Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder. It is characterized by the presence of a monoclonal (M) protein in the serum or urine that is commonly discovered during laboratory work-up of a variety disorders. MGUS is a precursor to various hematologic disorders including multiple myeloma (MM), Waldenström macroglobulinemia (WM), solitary plasmacytoma, and immunoglobulin light chain amyloidosis (AL). Smoldering MM (SMM) is a clinically-defined disorder similar to MGUS, but has a much higher risk of progression to MM or a related disorder. SMM is not a unique intermediate biologic stage between MGUS and MM, but it consists of a heterogeneous mixture of patients, some of whom have a biologic premalignancy and have a clinical course resembling MGUS, and some who have an asymptomatic malignancy that will develop end-organ damage typical of MM within a few years. Unfortunately, at the current time, there is no single pathologic or molecular feature that reliably distinguishes patients with SMM who have premalignancy from those with asymptomatic malignancy. MGUS and SMM are usually asymptomatic but can be causally related to a variety of systemic disorders. They also carry a lifelong risk of progression to MM (see Chapter 91 ) or a related malignancy (see box on Diagnosis of MGUS and SMM: Role of Screening .)

Monoclonal Gammopathy of Undetermined Significance

MGUS is defined by the presence of a serum monoclonal (M) protein of <3 g/dL (or increased serum free light chain (FLC) level with abnormal free light chain (FLC ratio), <10% clonal bone marrow plasma cells (BMPC) with no evidence of SMM, end-organ damage, or other myeloma defining events (MDEs) ( Table 90.1 ). There are three major subtypes of MGUS: IgM MGUS, non-IgM MGUS, and light-chain MGUS (LC-MGUS). IgM MGUS carries a risk of progression to WM (see Chapter 92 ), although patients can rarely develop IgM MM. Non-IgM MGUS is associated with a risk of progression to MM, and LC-MGUS is a precursor of light chain MM. All forms of MGUS can lead to AL amyloidosis (see Chapter 93 ).

Table 90.1

International Myeloma Working Group Diagnostic Criteria for Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma and Related Disorders

