunoglobulin E (IgE) MGUS are uncommon.

Definition – Non-IgM MGUS is defined by the presence of a non-IgM serum M-protein at a concentration <3 g/dL (<30 g/L); bone marrow with <10 percent monoclonal plasma cells (if performed); absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, kidney impairment) related to the proliferative process; and absence of MM defining biomarkers (table 1) [6]. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Diagnostic criteria'.)

Risk of progression to malignancy – Individuals with non-IgM MGUS are at risk for progression to smoldering MM (a more advanced premalignant stage) and to symptomatic MM. Less frequently, these individuals progress to plasmacytoma, AL amyloidosis, or related plasma cell malignancy. Besides progression to malignancy, patients with MGUS can also develop a variety of nonmalignant disorders that are related to the effect of the paraprotein on organs such as the kidney, skin, and peripheral nerves. These disorders, which are related to the unique characteristics of the paraprotein, are sometimes collectively referred to as monoclonal gammopathy of clinical significance to indicate that MGUS can cause clinical problems even without progression to malignancy.

Individuals with non-IgM MGUS progress to more advanced disease at a rate of approximately 1 percent per year [4,5,7-15]. In one study that included >1100 persons with non-IgM MGUS followed for a median of >30 years, the risk of progression was 0.8 events per 100 person-years and remained stable over the time course [4,5].

Risk factors for progression include M-protein ≥1.5 g/dL (≥15 g/L) and abnormal free light chain ratio. The risk of progression at 20 years increases with the number of these risk factors: neither factor (7 percent), one factor (20 percent), and both factors (30 percent) [4,5]. Clinical risk stratification is described in more detail separately. (See 'Risk stratification to estimate risk of progression' below.)

IgM MGUS — IgM MGUS accounts for approximately 15 to 22 percent of MGUS cases [4,5].

Definition – IgM MGUS is defined by the presence of an IgM serum M-protein at a concentration <3 g/dL (<30 g/L); bone marrow with <10 percent monoclonal plasma cells (if performed); and absence of end-organ damage (eg, anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly) related to the proliferative process (table 1) [6]. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Diagnostic criteria'.)

Risk of progression to malignancy – Individuals with IgM MGUS are at risk for progression to smoldering Waldenström macroglobulinemia (a more advanced premalignant stage) and to symptomatic Waldenström macroglobulinemia (WM) and other non-Hodgkin lymphomas, including chronic lymphocytic leukemia, as well as to AL amyloidosis [5,16]. Infrequently, IgM MGUS can progress to IgM multiple myeloma.

Individuals with IgM MGUS progress to more advanced disease at a rate of 1 to 2 percent per year [4,5,7-19]. In one study with long-term follow-up of 210 persons with IgM MGUS, the risk of progression was 2 percent per year in the first 10 years and 1 percent per year thereafter (1.1 events per 100 person-years) [4,5].

Risk factors for progression include M-protein ≥1.5 g/dL (≥15 g/L) and abnormal free light chain ratio. The risk of progression at 20 years increases with the number of these risk factors: neither factor (19 percent), one factor (41 percent), and both factors (55 percent) [4,5]. MYD88 (L265P) mutation may also be associated with a higher rate of IgM MGUS progression [19-21]. Clinical risk stratification is described in more detail separately. (See 'Risk stratification to estimate risk of progression' below.)

Light chain MGUS — In light chain MGUS (LC-MGUS), the secreted M-protein lacks the immunoglobulin heavy chain component. Prevalence of LC-MGUS has been estimated at approximately 0.8 percent [22]. However, most studies evaluating MGUS prevalence and risk of progression have not included LC-MGUS as it is a relatively newly defined entity. As such, the true prevalence and risk of progression remains to be defined.

Definition – LC-MGUS is defined by the presence of an abnormal serum free light chain (FLC) ratio with an increased level of the involved light chain (kappa or lambda); no immunoglobulin heavy chain (IgG, IgA, IgD, or IgM); bone marrow with <10 percent monoclonal plasma cells (if performed); absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, kidney impairment) related to the proliferative process; and absence of MM defining biomarkers (table 1) [6,22]. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Diagnostic criteria'.)

