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Clinical course and management of monoclonal gammopathy of undetermined significance

Clinical course and management of monoclonal gammopathy of undetermined significance
Author:
S Vincent Rajkumar, MD
Section Editor:
Robert A Kyle, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Oct 2022. | This topic last updated: Mar 24, 2022.

INTRODUCTION — Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder.

MGUS occurs in over 3 percent of the general population over the age of 50 years and is typically detected as an incidental finding when patients undergo a protein electrophoresis as part of an evaluation for a wide variety of clinical symptoms and disorders (eg, peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, or elevated erythrocyte sedimentation rate).

The clinical course and management of patients 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) [1-7].

Non-IgM MGUS (IgG, IgA, or IgD MGUS) is the most common subtype of MGUS [7,8]. A minority of cases will progress to the more advanced premalignant stage smoldering multiple myeloma (SMM) and to symptomatic multiple myeloma (MM). Less frequently, these patients progress to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder. (See 'Non-IgM and IgM MGUS' below.)

IgM MGUS accounts for approximately 15 percent of MGUS cases. IgM MGUS can progress to smoldering Waldenström macroglobulinemia (WM) and to symptomatic WM as well as non-Hodgkin lymphoma (NHL) [7,9]. Infrequently, IgM MGUS can progress to IgM MM. (See 'Non-IgM and IgM MGUS' below.)

Light chain MGUS (LC-MGUS) is a unique subtype of MGUS in which the secreted monoclonal protein lacks the immunoglobulin heavy chain component. LC-MGUS may progress to idiopathic Bence Jones proteinuria, light chain MM, AL amyloidosis, or light chain deposition disease [2]. (See 'Light chain MGUS' below.)

Studies that provide the majority of information regarding the risk of progression of MGUS only included patients with non-IgM MGUS and IgM MGUS; LC-MGUS is a relatively newly defined entity that may progress to light chain SMM (LC-SMM, idiopathic Bence Jones proteinuria) and then to light chain MM [10]. In general, patients with MGUS progress to more advanced disease at a rate of 1 percent per year. When compared with non-IgM MGUS, the rate may be slightly higher for IgM MGUS and slightly lower for LC-MGUS. The following sections describe information on the rate of disease progression. Clinically, patients may be stratified by risk of progression based on the presence or absence of adverse risk factors. (See 'Risk stratification' below.)

While only a small fraction of patients 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 patients diagnosed with MM had a preceding MGUS, with 75 percent having a detectible M-protein ≥8 years prior to the diagnosis of MM [4,5]. Likewise, another large study showed that all patients 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 more than 11 years prior to the diagnosis of amyloidosis [11].

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

Patients with MGUS progress to more advanced disease at a rate of 1 percent per year. The following describes the clinical course of 1384 persons with MGUS followed for a median of 34.1 years (14,130 person-years) [7,8]:

The median age at diagnosis was 72 years. 1300 persons (94 percent) died during follow-up; nearly 90 percent of deaths were due to causes other than disease progression. The median survival was shorter than that of age- and sex-matched controls from the general population (8.1 versus 12.4 years).

147 persons (11 percent) developed MM, WM, amyloidosis, or a malignant lymphoproliferative disorder. The number of persons progressing to a plasma cell neoplasm or a related disorder was 6.5 times that expected in the general population. The cumulative probability of progression to one of those disorders at 10, 20, 30, and 40 years was 10, 18, 28, and 36 percent, respectively, for a rate of progression of approximately 1 percent per year.

Non-IgM MGUS was detected in 1129 persons (82 percent). The risk of progression was just under 1 percent per year (0.8 events per 100 person-years) and remained stable over the time course. Persons with non-IgM MGUS were at increased risk of progressing to MM, plasmacytoma, and AL amyloidosis, but not WM, chronic lymphocytic leukemia (CLL), and NHL.

IgM MGUS was detected in 210 persons (15 percent). 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). Persons with IgM MGUS were at increased risk of progressing to WM, AL amyloidosis, NHL, and CLL, but not MM or plasmacytoma.

Risk factors for progression included M-protein ≥1.5 g/dL and abnormal free light chain (FLC) ratio. The risk of progression at 20 years among persons with non-IgM MGUS was 30, 20, and 7 percent among those with both, one, or neither risk factor, respectively. Corresponding risk among patients with IgM MGUS was 55, 41, and 19 percent, respectively. Progression was also increased among patients with decreased concentrations of two uninvolved immunoglobulins. The age at diagnosis and the duration of follow-up were not risk factors for progression.