Disorder	Disease Definition
IgM monoclonal gammopathy of undetermined significance (IgM MGUS)	All three criteria must be met: Serum IgM monoclonal protein <3 g/dL Bone marrow lymphoplasmacytic infiltration <10% No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder
Non-IgM monoclonal gammopathy of undetermined significance (MGUS)	All three criteria must be met: Serum monoclonal protein (non-IgM type) <3 g/dL Clonal bone marrow plasma cells <10% ^a Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder
Light chain MGUS	All criteria must be met: Abnormal FLC ratio (<0.26 or >1.65) Increased level of the appropriate involved light chain (increased kappa free light chain (FLC) in patients with ratio >1.65 and increased lambda FLC in patients with ratio <0.26) No immunoglobulin heavy chain expression on immunofixation Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder Clonal bone marrow plasma cells <10% Urinary monoclonal protein <500 mg/24 h
Smoldering multiple myeloma	Both criteria must be met: Serum monoclonal protein (IgG or IgA) ≥3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal bone marrow plasma cells 10%–60% Absence of myeloma defining events or amyloidosis
Multiple myeloma	Both criteria must be met: Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma Any one or more of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2·75 mmol/L (>11 mg/dL) Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 μmol/L (>2 mg/dL) Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomograph (CT), or positron emission tomography-CT (PET-CT) Clonal bone marrow plasma cell percentage ≥60% Involved:uninvolved serum FLC ratio ≥100 (involved FLC level must be ≥100 mg/L) >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size)
Smoldering Waldenström macroglobulinemia (also referred to as indolent or asymptomatic Waldenström’s macroglobulinemia)	Both criteria must be met: Serum IgM monoclonal protein ≥3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥10% No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Waldenström macroglobulinemia	All criteria must be met: IgM monoclonal gammopathy (regardless of the size of the M protein) ≥10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (e.g., surface IgM ⁺ , CD5 ^+/− , CD10 ⁻ , CD19 ⁺ , CD20 ⁺ , CD23 ⁻ ) that satisfactorily excludes other lymphoproliferative disorders including chronic lymphocytic leukemia and mantle cell lymphoma Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder
Solitary plasmacytoma	All 4 criteria must be met Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder
Solitary plasmacytoma with minimal marrow involvement ^b	All four criteria must be met Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Clonal bone marrow plasma cells <10% Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder
Systemic AL amyloidosis	All four criteria must be met: Presence of an amyloid-related systemic syndrome (such as renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement) Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy) Evidence that amyloid is light-chain related established by direct examination of the amyloid using mass spectrometry (MS)-based proteomic analysis, or immuno-electron microscopy Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein, abnormal FLC ratio, or clonal plasma cells in the bone marrow) Note: Approximately 2%–3% of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder listed above; the diagnosis of AL amyloidosis must be made with caution in these patients. Patients with AL amyloidosis who also meet criteria for multiple myeloma are considered to have both diseases.
POEMS syndrome	All four criteria must be met Polyneuropathy Monoclonal plasma cell proliferative disorder (almost always lambda) Any one of the following three other major criteria: 1 Sclerotic bone lesions 2 Castleman’s disease 3 Elevated levels of vascular endothelial growth factor (VEGF) ^† Any one of the following six minor criteria 1 Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) 2 Extravascular volume overload (edema, pleural effusion, or ascites) 3 Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic) ^‡ 4 Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails) 5 Papilledema 6 Thrombocytosis/polycythemia Note: Not every patient meeting the above criteria will have POEMS syndrome; the features should have a temporal relationship to each other and no other attributable cause. Anemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present. ^† The source data do not define an optimal cut off value for considering elevated VEGF level as a major criterion. We suggest that VEGF measured in the serum or plasma should be at least three- to fourfold higher than the normal reference range for the laboratory that is doing the testing to be considered a major criterion. ^‡ In order to consider endocrinopathy as a minor criterion, an endocrine disorder other than diabetes or hypothyroidism is required since these two disorders are common in the general population.

From Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol . 2014;15:e538–e548, with permission from Elsevier.

a A bone marrow can be deferred in patients with low-risk MGUS (IgG type, M protein <15 g/L, normal free light chain ratio) in whom there are no clinical features concerning for myeloma.

b Solitary plasmacytoma with 10% or more clonal plasma cells is considered as multiple myeloma.

Epidemiology

Prevalence

With conventional testing, MGUS can be detected in approximately 4% of normal persons 50 years of age and older. Age-adjusted rates are greater in men than in women. The prevalence increases with age, exceeding 7.5% among those 85 years or older. Sensitive mass spectrometry studies show that the overall prevalence of MGUS is higher and is estimated at approximately 5% of the general population age 50 years and older. The prevalence of MGUS is higher in Blacks compared to Whites. In a large population-based study ( n = 12,482) of persons 50 years of age and older, using samples from the National Health and Nutrition Examination Survey (NHANES), the adjusted prevalence of MGUS was significantly higher in Blacks (3.7%) compared to Whites (2.3%) or Hispanics (1.8%) ( P < .001). A subsequent NHANES study found that the racial disparity in prevalence occurs even at younger ages, with MGUS having an onset approximately a decade earlier in Blacks compared with Whites. Table 90.2 gives the estimated prevalence of MGUS by race and age based on NHANES studies.

Table 90.2

Prevalence of Monoclonal Gammopathy of Undetermined Significance (%), by Race/Ethnicity and Age