When interpreting the FLC assay in clinical practice, clinicians should refer to the normal reference range specified by the laboratory reporting the result. Reference ranges differ between assays from different manufacturers and are dependent upon the instrument used for measurement. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)

FLC concentration is affected by any type of kidney dysfunction, and the reference intervals used for the FLC ratio (and FLC level) should be adjusted for the estimated glomerular filtration rate (eGFR) [23,24]; for the serum FLC assay developed by The Binding Site:

eGFR ≥60 mL/min/1.73 m2

-FLC ratio 0.26 to 1.65

-Serum free kappa 3.3 to 19.4 mg/L

-Serum free lambda 5.7 to 26.3 mg/L

eGFR 45 to 59 mL/min/1.73 m2

-FLC ratio 0.46 to 2.62

-Serum free kappa 7.8 to 83.6 mg/L

-Serum free lambda 7.3 to 65.1 mg/L

eGFR 30 to 44 mL/min/1.73 m2

-FLC ratio 0.48 to 3.38

-Serum free kappa 8.8 to 103.3 mg/L

-Serum free lambda 8.2 to 73.2 mg/L

eGFR <30 mL/min/1.73 m2

-FLC ratio 0.54 to 3.30

-Serum free kappa 11.7 to 265 mg/L

-Serum free lambda 12.6 to 150.9 mg/L

Risk of progression to malignancy – Individuals with LC-MGUS may progress to light chain smoldering myeloma (a more advanced premalignant stage, previously termed idiopathic Bence Jones proteinuria), and to light chain MM, AL amyloidosis, or light chain deposition disease [22,25]. The estimated risk of progression is 0.3 percent per year [22].

Development of other conditions — A minority of persons with MGUS will present with or develop a nonmalignant symptomatic disorder related to the monoclonal immunoglobulin termed monoclonal gammopathy of clinical significance (table 2). Some of these disorders may improve with control of the M-protein. (See 'Monoclonal gammopathy of clinical significance' below.)

Additionally, MGUS has been associated with multiple health-related problems, including fractures, infections, neuropathies, thrombosis, and increased mortality [23,26]. However, most studies that have demonstrated these associations have been based on clinical cohorts, where MGUS is diagnosed during a work-up for an unrelated medical condition. This design has an inherent selection bias, potentially identifying false associations between MGUS and other conditions. These false associations were illustrated in a large screening study that was only able to confirm 14 out of 75 previously reported associations [27]. Ongoing screening studies (eg, iStopMM) are expected to provide higher quality data regarding potential associations and risk. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Associated conditions'.)

Survival — It is not clear if and to what extent MGUS impacts survival. While the probability of progression of MGUS at 25 years is 25 to 30 percent, the median age at diagnosis is 65 to 70 years, and the probability of progressing during an individual's lifetime is approximately 10 percent due to a high rate of death from competing causes [28]. For this reason, the median survival of individuals with MGUS is expected to be only slightly shorter than that of age-matched controls. However, persons with MGUS may have other diagnoses that led to the identification of the M-protein and may impact survival.

Studies that have investigated the survival of persons with MGUS have had mixed results:

In a series of 1384 persons with MGUS followed for a median of 34 years, the median survival was shorter than that of a comparable United States population (8.1 versus 12.4 years) [5].

A study from Sweden indicated that persons with clinically diagnosed MGUS have a significantly reduced life expectancy when compared with the general population, and an excess risk of dying not only from well-described malignant transformations (eg, MM, WM, amyloidosis), but also from bacterial infections as well as heart, liver, and kidney diseases [29]. The mechanisms for the latter are unclear and may be related to the underlying conditions leading to the initial diagnosis of MGUS.

A single-center retrospective study of 1400 persons with MGUS reported that those with an M-protein <1.5 g/dL (<15 g/L) had the same life expectancy as the general population [30].

MANAGEMENT

Education — Individuals with MGUS and their caregivers need appropriate information and support concerning the clinical and psychological ramifications of a diagnosis of MGUS. Key messages include:

MGUS is an asymptomatic disorder that has a small chance of progression to a hematologic malignancy. In addition, a minority of persons with MGUS will present with or develop a nonmalignant symptomatic disorder related to the monoclonal immunoglobulin (table 2). (See 'Clinical course' above.)

