Monoclonal Gammopathies of Undetermined Significance and Smoldering Multiple Myeloma

S. Vincent Rajkumar

Robert A. Kyle

John A. Lust

INTRODUCTION

Nomenclature

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, pre-malignant clonal plasma cell proliferative disorder.¹, ², ³, ⁴ It was initially referred to as essential hyperglobulinemia by Jan Waldenström, as well as several other terms such as benign, idiopathic, asymptomatic, nonmyelomatous, discrete, cryptogenic, and rudimentary monoclonal gammopathy; dysimmunoglobulinemia; lanthanic monoclonal gammopathy; idiopathic paraproteinemia; and asymptomatic paraimmunoglobulinemia.⁵, ⁶ However, because there is an indefinite risk of progression to multiple myeloma (MM) or related disorder such as Waldenström macroglobulinemia (WM) or amyloidosis (AL), the term MGUS is now the accepted nomenclature.¹, ², ⁷, ⁸ Smoldering multiple myeloma (SMM) is a clinically defined pre-malignant stage between MGUS and MM.⁹, ¹⁰ MGUS and SMM must be differentiated from MM, and from a number of related plasma cell disorders using the criteria listed on Table 97.1.⁸, ¹¹

Detection of Monoclonal Proteins

Immunoglobulins consist of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type. The various types of immunoglobulins are designated by capital letters that correspond to the isotype of their heavy chains, which are designated by Greek letters: gamma (γ) constitutes immunoglobulin G (IgG), alpha (α) is found in IgA, mu (µ) is present in IgM, delta (δ) occurs in IgD, and IgE is characterized by epsilon (ε). IgG1, IgG2, IgG3, and IgG4 are the subclasses of IgG; the subclasses of IgA are IgA1 and IgA2. Kappa (κ) and lambda (λ) are the two types of light chains. An intact immunoglobulin consists of two heavy chains of the same class and two light chains of the same type. A monoclonal increase in immunoglobulins results from a clonal process such as MGUS or MM, and a polyclonal increase in immunoglobulins is caused by a reactive or inflammatory process. The monoclonal immunoglobulin secreted by clonal plasma cells in MGUS, SMM, MM, and related monoclonal gammopathies is referred to as a monoclonal protein or M protein.

Electrophoresis and Immunofixation

Monoclonal proteins are detected using agarose gel or capillary electrophoresis of the serum and urine.¹² An M-protein is usually visible as a localized band on protein electrophoresis, and as a tall narrow spike or peak in the β or γ region or, rarely, in the α2-globulin area of the densitometer tracing (Fig. 97.1A). A polyclonal increase in immunoglobulins produces a broad band or broad-based peak that migrates in the γ region. A suspected M protein on electrophoresis must be confirmed on immunofixation, which also determines the immunoglobulin heavy-chain class and its light chain type.¹³ In addition, immunofixation is also done when MM, WM, AL (light chain) amyloidosis, or a related disorder is suspected, because small M proteins may not be detected with electrophoresis alone. Immunofixation is performed using commercial kits or systems such as Sebia, or Pentafix (Fig. 97.1B).

Quantitative Immunoglobulins

In patients with detectable M proteins, another assay that aids in monitoring is quantitation of immunoglobulins performed with a rate nephelometer. It can accurately measure 7S IgM, polymers of IgA, and aggregates of IgG. However, levels of IgM obtained by nephelometry may be 1,000 to 2,000 mg/dl higher than those expected on the basis of the serum protein electrophoretic tracing. The quantitative IgG and IgA levels may be increased similarly.¹⁴

Serum Free Light Chain Assay

The serum free light chain (FLC) assay (Freelite^TM, The Binding Site Limited, Birmingham, UK) is an automated nephelometric assay that measures free kappa (κ) and lambda (λ) light chains that are not bound to intact immunoglobulin.¹⁵, ¹⁶ The normal serum free-κ level is 3.3 to 19.4 mg/L and the normal free-λ level is 5.7 to 26.3 mg/L.¹⁷ The normal ratio for FLC-κ/λ is 0.26 to 1.65. The normal reference range in the FLC assay reflects a higher serum level of free λ light chains than would be expected given the usual κ/λ ratio of 2 for intact immunoglobulins. This occurs because the renal excretion of free κ (which exists usually in a monomeric state) is faster than free λ (which is usually in a dimeric state).¹⁵, ¹⁶ Patients with a κ/λ FLC ratio <0.26 are considered to have a monoclonal λ free light chain and those with ratios >1.65 are defined as having a monoclonal κ free light chain. If the FLC ratio is >1.65, κ is referred to as the “involved” FLC and λ the “uninvolved” FLC, and vice versa if the ratio is less than 0.26.