Age Group (Years)	Blacks % (95%CI)	Whites % (95%CI)	Hispanic American % (95%CI)	Total ^a % (95%CI)
10–19	0.00 (NA)	0.00 (NA)	0.11 (0.02–0.84)	0.01 (0.00–0.07)
20–29	0.26 (0.08–0.84)	0.00 (NA)	0.00 (NA)	0.03 (0.01–0.11)
30–39	0.81 (0.43–1.53)	0.32 (0.11–0.99)	0.23 (0.06–0.79)	0.49 (0.27–0.91)
40–49	3.26 (2.04–5.18)	0.53 (0.20–1.37)	2.20 (1.22–3.95)	0.88 (0.53–1.47)
50–59	2.19 (1.32–3.60)	1.01 (0.62–1.66)	0.85 (0.33–2.23)	1.20 (0.83–1.72)
60–69	3.48 (2.26–5.33)	2.43 (1.72–3.43)	2.41 (1.69–3.44)	2.45 (1.85–3.23)
70–79	5.67 (3.66–8.70)	3.44 (2.55–4.63)	2.51 (1.36–4.58)	3.43 (2.64–4.47)
80+	8.56 (4.92–14.47)	4.42 (3.31–5.87)	3.97 (1.33–11.22)	4.58 (3.54–5.90)

Modified from Landgren O, Graubard BI, Kumar S, et al. Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10–49 years old: a population-based study from the National Health and Nutrition Examination Survey. Blood Cancer J . 2017;7:e618.

a Includes “Other” race/ethnicity group.

The increased risk of MGUS seen in African Americans has also been found in Black people living in Ghana. Furthermore, studies show that the racial disparity between Blacks and Whites persists even after adjusting for socio-economic status, suggesting that the disparity in incidence is more likely due to genetics rather than environmental factors. Recent studies show that the t(11;14) translocation type of MGUS may be responsible for most of the increased disparity in MGUS between Blacks and Whites. The probability of having one of three specific subtypes, namely t(11;14), t(14;16), or t(14;20) was significantly higher in the 120 individuals with the highest African ancestry (≥80%) compared with the 235 individuals with lowest African ancestry (<0.1%) (51% vs. 33%, respectively, P value = 0.008). Studies in other racial groups are limited, but so far an increased risk has not been seen in Japanese individuals, or in Hispanics living in the United States when compared to the White population of Olmsted County.

Incidence

The annual incidence of MGUS in males is estimated to be 120/100,000 at age 50, and rises to 530/100,000 at age 90 years. The rates for women are 60/100,000 at age 50, and 370/100,000 at age 90. When MGUS is first diagnosed, it is estimated that the condition has already been present in an undiagnosed form for a median of over 10 years.

Other Risk Factors

First-degree relatives of patients with MGUS and MM have a two- or threefold higher risk of MGUS compared to those with no known affected relatives. Obesity, exposure to pesticides, and immunosuppression are also known risk factors for MGUS.

Diagnosis of Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma: Role of Screening

Routine screening is not recommended for MGUS since there are no randomized trials to support such a strategy. There are also no interventions to offer to patients who are diagnosed with MGUS. However, we do not have interventions to prevent end organ damage for patients with high-risk SMM. Since these patients are asymptomatic, diagnosis is incidental. Thus many patients who can potentially benefit from early intervention will go unidentified. This dilemma has led to consideration of screening in high-risk populations, namely Blacks with one affected first-degree relative with MM, and in all others with two or more affected first-degree relatives. In these subsets of the population, the prevalence of MGUS is likely greater than 10%–15%, and the probability of finding patients with high-risk SMM is higher. In our practice, we recommend such selected screening, until we have results of a large, randomized trial in Iceland, which is investigating the role of screening as well as the role of more aggressive follow-up of monoclonal gammopathies.

Pathobiology

MGUS likely originates when plasma cells are dividing in response to antigenic stimulation. During this period of antigenic stimulation they acquire a primary cytogenetic abnormality that established the MGUS clone ( Fig. 90.1 ). The primary cytogenetic abnormalities associated with the onset of MGUS consist of two major types: trisomies and immunoglobulin heavy chain (IgH) translocations ( Table 90.3 ). IgH translocations involve the immunoglobulin heavy chain switch region on chromosome 14q32, and one of five common partner chromosomes loci: 11q13 (CCND1 [cyclin D1 gene]), 4p16.3 (FGFR-3 and MMSET), 6p21 (CCND3 [cyclin D3 gene]), 16q23 (c-MAF), and 20q11 (MAF-B).