Not all persons with MGUS have the same risk of disease progression. The risk of progression to a serious disease ranges widely from 0.6 to 3.4 percent/year according to the initial value of serum monoclonal (M)-protein [4,31-34], or from 0.25 to 2.9 percent/year according to a risk stratification model [35,36]. (See 'Risk stratification to estimate risk of progression' below.)

Persons with MGUS are monitored for disease progression and for potential complications. There are a variety of acceptable monitoring schedules. Most experts use a risk stratification system to provide more intensive monitoring for individuals more likely to progress (algorithm 1). (See 'Risk stratified monitoring' below.)

There is no known role for chemotherapy in the management of MGUS. Only a minority of persons will progress to symptomatic disease, and there is no data that treatment of asymptomatic disease affects mortality.

There is no role for routine screening for monoclonal gammopathy in asymptomatic persons. Such screening is unproven, would be associated with costs for payers, and may cause undue emotional burden on individuals with a low risk of progressing to a symptomatic disorder. However, screening can be considered after discussing benefits and potential harms in selected individuals over the age of 50 at high risk of having MGUS or smoldering multiple myeloma, such as those with two or more affected first-degree relatives with multiple myeloma or related disorder. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Screening'.)

Risk stratification to estimate risk of progression — We risk stratify persons with MGUS to select an appropriate monitoring strategy (algorithm 1). For non-light chain MGUS, we use the risk stratification system promoted by the International Myeloma Working Group (IMWG) [36]. Risk factors for progression of light chain MGUS have not been adequately defined. Some experts suggest that LC-MGUS with an FLC ratio <8 may not need bone marrow evaluation.

The risk stratification system promoted by the IMWG combines three adverse risk factors to predict the risk of progression of MGUS (non-IgM and IgM) to multiple myeloma (MM) or a related malignancy [35,36]:

Serum M-protein level ≥1.5 g/dL (≥15 g/L)

Non-IgG MGUS (ie, IgA, IgM, IgD MGUS)

Abnormal serum free light chain (FLC) ratio (ie, ratio of kappa to lambda free light chains <0.26 or >1.65)

The number of risk factors is used to estimate the absolute risk of disease progression over 20 years and the estimated risk of disease progression when accounting for death as a competing risk, as follows:

Three risk factors (high risk MGUS) – 58 percent (27 percent accounting for death as a competing risk)

Two risk factors (high-intermediate risk MGUS) – 37 percent (19 percent accounting for death as a competing risk)

One risk factor (low-intermediate risk MGUS) – 21 percent (10 percent accounting for death as a competing risk)

No risk factors (low risk MGUS) – 5 percent (2 percent accounting for death as a competing risk)

Several large studies support the use of these factors as predictors of progression [4,5,31-33,35,37,38].

Ongoing studies are evaluating whether persons with a higher risk of progression may also be identified using the iStopMM risk model, which uses MGUS isotype, serum M-protein level, FLC ratio, and immunoglobulin levels to predict the likelihood of having ≥10 percent bone marrow plasma cells. Use of risk models to guide bone marrow biopsy is described separately. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Bone marrow aspiration and biopsy'.)

Other factors may predict progression but are not used in the risk stratification model, including: urine FLC, increasing percentage of bone marrow plasma cells and malignant bone marrow plasma cell immunophenotype, immunoparesis (decreased levels of uninvolved immunoglobulins), increased markers of bone turnover, and gene expression signature [13,31-33,38-49]. The risk of progression also appears to be lower among persons with MGUS who have a concomitant autoimmune disease [50,51].

Monitoring for progression

Rationale for monitoring — The benefit of monitoring persons with MGUS has not been proven in a prospective study. However, three separate studies from Sweden and the US have consistently shown that having known precursor disease before the development of multiple myeloma (MM) is associated with superior outcomes in MM, including improved survival and less morbidity at the time of diagnosis.