The serum FLC assay can be used in place of urine protein electrophoresis and immunofixation in the initial screening algorithm for M proteins. In a study of 428 patients, Katzmann et al. found that urine studies can be eliminated by using the serum FLC assay in combination with the SPEP and immunofixation.¹⁸ However, if a monoclonal plasma cell disorder is identified on screening, a 24-hour urine collection followed by electrophoresis and immunofixation should always be done to aid in the assessment of disease progression and response to therapy over time. In addition to its role as a substitute for urine studies in the screening of plasma cell disorders, the FLC assay is used to predict prognosis in MGUS, SMM, AL, and solitary plasmacytoma.¹⁹, ²⁰, ²¹

In addition, it is also used to monitor oligo-secretory MM, nonsecretory MM, light chain only form of MM, and AL amyloidosis.¹⁶, ²², ²³, ²⁴ In order to use the FLC assay to monitor disease progression, the baseline FLC ratio must be abnormal and the involved FLC level ≥100 mg/L.²⁴, ²⁵

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

Definition

MGUS is defined by the presence of a serum M protein <3 g/dl, bone marrow plasma cells <10%, and absence of anemia, hypercalcemia, lytic bone lesions, or renal failure that can be attributed to the plasma cell proliferative disorder (Table 97.1).²⁶, ²⁷ In the case of IgM MGUS, there should be no evidence of
lymphadenopathy or organomegaly attributable to the clonal lymphoid/plasma cell proliferative disorder. A new subtype of MGUS termed light chain MGUS is defined by the presence of an abnormal FLC ratio (<0.26 or >1.65), elevated level of involved FLC, no immunoglobulin heavy chain (IGH) expression on immunofixation, bone marrow plasma cells <10%, and absence of anemia, hypercalcemia, lytic bone lesions, or renal failure that can be attributed to the plasma cell proliferative disorder (Table 97.1).⁴ A diagnosis of MGUS requires exclusion of plasma cell malignancies (MM, solitary plasmacytoma, and WM), monoclonal immunoglobulin deposition disorders (AL, light chain deposition disease), as well as SMM. In addition to these closely related disorders which are unique progression events, MGUS can be associated with a variety of malignant and nonmalignant disorders where the association between the monoclonal process and the associated disorder can vary from a coincidental finding to a direct paraprotein related syndrome.