Figure 90.1, PATHOGENESIS OF MONOCLONAL GAMMOPATHIES.

Table 90.3

Primary Cytogenetic Abnormalities in Monoclonal Gammopathy of Undetermined Significance

Subtype	Gene(s) Affected
Trisomies	Usually involving odd-numbered chromosomes with the exception of chromosomes 1, 13, and 21. Multiple genes affected
Primary immunoglobulin rearrangements ^a
t(11;14) (q13;q32)	CCND1 (cyclin D1)
t(4;14) (p16;q32)	FGFR-3 and MMSET
t(14;16) (q32;q23)	C-MAF
t(14;20) (q32;q11)	MAFB
t(6;14) (p21;q32)	CCND3 (cyclin D3)
Other IgH translocations	The genes affected vary depending on the partner chromosome

a Other rare partner chromosomes have been described. Some patients have combined IgH translocations and trisomies, but they should be classified based on the IgH translocation.

MGUS may stay dormant or acquire secondary cytogenetic abnormalities and progress to MM or a related malignancy. The rate of progression of MGUS is approximately 1% per year regardless of the known duration of antecedent MGUS, indicating a random hit model of progression. Although the precise pathogenetic steps are unclear, there appear to be two main pathways involved, namely, MYC translocations and mutations in the MAP kinase pathway. The presence of MYC structural variants is associated with a significantly shorter median time to progression (TTP) compared to the absence of such abnormalities. Other abnormalities associated with progression include chromosome 1q21 (gain 1q), p16 methylation, p53 mutations, and changes in the bone marrow microenvironment, including induction of angiogenesis and suppression of cell-mediated immunity, affecting things such as T-cell production.

Progression is also associated with increase in receptor activator of nuclear factor κB ligand (RANKL) expression by osteoblasts and possibly plasma cells accompanied by decreased stromal cell secretion of the RANKL decoy receptor, osteoprotegerin (OPG). There is also release of macrophage inflammatory protein–1α (MIP-1α) and MIP-1β by myeloma cells. Collectively these changes promote osteoclast activation through the nuclear factor κB (NF-κB) pathway. In addition, there is simultaneous inhibition of osteoblasts mediated by increased dickkopf 1 (DKK-1) expression by myeloma cells. The combination of osteoclast activation and inhibition of osteoblast differentiation is thought to be the mechanism behind the development of osteolytic lesions in MM, and may also explain increased risk of fractures seen in MGUS even in absence of progression to MM.

Clinical Manifestations

MGUS is an asymptomatic condition. It is typically detected as an incidental finding when electrophoresis and immunofixation of the serum and/or urine, or the serum FLC assay are performed during the work-up of suspected MM or WM, including symptoms such as unexplained weakness or fatigue, increased erythrocyte sedimentation rate, anemia, unexplained back pain, osteoporosis, osteolytic lesions or fractures, hypercalcemia, proteinuria, renal insufficiency, or recurrent infections. MGUS may also be detected during work-up of patients with symptoms suggestive of AL amyloidosis such as unexplained sensorimotor peripheral neuropathy, carpal tunnel syndrome, refractory congestive heart failure, nephrotic syndrome, orthostatic hypotension, malabsorption, weight loss, change in the tongue or voice, paresthesias, numbness, increased bruising, bleeding, and steatorrhea.

Association of Monoclonal Gammopathy of Undetermined Significance With Other Diseases

Although most patients diagnosed with MGUS are asymptomatic, some can have disorders that are causally related to the M protein, without any evidence of overt progression to MM or related malignancy ( Table 90.4 ). In fact, increasingly MGUS is diagnosed in such situations, during work-up of unexplained renal, neuropathic, or other organ dysfunction. Over a hundred different medical conditions have been reported to be associated with MGUS, but most such reported associations are coincidental rather than causal. The important causal related disorders are discussed below.