Clinical follow-up of precursor disease is associated with improved survival and less morbidity in those who progress to MM, although it is not known whether this is due to earlier detection and initiation of treatment or lead-time bias. In a Swedish population-based cohort of >14,700 patients with MM, overall survival was superior in those with a prior diagnosis of MGUS (HR 0.86) despite having more comorbidities overall [52]. Similarly, a study of the US SEER database that included >17,400 patients with MM found that patients with a previous diagnosis of MGUS were less likely to have a major complication at MM diagnosis (odds ratio 0.68) and had superior disease-specific survival (HR 0.85) and overall survival (HR 0.87) from the time of MM diagnosis [53]. These findings were further validated in a single center study of 774 individuals with previously diagnosed precursor disease (MGUS or smoldering MM [SMM]) that reported superior overall survival (HR 0.68) in those with a prior diagnosis of SMM when compared with 1548 matched patients with MM without previously identified MGUS or SMM [54].

The efficacy of periodic monitoring was evaluated in a single-institution retrospective analysis of 116 people with MGUS who later developed MM [55]. Individuals evaluated at least every two years were considered to have optimal follow-up. Of the 80 people with optimal follow-up, disease progression was identified by routine laboratory follow-up in only 13 persons (16 percent). Disease progression to symptomatic MM was identified in the rest of the cases by:

Serious MM-related complications (45 percent)

Diagnostic work-up of less serious symptoms reported by the individual (25 percent)

Incidental finding in the context of work-up of another condition (11 percent)

Unknown (3 percent)

In patients with high-risk MGUS (serum M-protein ≥1.5 g/dL [≥15 g/L] and/or non-IgG MGUS), disease progression was identified by routine laboratory follow-up in 21 percent. This study suggests that close follow-up of the general population of patients with MGUS may not achieve its purpose of identifying the progression to MM prior to an adverse MM-related complication. It also demonstrates that most patients who progress to MM will have symptoms that prompt further investigation. However, patients with high-risk MGUS have a higher rate of transformation and a greater chance of having progression identified by routine periodic testing before a serious MM-related complication occurs.

Risk stratified monitoring — All persons with MGUS should be monitored for progression [56]. We use a risk stratified approach that provides more intensive monitoring for patients more likely to progress (algorithm 1). It is consistent with the approach promoted by the International Myeloma Working Group (IMWG) [36].

Most experts agree that all individuals should undergo laboratory evaluation for disease progression six months after diagnosis with serum protein electrophoresis (SPEP) to measure M-protein, serum FLC assay, complete blood count, creatinine, and serum calcium [33,57].

If this repeat testing is stable (ie, no "red flags" as defined below), the frequency of subsequent laboratory testing is adjusted to prioritize its use in patients for whom testing is most likely to provide value:

Individuals with low-risk MGUS (ie, IgG MGUS with serum M-protein <1.5 g/dL [<15 g/L] and normal serum FLC ratio) have a risk of progression of only 5 percent over 20 years, and may be followed with bloodwork every 2 to 3 years [5,35,55,57]. Risk factors for progression of LC-MGUS are not adequately defined, although some experts manage LC-MGUS with an FLC ratio <8 as low risk MGUS. Referral to a specialist is appropriate if there are findings concerning for progression or uncertainty regarding the diagnosis.

All other individuals are followed with annual SPEP, serum FLC assay, complete blood count, creatinine, and serum calcium. Such patients are usually followed in consultation with a specialist. As with many cancer screening programs, we stop monitoring in the very old or frail and in those with a life expectancy less than five years.

In individuals with MGUS who have an abnormal FLC ratio, some have suggested annual testing of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and urine albumin in order to detect amyloidosis [58,59]. There are no data to recommend such testing on a routine basis; NT-proBNP can be included if there are clinical concerns for amyloidosis.