TABLE 97.1 DIAGNOSTIC CRITERIA FOR PLASMA CELL DISORDERS

Disorder	Disease Definition	References
Monoclonal gammopathy of undetermined significance (MGUS)	All three criteria must be met: Serum monoclonal protein <3 g/dl Clonal bone marrow plasma cells <10%, and 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; or in the case of IgM MGUS no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.	(275)
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 κ FLC in patients with ratio >1.65 and increased λ FLC in patients with ratio <0.26) No immunoglobulin heavy chain expression on immunofixation Clonal bone marrow plasma cells <10%, and 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; or in the case of IgM MGUS no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.	(4)
Smoldering multiple myeloma (also referred to as asymptomatic multiple myeloma)	Both criteria must be met: Serum monoclonal protein (IgG or IgA) ≥3 g/dl and/or clonal bone marrow plasma cells 10-60%, and Absence of end organ damage such as lytic bone lesions, anemia, hypercalcemia, or renal failure that can be attributed to a plasma cell proliferative disorder	(275)
Multiple myeloma	All three criteria must be met except as noted: Clonal bone marrow plasma cells ≥10% Presence of serum and/or urinary monoclonal protein (except in patients with true nonsecretory multiple myeloma), and Either ≥60% clonal plasma cells in the marrow or evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically Hypercalcemia: Serum calcium ≥ 11.5 mg/dl or Renal insufficiency: Serum creatinine >1.73 mmol/L (or >2 mg/dl) or estimated creatinine clearance less than 40 ml/min Anemia: Normochromic, normocytic with a hemoglobin value of >2 g/dl below the lower limit of normal or a hemoglobin value <10 g/dl Bone lesions: Lytic lesions, severe osteopenia or pathologic fractures	(276, 277)
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%, and No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.	(75, 277, 278, 279, 280)
Smoldering Waldenström macroglobulinemia (also referred to as indolent or asymptomatic Waldenström macroglobulinemia)	Both criteria must be met: Serum IgM monoclonal protein ≥3 g/dl and/or bone marrow lymphoplasmacytic infiltration ≥10%, and No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.	(75, 277, 278, 279, 280, 281)
Waldenström macroglobulinemia	All criteria must be met: IgM monoclonal gammopathy (regardless of the size of the M protein), and ≥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.	(75, 277, 278, 279, 280)
Solitary plasmacytoma	All four 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 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	(81, 282)
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 (possibly using mass spectrometry (MS)-based proteomic analysis, or immunoelectron microscopy; note that immunohistochemistry results to type amyloid may be unreliable), and Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein, abnormal free light chain 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.	(283)
POEMS syndrome	All four criteria must be met Polyneuropathy Monoclonal plasma cell proliferative disorder (almost always λ) Any one of the following three other major criteria: Sclerotic bone lesions Castleman’s disease Elevated levels of vascular endothelial growth factor (VEGF)^a Any one of the following six minor criteria Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) Extravascular volume overload (edema, pleural effusion, or ascites) Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)^b Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails) Papilledema Thrombocytosis/polycythemia	(137, 284)
FLC, free light chain.
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.
^aThe 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 ^bIn order to consider endocrinopathy as a minor criterion, an endocrine disorder other than diabetes or hypothyroidism is required inasmuch as these two disorders are common in the general population
Modified from Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3-9.

Epidemiology

Prevalence

MGUS is the most common plasma cell proliferative disorder (Fig. 97.2). The prevalence of MGUS has been estimated in a large population-based study that included 21,463 of the 28,038 enumerated residents (77%) of Olmsted County, Minnesota, who were 50 years or older.³ MGUS was identified in 694 (3.2%) of these subjects. Age-adjusted rates were greater in men than in women, 4.0% versus 2.7% (P < 0.001; Fig. 97.3). The prevalence of MGUS was 5.3% among persons 70 years or older and 7.5% among those 85 years or older. Several other studies have reported similar prevalence estimates (Table 97.2).²⁸ In addition, approximately 1% of the general population over the age of 50 have light chain MGUS.⁴

The incidence of M proteins is higher in blacks than in whites. In the study by Cohen et al., the prevalence of an M protein was 8.4% in 916 blacks and 3.6% in whites.²⁹ Landgren et al., in a study of 4 million African American and white males admitted to Veterans Affairs Hospitals, found that the prevalence of MGUS was 0.98% in African Americans and 0.4% in whites.³⁰ The age-adjusted prevalence ratio of MGUS in African Americans compared with whites was 3.0 (95% confidence interval, 2.7 to 3.3). The increase of MGUS in blacks may be related to genetic or environmental factors. A population-based study found that the increased risk of MGUS seen in African Americans was also seen in blacks in Ghana, suggesting that the racial disparity may be due more to genetic factors.³¹

Furthermore, a study of women in the southern part of the United States found that the racial disparity between blacks and whites persisted even after adjusting for socioeconomic status, again suggesting that the differences were more likely genetic rather than environmental.³²

FIGURE 97.1. Monoclonal (M) protein on serum protein electrophoresis. Note tall, narrow-based peak of fast γ mobility (A). Immunofixation of serum with antisera to immunoglobulin G (IgG), IgA, IgM, κ, and λ shows a localized band with IgG and κ, indicating an IgG κ monoclonal protein (B).

One study found that only 2.7% of elderly Japanese patients had a monoclonal gammopathy.³³ A subsequent population-based study in Japan found that the risk of MGUS was lower compared with the white population of Olmsted County.³⁴

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.³⁵ The rates for women are 60/100,000 at age 50, and 370/100,000 at age 90. The fact that the increased prevalence of MGUS with rising age is not just related to accumulation of new cases but due to an actual increase in incidence suggests that an age-related cumulative damage model is at play in the pathogenesis of MGUS.