Table 90.4

Non-Malignant Diseases Associated With Monoclonal Gammopathy of Undetermined Significance and May Respond to Lymphoplasmacytic Cell-Directed Therapy

Primary Organ Involved	Clinical Presentation	Role of Monoclonal Protein/Pathophysiology
Schnitzler syndrome	Chronic urticaria, fever, bone pain, IgM-MGUS	Unclear
Insulin autoimmune syndrome	Episodic confusion, diaphoresis, dizziness, lethargy, palpitation, seizure	Antibody to insulin causing its inactivation
TEMPI	Telangiectasias, erythrocytosis, elevated erythropoietin level, MGUS, perinephric fluid collections, and intrapulmonary shunting	Unclear
Rheumatologic
scleromyxedema	Waxy papules or plaques, arthralgia, restrictive lung disease, seizure	Unclear
Progressive glomerulonephritis with monoclonal immunoglobulin deposits	Hematuria, hypertension, proteinuria, renal impairment, mostly IgG3κ-MGUS	Granular deposition of immunoglobulin in glomeruli
Sporadic late-onset nemaline myopathy	Muscular weakness and atrophy frequently resulting in “head drop,” respiratory insufficiency, congestive heart failure	Unclear
Crystalline keratopathy	Decreased visual acuity, corneal opacity, IgGκ-MGUS	Corneal deposition of antibody forming a crystalline structure
Crystal-storing histiocytosis	Mass or tissue infiltration, which may involve the bone marrow, breast, gastrointestinal tract, kidneys, lymph node, skin, or spleen	Accumulation of light chain crystals in histiocytes

MGUS, Monoclonal gammopathy of undetermined significance.

From Go RS, Rajkumar SV. How I manage monoclonal gammopathy of undetermined significance. Blood . 2018;131;163–173. © American Society of Hematology.

Monoclonal Gammopathy Associated Neuropathy

Approximately 3% to 5% of patients with monoclonal gammopathy have a peripheral neuropathy, and approximately 3% to 5% of patients with a peripheral neuropathy have evidence of an M protein. IgM MGUS associated neuropathy presents as a chronic distal, acquired, demyelinating, symmetric sensory neuropathy (DADS-M). In approximately half of these patients, the IgM M protein binds to myelin-associated glycoprotein (MAG). In contrast, patients with non-IgM associated neuropathy have a varied presentation, but the clearest association is in patients who present with features similar to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with predominantly motor involvement with distal and proximal involvement. MGUS neuropathy must be differentiated from two other plasma cell disorders that cause neuropathy that have been well characterized and have strict diagnostic criteria, namely immunoglobulin light chain (AL) amyloidosis, and neuropathy associated with POEMS (polyneuropathy, organomegaly).

Monoclonal Gammopathy Associated Renal Disorders

A substantial proportion of cases with “idiopathic” immune-complex mediated membranoproliferative glomerulonephritis (MPGN) are now felt to be related to MGUS. MGUS can cause proliferative glomerulonephritis by direct deposition of M protein in the mesangium and along capillary walls, resulting in an immune complex-mediated proliferative glomerulonephritis. It can also cause glomerulonephritis by, indirectly, activating the alternative pathway of complement resulting in deposition of complement factors in the glomeruli, resulting in C3 glomerulopathy. The term monoclonal gammopathy of renal significance (MGRS) is used to describe renal diseases such as those caused by a premalignant MGUS clone, and the aforementioned M protein-related disorders such as AL amyloidosis and monoclonal immunoglobulin deposition disease.

Monoclonal Gammopathy Associated Dermatologic Diseases

A variety of dermatologic diseases have been associated with MGUS including lichen myxedematosus (papular mucinosis, scleromyxedema), scleredema (Buschke disease), pyoderma gangrenosum, diffuse plane xanthomatosis, and subcorneal pustular dermatosis. Other skin disorders associated with MGUS are necrobiotic xanthogranuloma and Schnitzler syndrome, a rare disorder characterized by chronic urticaria and an IgM monoclonal gammopathy.