The following findings, if otherwise unexplained, should be considered "red flags" that necessitate further investigation (eg, bone marrow or tissue biopsy, imaging) (algorithm 2):

Bone pain

Fatigue/generalized weakness

Constitutional "B" symptoms (unintentional weight loss, fever, night sweats)

Neurologic symptoms (neuropathy, headache, dizziness, loss of vision/hearing)

Bleeding

Symptoms suggestive of amyloidosis (macroglossia, neuropathy, periorbital purpura, nephrotic range proteinuria, restrictive cardiomyopathy, unexplained elevated NT-proBNP or hepatomegaly)

Lymphadenopathy, hepatomegaly, or splenomegaly

Anemia, elevated creatinine, hypercalcemia

Increase in serum M-protein level ≥50 percent (provided absolute increase ≥0.5 g/dL [≥5 g/L]) or serum M-protein ≥3 g/dL (≥30 g/L)

Increase in involved serum FLC level by ≥50 percent or involved/uninvolved FLC ratio ≥100 (provided involved FLC level is at least 100 mg/L)

Urine M-protein ≥500 mg in 24 hours

The evolution from MGUS to MM may be abrupt [55,60]. As a result, individuals should be advised to obtain medical evaluation promptly if clinical symptoms occur. This risk stratified follow-up places a high value on minimizing undue psychological and financial stress on individuals unlikely to progress and places a low value on the unknown benefit of the small chance of detecting disease progression early through laboratory testing.

Monitoring for complications — Many associations between MGUS and other health-related problems have been based on clinical cohorts, where MGUS is diagnosed during the work-up for an unrelated medical condition. This design has an inherent selection bias, potentially identifying false associations between MGUS and other conditions.

Monoclonal gammopathy of clinical significance — The term "monoclonal gammopathy of clinical significance" (MGCS) has been proposed to identify persons that would otherwise meet the criteria for MGUS, but demonstrate organ damage related to the immunoglobulin or other mechanisms (table 2) [61]. The related term "monoclonal gammopathy of renal significance" (MGRS) is used to describe such cases demonstrating kidney impairment and monoclonal immunoglobulin deposits in the kidney by immunofluorescence [62]. Similarly, numerous terms have been used for MGUS-associated peripheral neuropathies. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance" and "Immune-mediated neuropathies".)

Identifying cases of MGCS and MGRS is complicated since the signs and symptoms are nonspecific and variable. Care must be taken to distinguish those complications that are truly secondary to the monoclonal gammopathy from those due to an unrelated process. For some of these entities, therapy directed at the underlying B cell clone may reverse organ damage and prevent further complications. For others, immediate intervention is not necessary as the risks of treatment outweigh the benefits. Importantly, identification of one of these complications does not alter the plan of monitoring for progression described separately. (See 'Risk stratified monitoring' above.)

The broad array of MGCS range from systemic disorders impacting many organ systems (eg, AL amyloidosis, type I cryoglobulinemia, monoclonal immunoglobulin deposition diseases) to disorders primarily impacting one organ system such as the kidney (eg, acquired Fanconi syndrome), nervous system (eg, IgM-associated peripheral neuropathy), or skin (eg, macroglobulinosis, scleromyxedema) (table 2). (See "Scleromyxedema".)

The mechanism of organ damage is variable and sometimes unknown. Well-described mechanisms include the deposition of monoclonal immunoglobulin in tissue (eg, AL amyloidosis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits) and autoantibody activity of the monoclonal immunoglobulin (eg, bullous skin disease, acquired von Willebrand disease). Other suggested mechanisms include complement alternate pathway activation (eg, C3 glomerulonephritis) and cytokine-mediated organ damage (eg, POEMS syndrome).

Fracture — Individuals with MGUS have an increased risk of axial (skull, vertebral/pelvis, and sternum/costae), but not peripheral (arm and leg), bone fractures [63-65], with the highest risk being noted in those with reduced lumbar bone mineral density [66]. The pathophysiologic basis for this finding is unclear, although both an imbalance between bone resorption and bone formation and altered bone microstructure have been postulated [66-69]. Our approach to bone health in persons with MGUS is as follows:

We counsel about the risk of fracture and have a low threshold to evaluate for suspected fracture.

We encourage participation in osteoporosis screening programs designed for the general population as there are no studies to support an adjusted screening for osteoporosis in individuals with MGUS (See "Screening for osteoporosis in postmenopausal women and men".)