Risk Factors

The incidence and prevalence of MGUS rises with age.³, ³⁵ MGUS is also more common in males. Blacks have a higher risk of MGUS than whites as discussed above.²⁹, ³⁰, ³¹, ³², ³⁶ In addition to age, race, and gender, there are other risk factors that have been identified, both genetic and environmental. First-degree relatives of patients with MGUS and MM have a two- to threefold higher risk of MGUS compared to those with no known affected relatives.³⁷, ³⁸, ³⁹ Obesity and immunosuppression are also known risk factors for MGUS.³², ⁴⁰, ⁴¹

FIGURE 97.2. Distribution of 1,733 cases of monoclonal gammopathy seen at the Mayo Clinic in 2011. MGUS, monoclonal gammopathy of undetermined significance.

Pathophysiology

MM is almost always preceded by the asymptomatic pre-malignant MGUS stage.⁴², ⁴³ For the screening arm of the nationwide population-based prospective prostate, lung, colon, ovarian (PLCO) cancer screening trial, annual blood samples were collected on 77,469 healthy adults. From this cohort, a joint study by the National Cancer Institute and the Mayo Clinic identified 71 individuals who developed MM during the course of the study. Serial serum samples (up to 6) obtained 2.0 to 9.8 years prior to MM diagnosis were then studied. The study found that an asymptomatic MGUS phase always preceded MM and was found in 100% of cases 6 years prior to MM.⁴²

The events responsible for malignant transformation of MGUS to MM or a related plasma cell proliferative disorder are unknown. Genetic changes, bone marrow angiogenesis, various cytokines related to MM bone disease, and infectious agents may play a role in the progression of MGUS to MM or a related disorder.⁴⁴, ⁴⁵ However, the specific role of these alterations is not well understood.

Initiation of the Clone

The precise sequence of events that leads to the initiation of the MGUS clone are not known. However, antigenic stimulation and/or immunosuppression are thought to be predisposing factors. Toll-like receptors (TLRs) are normally expressed by B lymphocytes, and are essential for these cells to recognize infectious agents and pathogen-associated molecular patterns (PAMP) which then initiate the host-defense response.⁴⁶, ⁴⁷, ⁴⁸ The aberrant expression of TLRs by plasma cells may be an initiating event that causes these cells to respond abnormally to TLR-specific ligands resulting in increased MM cell proliferation, survival, and resistance to apoptosis, mediated in part by autocrine interleukin-6 (IL-6) production.⁴⁶, ⁴⁷

Immunosuppression may also contribute to the initiation of monoclonal gammopathies inhibiting tumor surveillance.

Monoclonal proteins are known to arise in the context of immunosuppressive states such as bone marrow or stem cell transplantation (SCT), organ transplantation, and human immunodeficiency virus (HIV) infection.⁴⁰, ⁴¹, ⁴⁹, ⁵⁰, ⁵¹ Moreover, patients undergoing renal transplantation develop monoclonal proteins dependent on the level of immunosuppression to which they are subjected.⁴¹

FIGURE 97.3. Prevalence of monoclonal gammopathy of undetermined significance, according to age. Of 21,463 residents 50 years of age or older, 694 had a monoclonal protein. The I bars represent 95% confidence interval. Years of age older than 90 have been condensed to 90 years of age (χ-axis). (From Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362-1369. Used with permission.)

Cytogenetic Changes

Cytogenetic changes are common in MM and in MGUS. On the basis of fluorescence in situ hybridization studies, almost all patients with MM have either IGH translocations involving chromosome 14q32 or trisomies. These cytogenetic changes referred to as “primary cytogenetic abnormalities” are also are present in MGUS.⁵² Thus, approximately 50% of patients with MGUS have primary translocations on chromosome 14q32 (IgH translocated MGUS/SMM).⁵², ⁵³ The most common partner chromosome loci are 11q13, 4p16.3, 6p21, 16q23, and 20q11.⁵⁴, ⁵⁵, ⁵⁶ These translocations lead to the dysregulation of oncogenes such as CCND1 (cyclin D1) (11q13), FGFR3/WHSC1 (fibroblastic growth factor receptor 3/Wolf-Hirschhorn syndrome candidate; 4p16.3), CCND3 (cyclin D3; 6p21), MAF (16q23), and MAFB (20q11). The dysregulation of these oncogenes is thought to be critical for the initiation of the MGUS clone rather than progression of MGUS to MM. Approximately 40% of patients (40%) with MGUS have trisomies of odd-numbered chromosomes leading to hyperdiploidy (IgH nontranslocated MGUS). In a small subset, there are likely both IgH translocations and trisomies, and in some neither abnormality can be detected.