Similar progression rates have been noted in other studies [8,9,12-22]. An Italian study of 136 consecutive cases of IgM MGUS identified a MYD88 (L265P) mutation at the time of diagnosis in 71 cases (52 percent) [23]. After a median follow-up of 34 months, nine developed WM and two developed marginal zone lymphoma. Of these 11 patients with progression, nine (82 percent) had the MYD88 (L265P) mutation at the time of diagnosis, suggesting that presence of the MYD88 (L265P) mutation was associated with a higher rate of progression.

Light chain MGUS — Light chain MGUS (LC-MGUS) is defined by the presence of an abnormal serum FLC ratio (<0.26 or >1.65), increased level of the involved FLC above the reference range, no monoclonal immunoglobulin heavy chain (IgG, IgA, IgD, or IgM), bone marrow with <10 percent monoclonal plasma cells (if performed), and absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, renal insufficiency) related to the proliferative process [2,6]. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Light chain MGUS'.)

LC-MGUS may progress through idiopathic Bence Jones proteinuria to light chain MM, AL amyloidosis, or light chain deposition disease. The estimated risk of progression is 0.3 percent per year [2]. Once idiopathic Bence Jones proteinuria is identified, the rate of progression is higher. In one series of seven patients with idiopathic Bence Jones proteinuria, only two had a benign course after an 8- to 12-year follow-up [24]. The other five patients progressed to symptomatic or asymptomatic MM, accompanied by amyloidosis in one.

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 a patient's lifetime is approximately 10 percent due to a high rate of death from competing causes [25]. For this reason, the median survival of patients 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 patients 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) [7].

A study from Sweden indicated that patients with 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 renal diseases [26]. 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 patients with MGUS reported that patients with an M-protein <1.5 g/dL had the same life expectancy as the general population [27].

MANAGEMENT — The management of a patient with MGUS requires an understanding of the risk of progression to symptomatic disease requiring therapy. It is paramount to deliver the appropriate balance of information about this asymptomatic disorder that has a small chance of progression to a more serious disorder [28]. Patients and their families need appropriate information and support concerning the clinical and psychological ramifications of a diagnosis of MGUS.

Patients with MGUS should be monitored for disease progression and for potential complications. 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 [8,29-32], or from 0.25 to 2.9 percent/year according to a risk stratification model [33,34]. There are a variety of acceptable monitoring schedules for patients with MGUS. Our approach uses a risk stratification system to provide more intensive monitoring for patients more likely to progress (algorithm 1).

There is no known role for chemotherapy in the management of MGUS. Only a minority of patients will progress to symptomatic disease, and there is no data that treatment of asymptomatic disease affects mortality. A number of trials are ongoing to determine if the early use of drugs and other agents (eg, lenalidomide, bisphosphonates) can delay the progression of MGUS and/or smoldering multiple myeloma.

Risk stratification — As described above, patients with MGUS progress to a symptomatic plasma cell proliferative disorder or lymphoproliferative disorder at a rate of 1 percent per year. No single factor can differentiate a patient with MGUS who will have a benign clinical course from one in whom a malignant plasma cell or lymphoproliferative disorder will eventually develop. Numerous studies have investigated potential predictors of disease progression. Of these, three adverse risk factors have been combined to create a risk-stratification model that is useful in predicting the risk of progression of MGUS (non-IgM and IgM) to multiple myeloma (MM) or a related malignancy:

Serum M-protein level ≥1.5 g/dL [8,29-31]

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) [33,35]

The absolute risk of disease progression over 20 years for patients with various combinations of risk factors is [33,34]:

3 risk factors (high risk MGUS) – 58 percent

2 risk factors (high-intermediate risk MGUS) – 37 percent

1 risk factor (low-intermediate risk MGUS) – 21 percent

No risk factors (low risk MGUS) – 5 percent

Other studies support the use of these factors as predictors of progression. As examples:

This risk stratification was validated in a retrospective study of 728 cases of MGUS diagnosed and followed for a median of 10 years in Sweden [36]. This analysis confirmed an incremental increase in the likelihood of progression with each of the three factors described above. In addition, it suggested that reduction in the levels of uninvolved immunoglobulin isotypes (ie, immunoparesis) was associated with progression to lymphoid hematologic disorders (hazard ratio [HR] 2.80) and myeloma (HR 2.77).