We reserve bisphosphonates for individuals with another indication for their use, such as osteoporosis or osteopenia on bone mineral density (BMD) studies; Prophylactic bisphosphonates have not been proven to be beneficial for individuals with MGUS alone. (See "Bisphosphonate therapy for the treatment of osteoporosis".)

The largest population-based study evaluated fracture risk in 5326 adults with MGUS and >20,000 matched controls from Sweden [65]. Those with MGUS had an increased risk of fracture at 5 years (HR = 1.74, 95% CI 1.58-1.92) and 10 years (HR = 1.61, 95% CI 1.49-1.74). This increased risk was greatest for axial fractures. The risk of fracture did not differ by MGUS isotype (ie, IgG versus IgA) or M-protein concentration at diagnosis. Fracture did not predict for disease progression to MM or Waldenström macroglobulinemia (WM).

Individuals with MGUS have similar BMD when compared with the general population. This was illustrated in a screening study from Iceland that included >5700 older adults who underwent quantitative computerized tomography of the lumbar spine and hip to evaluate BMD [70]. Subjects with MGUS had similar BMD to those without MGUS. Fracture risk was not increased for the group as a whole, although subgroup analysis suggested an increased fracture risk among males with MGUS (HR 1.46; 95% CI 1.03-2.08).

Infections — Several studies have observed an increased incidence of infections in individuals with MGUS, both in clinical and screened cohorts. While the exact mechanisms are unclear, this likely reflects underlying immunodeficiency and hypogammaglobulinemia.

A cohort of 1237 individuals with MGUS from Denmark found a 2.2-fold increase in risk of infection compared to the general population [71]. A screening study from Olmsted County in Minnesota that included 605 individuals with MGUS noted an increased risk of upper respiratory bacterial infection, spontaneous bacterial peritonitis, and mycobacterium infection compared with >16,700 controls [27]. Similarly, in a Swedish study based on 5326 individuals with MGUS and >20,000 matched controls, those with MGUS had twofold increased risk of developing any infection at 5- and 10-year follow up [72]. Specifically, there was an increased risk of bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis) and viral (influenza, herpes zoster) infections.

Thromboembolic disease — A number of studies have reported an increased incidence of venous thromboembolic disease (VTE) and arterial thrombosis in individuals with MGUS [73-79]. While the mechanisms involving this increased incidence are unclear, a hypercoagulable state secondary to ongoing clonal plasma cell activity has been suggested for individuals with MGUS, MM, WM, and systemic amyloidosis [77,80]. MGUS should not be considered an independent risk factor for thrombosis or a sole indication for anticoagulation.

Second malignancies — Persons with MM and to some extent also those with MGUS have a higher incidence of developing second cancers [81]. We encourage persons with MGUS to participate in age-appropriate cancer screening programs. No additional cancer screening is recommended for this population.

In a large clinical cohort from Sweden, persons with MGUS were reported to have excessive rates of acute myeloid leukemia/myelodysplastic syndrome (standardized incidence ratio [SIR] 8.01; 95% CI 5.40-11.43) and solid malignancy (SIR 1.56; 95% CI 1.44-1.68) when compared with the general population [82]. The association seen is likely inflated; persons who are ill enough to be evaluated for MGUS are likely to have more medical problems and cancers than persons who never have the need for such a test. As discussed above, in asymptomatic conditions such as MGUS, true associations can be demonstrated only if all persons are tested uniformly for the presence or absence of a condition. (See 'Development of other conditions' above.)

A subsequent population-based study evaluated the risk of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) in 17,315 persons aged 50 years and older screened for MGUS and followed for a mean of 25 years [83]. Of the 605 persons with MGUS, seven were subsequently diagnosed with MDS and two were diagnosed with AML. When compared with those without MGUS, persons with MGUS demonstrated a slightly higher risk of developing MDS (RR 2.40; 95% CI 1.08-5.32) but not an increased risk of developing AML (RR 1.36; 95% CI 0.32-5.74) or ALL. Unlike the Swedish study, this was a study in which all persons were screened for the presence or absence of MGUS, and thereby did not have the problem of ascertainment bias. This study shows that the risk of AML/MDS with MGUS is much lower than that estimated in the Swedish study.