Other Associations of Monoclonal Gammopathy of Undetermined Significance

MGUS has been associated with an increased risk of fractures and deep vein thrombosis, and has been linked to chronic lymphocytic leukemia, hairy cell leukemia, T-cell lymphoma, and other malignancies, but the significance of these associations is not known. MGUS has also been associated with acquired von Willebrand disease, Gaucher disease, pure red cell aplasia, connective tissue disorders, various neurologic disorders. and can occasionally be the cause of systemic capillary leak syndrome.

Laboratory Manifestations

The hallmark of MGUS is the presence of an M protein in the serum and/or urine. M proteins are detected using protein electrophoresis of the serum and urine. The M protein appears as a narrow peak (like a church spire) on the densitometer tracing or as a dense, discrete band on agarose gel ( Fig. 90.2 ). Protein electrophoresis also permits quantitation of M proteins. Urine electrophoresis requires a 24-hour urine collection. Immunofixation of the serum and urine is more sensitive than protein electrophoresis and is used to identify the type of M protein heavy and light chains (IgM kappa, IgG lambda, etc.).

Figure 90.2, SERUM PROTEIN ELECTROPHORESIS.

The FLC assay is a nephelometric assay that measures free kappa (κ) and lambda (λ) light chains that are not bound to intact immunoglobulin. Patients with abnormally low kappa/lambda FLC ratios are considered to have a monoclonal lambda FLC, and those with abnormally high ratios are defined as having a monoclonal kappa FLC. The serum FLC assay is more sensitive than electrophoresis or immunofixation in detecting free monoclonal light chains, and must be done at diagnosis in conjunction with those tests.

At diagnosis, osteolytic bone disease must be excluded in order to distinguish MGUS from MM. The preferred method to detect bone disease is a whole-body low-dose computed tomography (CT). Positron emission tomography-CT (PET-CT) is an equally sensitive alternative to whole body low-dose CT. A unilateral bone marrow aspiration and biopsy, if indicated, must show less than 10% clonal BMPCs. For flow cytometry, plasma cells in MGUS typically stain positive for CD38 and CD138, and are positive only for one of the two light chain isotypes, indicating they are monoclonal (either kappa or lambda). Baseline cytogenetic abnormalities are best ascertained by fluorescent in situ hybridization (FISH) testing on the bone marrow sample at diagnosis ( Fig. 90.3 ). In patients suspected of monoclonal protein related disorders, confirmatory testing is needed, such as renal biopsy in patients with monoclonal gammopathy associated proliferative glomerulonephritis ( Fig. 90.4 ).

Figure 90.3, FLUORESCENT IN SITU HYBRIDIZATION (FISH).

Figure 90.4, PROLIFERATIVE GLOMERULONEPHRITIS DUE TO MONOCLONAL GAMMOPATHY.

Differential Diagnosis

MGUS is differentiated from MM and SMM by the size of the M protein, the BMPC percentage, and the presence or absence of anemia, renal failure, hypercalcemia, or lytic bone lesions (see Table 90.1 ). Because anemia and renal insufficiency are relatively common in the elderly population with MGUS, the causes of these conditions should be carefully investigated with adequate laboratory studies.

Prognosis

MGUS is associated with a life-long risk of progression to MM or a related disorder. In a study of 1384 patients from Southeastern Minnesota, the risk of progression of MGUS to MM or related malignancy was 1% per year. The true life-time probability of progression is lower when competing causes of death are taken into account, approximately 11% at 25 years. The risk of progression with MGUS does not diminish with time, even after over 30 years of follow-up. Progression events include MM, WM, solitary plasmacytoma, and AL amyloidosis. The risk of progression from MGUS has been estimated in several other studies, and the results mirror those seen in the Southeastern Minnesota study. No findings from the diagnosis of MGUS can reliably distinguish patients whose condition will remain stable indefinitely from those in whom MM or related malignancy develops. However, there are several known prognostic factors that assist in estimation of the risk of progression for appropriate counseling and management.

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