A study of 1384 persons with MGUS followed for a median of 34 years reported the following risk factors for progression: M-protein ≥1.5 g/dL and abnormal FLC ratio [7]. The risk of progression at 20 years among persons with non-IgM MGUS was 30, 20, and 7 percent among those with both, one, or neither risk factor, respectively. Corresponding risk among patients with IgM MGUS was 55, 41, and 19 percent, respectively. Progression was also increased among patients with decreased concentrations of two uninvolved immunoglobulins. The age at diagnosis and the duration of follow-up were not risk factors for progression.

In a retrospective case control study, the presence of an abnormal (monoclonal) kappa/lambda FLC ratio in the serum was associated with a significantly higher risk of disease progression (relative risk [RR] 2.5, 95% CI 1.6-4.0) [35].

In a large cohort study involving 1148 patients, the risk of progression in patients with an abnormal FLC ratio was significantly higher compared with patients with a normal ratio (HR 3.5; 95% CI 2.3-5.5) [33]. This effect was independent of the size and type of the serum M-protein.

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, increased markers of bone turnover, and gene expression signature [18,29-31,36-47]. The risk of progression also appears to be lower among persons with MGUS who have a concomitant autoimmune disease [48,49]. Risk factors for progression of light chain MGUS have not been defined yet.

Monitoring for progression — We use a risk stratification approach to monitor for progression that provides more intensive monitoring for patients more likely to progress (algorithm 1). All patients with MGUS should be followed over time with history and physical examination to identify signs and symptoms of progressive disease [28]. The role of laboratory testing in the longitudinal care of patients with MGUS is less clear. Most experts agree that all patients should undergo laboratory evaluation for disease progression six months after diagnosis with serum protein electrophoresis (SPEP) to measure M-protein, serum FLC assay (or urine protein electrophoresis [UPEP]), complete blood count, creatinine, and serum calcium [31,50]. While some experts incorporate periodic laboratory testing into the subsequent follow-up of all patients, we risk stratify to identify patients for whom laboratory testing is most likely to provide value:

Patients with low-risk MGUS (serum M-protein <1.5 g/dL, IgG type, and normal serum FLC ratio) have a risk of progression of only 5 percent over 20 years, and may be followed with history and physical examination alone [7,33,50,51].

All other patients are followed with annual SPEP, serum FLC assay (or urinary M-protein), complete blood count, creatinine, and serum calcium. As with many other cancer screening programs, we discontinue screening in patients age 80 years and older and in those with a life expectancy less than five years.

In patients 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 [52,53]. There are no data to recommend such testing on a routine basis; we include NT-proBNP if there are clinical concerns for amyloidosis.

The following signs or symptoms, 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, 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) or serum M-protein ≥3 g/dL

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 [51,54]. As a result, patients 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 patients unlikely to progress and places a low value on the unknown benefit of the small chance of detecting disease progression early through laboratory testing.

The efficacy of periodic monitoring was evaluated in a single-institution retrospective analysis of 116 patients with MGUS who later developed MM [51]. Patients evaluated at least every two years were considered to have optimal follow-up. Of the 80 patients with optimal follow-up, disease progression was identified by routine laboratory follow-up in only 13 patients (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 patient (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 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.

Monitoring for complications

Monoclonal gammopathy of clinical significance — The term "monoclonal gammopathy of clinical significance" (MGCS) has been proposed to identify patients that would otherwise meet the criteria for MGUS, but demonstrate organ damage related to the immunoglobulin or other mechanisms [55]. The related term "monoclonal gammopathy of renal significance" (MGRS) is used to describe such cases demonstrating renal insufficiency and monoclonal immunoglobulin deposits in the kidney by immunofluorescence [56]. 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 'Monitoring for progression' 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 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 — Patients with MGUS have an increased risk of axial (skull, vertebral/pelvis, and sternum/costae), but not peripheral (arm and leg), bone fractures [57-59], with the highest risk being noted in those with reduced lumbar bone mineral density [60]. 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 [60-63].

The largest population-based study evaluated fracture risk in 5326 patients with MGUS and 20,161 matched controls from Sweden [59]. Patients 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 isotype (ie, IgG versus IgA) or M-protein concentration at diagnosis. Fracture did not predict for disease progression to MM or Waldenström macroglobulinemia (WM).

Patients with MGUS should be evaluated for osteoporosis and osteopenia with a dual energy X-ray absorptiometry (DEXA) scan and have their vitamin D and calcium intake optimized [64]. Prophylactic bisphosphonates have not been proven to be beneficial for patients with MGUS. Bisphosphonates should be used in these patients only if they have another indication for their use, such as osteoporosis or osteopenia on bone mineral density studies. (See "Bisphosphonate therapy for the treatment of osteoporosis".)