These studies suggest that persons with MGUS may have a slightly higher risk of developing MDS. There does not appear to be any excess risk of ALL, and data are limited to determine if there is any increase in the risk of AML. AML has a low incidence in the general population; as a result, an increase in the relative risk in persons with MGUS does not translate into a high likelihood of developing AML.

Pregnant persons — Rarely, MGUS is detected during pregnancy. In published literature, data regarding such persons is limited to case reports and extrapolation of small case series of multiple myeloma during pregnancy [84-87]. In our limited experience with MGUS during pregnancy, there have been no complications in the birthing mother or child. The monoclonal protein can be present in the neonate's blood, especially if it is of the IgG type, but disappears within 6 to 12 months after birth.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Monoclonal gammopathy of undetermined significance".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topic (see "Patient education: Monoclonal gammopathy of undetermined significance (The Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical course – There are three distinct clinical types of monoclonal gammopathy of undetermined significance (MGUS), each with a risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder (table 1 and algorithm 2) (see 'Disease progression' above):

Non-IgM MGUS (IgG, IgA, or IgD MGUS) is the most common subtype. It can progress to smoldering multiple myeloma (SMM) and multiple myeloma (MM). Less frequently, it progresses to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder.

IgM MGUS can progress to smoldering Waldenström macroglobulinemia and symptomatic Waldenström macroglobulinemia as well as non-Hodgkin lymphoma. Rarely, it progresses to IgM MM.

Light chain MGUS (LC-MGUS) may progress to light chain SMM, light chain MM, or AL amyloidosis.

Association with other conditions – Rarely, MGUS will present with or develop a nonmalignant symptomatic disorder related to the monoclonal immunoglobulin termed monoclonal gammopathy of clinical significance (table 2). (See 'Monoclonal gammopathy of clinical significance' above.)

It is not known if and to what degree MGUS itself increases the risk of other conditions (eg, fractures, infections, thrombosis, and other cancers) or impacts overall survival. Most studies showing potential associations are based on clinical cohorts with inherent selection bias. (See 'Survival' above.)

Risk stratification – Risk stratification of non-LC-MGUS is based on three adverse risk factors:

Serum M-protein level ≥1.5 g/dL (≥15 g/L)

Non-IgG MGUS isotype

Abnormal serum free light chain (FLC) ratio (ie, ratio of kappa to lambda free light chains <0.26 or >1.65)

Estimated absolute risk of disease progression at 20 years increases with the number of risk factors: none (5 percent), one (21 percent), two (37 percent), and three (58 percent). (See 'Risk stratification to estimate risk of progression' above.)

Risk factors for progression of LC-MGUS are not adequately defined, although some experts manage LC-MGUS with an FLC ratio <8 as low risk MGUS.

Monitoring for progression – We use a risk stratified approach to provide more intensive monitoring for persons more likely to progress (algorithm 1). Six months after diagnosis, we measure serum protein electrophoresis (SPEP), serum FLC assay, complete blood count, creatinine, and serum calcium. (See 'Risk stratified monitoring' above.)

If this repeat testing is stable, the frequency of subsequent laboratory testing is adjusted based on risk of progression:

Individuals with low-risk MGUS (ie, IgG MGUS with serum M-protein <1.5 g/dL [<15 g/L] and normal serum FLC ratio) have a risk of progression of ≤5 percent over 20 years and may be followed with bloodwork every two to three years. This approach can also be offered to individuals with LC-MGUS and an FLC ratio <8. Referral to a specialist is appropriate if there are findings concerning for progression or uncertainty regarding the diagnosis.

All other persons are followed with annual SPEP, serum FLC assay, complete blood count, creatinine, and serum calcium in addition to a history and physical examination. Such patients are usually followed in consultation with a specialist.

The evolution from MGUS to advanced disease may be abrupt. As a result, we advise those with MGUS to request prompt medical evaluation if clinical symptoms occur. (See 'Monitoring for progression' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who made extensive contributions to earlier versions of this topic review.

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Topic 15772 Version 45.0

References

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