TABLE 97.2 PREVALENCE OF MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)

Study	Diagnostic Criteria	Number of MGUS Cases	Sample Size	Overall Prevalence (95% CI)
Aguzzi et al.²⁸⁵	M protein <30 g/L No evidence of B-cell lymphoproliferative disorder	1,015	35,005	2.9
Anagnostopoulos et al.²⁸⁶	M protein <30 g/L Bone marrow <10% No end organ damage	60	1,564	4.0
Axelsson et al.⁶	M protein <30 g/L Bone marrow smear No end organ damage	64	6,995	0.9
Carrel et al.²⁸⁷	M protein <30 g/L Bone marrow <10% No end organ damage	7	2,192	0.3
Cohen et al.²⁹	M protein <30 g/L No end organ damage	106	1,732	6.1
Iwanaga et al.³⁴	M protein <30 g/L Bone marrow <10% No end organ damage	1,088	52,781	2.1 (1.9 to 2.2)
Kyle et al.²⁸⁸	M protein <30 g/L Bone marrow <10% No end organ damage	15	1,200	1.3
Kyle et al.³	M protein <30 g/L No end organ damage	694	21,643	3.2 (3.0 to 3.5)
Landgren et al.³⁰	M protein <30 g/L No end organ damage	2,046	3,997,815	.05
Landgren et al.³¹	M protein <30 g/L No end organ damage	54	917	5.8 (4.3 to 7.4)
Malacrida et al.²⁸⁹	M protein <30 g/L No end organ damage	261	102,000	0.3
From Wadhera RK, Rajkumar SV. Prevalence of monoclonal gammopathy of undetermined significance: a systematic review. Mayo Clin Proc 2010;85:933-942.

Deletions of chromosome 13 have been found to have an adverse prognostic value in MM. However, this cytogenetic abnormality occurs early in the disease pathogenesis and present in the MGUS stage.⁵⁷, ⁵⁸ Although deletions of chromosome 13 confer an adverse effect on MM, there are no data that the rate of progression from MGUS to MM is accelerated because of this abnormality. K- and N–RAS mutations and deletion of 17p are uncommon in MGUS in contrast to MM.⁵⁹

Angiogenesis

Bone marrow angiogenesis is increased in MM and has prognostic value.⁶⁰ In a study of 400 patients with a spectrum of plasma cell disorders, the median microvessel density (in vessels per high-power field) was 1.3 in the 42 normal controls, 1.7 in AL, 3 in MGUS, 4 in SMM, 11 in MM, and 20 in relapsed MM.⁶¹

Thus bone marrow angiogenesis increases progressively from the pre-malignant MGUS stage to advanced MM. Using a chick embryo chorioallantoic membrane angiogenesis assay, Vacca et al. reported that 76% of MM bone marrow samples had increased angiogenic potential compared with 20% of MGUS samples.⁶² Their findings suggest that increased angiogenesis may play a role in progression of MGUS to MM.

Cytokines

There is overexpression of CD126 (IL-6 receptor α-chain) in MGUS compared to normal plasma cells.⁶³, ⁶⁴ IL-6 is a major growth factor for plasma cells and may therefore play a role in the clonal proliferation of plasma cells in MGUS. Another cytokine that is of importance is IL-1β. IL-1β is produced by plasma cells in all patients with MM, but is undetectable in most patients with MGUS.⁶⁵ IL-1β has strong osteoclast-activating factor activity, increases the expression of adhesion molecules, and induces paracrine IL-6 production. This activity parallels the development of osteolytic bone lesions, homing of MM cells to bone marrow, and IL-6-induced cell growth.⁶⁶, ⁶⁷

As the MGUS clone evolves with additional cytogenetic abnormalities and changes in the microenvironment, there is overexpression of receptor activator of nuclear factor-κB ligand (RANKL) by osteoblasts (and possible plasma cells) and macrophage inflammatory protein 1-α (MIP 1-α ) by plasma cells.⁶⁸, ⁶⁹ Furthermore, there is a reduction in osteoprotegerin, the decoy receptor for RANKL. This leads to osteoclast activation and bone resorption. In addition, increased dickkopf 1 (DKK-1) expression by MM cells is felt to play a major role in simultaneous suppression of osteoblasts and new bone formation.⁷⁰ This combination of factors is thought to be critical for development of lytic bone lesions in MM.