Thromboembolic disease — A number of studies have reported an increased incidence of venous thromboembolic disease (VTE) and arterial thrombosis in patients with MGUS [65-71]. While the mechanisms involving this increased incidence are unclear, a hypercoagulable state secondary to an ongoing clonal plasma cell activity has been suggested for patients with MGUS, MM, WM, and systemic amyloidosis [69,72].

Second malignancies — Persons with MGUS or MM have a higher incidence of developing second cancers [73]. We encourage patients with MGUS to participate in age-appropriate cancer screening programs. No additional cancer screening has been recommended for this population.

In a large series, 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 nonhematologic malignancy (SIR 1.56; 95% CI 1.44-1.68) when compared with the general population [74]. However, the general population in this study was not screened for the presence or absence of MGUS. The association seen is likely inflated; patients who are ill enough to be evaluated for MGUS are likely to have more medical problems and cancers than patients who never have the need for such a test. These study flaws are systematic biases, and therefore cannot be rectified and are likely to be amplified by large sample sizes. In asymptomatic conditions such as MGUS, true associations can be demonstrated only if all persons are tested uniformly for the presence or absence of the condition.

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 [75]. 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) and a trend toward an increased risk of developing AML (RR 1.36; 95% CI 0.32-5.74), which did not reach statistical significance. There was no increase in the risk of developing ALL. Unlike the Swedish study, this was a study in which all patients 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 patients 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 patients with MGUS does not translate into a high likelihood of developing AML.

Pregnant women — Rarely, MGUS is detected during pregnancy. In published literature, data regarding such patients is limited to case reports and extrapolation of small case series of MM during pregnancy [76-79]. In our limited experience with MGUS during pregnancy, there have been no complications in the 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 and prognosis – 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) (see 'Disease progression' above):

Non-IgM MGUS (IgG, IgA, or IgD MGUS) is the most common subtype of MGUS. It has the potential to progress to smoldering (asymptomatic) multiple myeloma and symptomatic multiple myeloma. Less frequently, these patients progress to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder.

IgM MGUS accounts for approximately 15 percent of MGUS cases. It is considered separately from non-IgM MGUS because it has the potential to progress to smoldering Waldenström macroglobulinemia and symptomatic Waldenström macroglobulinemia as well as non-Hodgkin lymphoma. Rarely, IgM MGUS can progress to IgM multiple myeloma.

Light chain MGUS is a unique subtype of MGUS in which the secreted monoclonal protein lacks the immunoglobulin heavy chain component. It may progress to idiopathic Bence Jones proteinuria, light chain multiple myeloma, or AL amyloidosis.

Patients with MGUS progress to more advanced disease at a rate of 1 percent per year. When compared with non-IgM MGUS, the rate may be slightly higher for IgM MGUS and slightly lower for light chain MGUS. (See 'Disease progression' above.)

The median survival of patients with MGUS is only slightly shorter than that of age-matched controls. (See 'Survival' above.)

Monitoring for progression – No treatment is required for patients with MGUS. Patients with MGUS should be followed over time with history and physical examination looking for signs and symptoms of progressive disease. All patients should undergo laboratory evaluation for disease progression six months after diagnosis with serum protein electrophoresis (SPEP), serum free light chain (FLC) assay (or urine protein electrophoresis), complete blood count, creatinine, and serum calcium.

While some experts incorporate periodic laboratory testing into the routine follow-up of all patients, we use a risk stratification system to identify patients for whom laboratory testing is most likely to provide value (algorithm 1) (see 'Monitoring for progression' above):

Patients with low-risk non-IgM MGUS (serum M-protein <1.5 g/dL, IgG subtype, and normal serum FLC ratio) may be followed with history and physical examination alone. They have a risk of progression of only 5 percent over 20 years.

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

The evolution from MGUS to advanced disease may be abrupt. As a result, patients should be advised to obtain medical evaluation promptly if clinical symptoms occur. (See 'Monitoring for progression' above.)

Optimizing bone health – Patients with MGUS are at increased risk of fracture and thromboembolic disease. They should be evaluated for osteoporosis with a dual energy X-ray absorptiometry (DEXA) scan and have their vitamin D and calcium intake optimized. If osteoporosis is present, then treatment with bisphosphonates may be considered at the same dosing and schedule used for osteoporosis in patients without MGUS. (See 'Fracture' above.)

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Topic 15772 Version 40.0

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