Clinical Features

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. Thus, MGUS is usually detected during the work-up of 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 is also 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.

Most cases of MGUS remain undiagnosed due to the asymptomatic nature of the condition. At age 60, the proportion of prevalent cases that are clinically recognized is only 13%.³⁵ This rate rises to 33% at age 80. When MGUS is first diagnosed, it is estimated that the condition has already been present in an undiagnosed form for a median duration of over 10 years.³⁵

For example, it is estimated that 56% of women age 70 diagnosed with MGUS have had the condition for over 10 years, including 28% for over 20 years. Corresponding values for men are 55% and 31%, respectively.

TABLE 97.3 CLASSIFICATION OF MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

Type	Risk of Progression
Non-IgM MGUS^a	1% per year risk of progression to multiple myeloma, AL amyloidosis, or related disorder
IgM MGUS^b	1.5% per year risk of progression to Waldenström macroglobulinemia; rare patients can progress to IgM multiple myeloma
Light chain MGUS^c	Risk of progression to light chain myeloma and AL amyloidosis. Rate of progression not defined.
IgM, immunoglobulin M; MGUS, monoclonal gammopathy of undetermined significance
^aAlmost all patients are IgG or IgA type. Occasional patients may have IgD or IgE monoclonal proteins. ^bNote that conventionally IgM MGUS is considered a subtype of MGUS. Thus, when the term MGUS is used, in general, it includes IgM MGUS. ^cBecause light chain MGUS was only defined in 2010, studies pertaining to MGUS prior to that time do not include patients with this entity; unless otherwise specified studies since then may also not include patients with light chain MGUS.
From Rajkumar SV. Preventive strategies in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Am J Hematol 2012;87:453-454.

There are three distinct categories of MGUS each with a different mode of progression: IgM MGUS, non-IgM MGUS, and light chain MGUS, each with a different mode and risk of progression (Table 97.3).⁴, ⁷, ⁷¹

Prognosis

Mayo Clinic Referral Population

The prognosis of MGUS was first established in a study of 241 patients seen at the Mayo Clinic from 1956 through 1970.¹ The actuarial rate of progression to MM or related disorder at 10 years was 17%; at 20 years, 34%; and at 25 years, 39% (Fig. 97.4).⁷² Of the 64 patients with progression, 44 (69%) had MM.

FIGURE 97.4. Actuarial analysis of incidence of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoproliferative disease after recognition of monoclonal protein in 241 patients with monoclonal gammopathy of undetermined significance. (From Kyle RA, , Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ 3rd. Long-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: the original Mayo Clinic series 25 years later. Mayo Clin Proc 2004;79:859-866.)

Southeastern Minnesota Study

The risk of progression has also been estimated in a larger population-based study of 1,384 persons with MGUS who resided in the 11 counties of southeastern Minnesota, the risk of progression of MGUS to MM or related disorder was found to be 1% per year.² The median age at diagnosis of MGUS was 72 years. The M-protein level at diagnosis ranged from unmeasurable to 3.0 g/dl. On the basis of the heavy-chain type of immunoglobulins, 70% of the M proteins were IgG, 12% IgA, and 15% IgM. A biclonal gammopathy was found in 45 patients (3%). The light chain type was κ in 61% and λ in 39%. A reduction of uninvolved (normal or background) immunoglobulins was found in 38% of 840 patients in whom quantitation of immunoglobulins was determined. The 1,384 patients in this study were followed up for a total of 11,009 person-years (median, 15.4 years; range, 0 to 35 years). During follow-up, MM, primary AL, lymphoma with an IgM serum M protein, WM, plasmacytoma, or chronic lymphocytic leukemia developed in 115 patients (8%). The cumulative probability of progression to one of these disorders was 10% at 10 years, 21% at 20 years, and 26% at 25 years (Fig. 97.5). Patients were at risk for progression even after 25 years or more of stable MGUS. Although the risk of progression is 1% per year, it must be emphasized that this does not take into account other competing causes of death in elderly patients. After adjusting for competing causes of death, the true lifetime probability of progression of MGUS for the average patient is only approximately 10% (Fig. 97.6).

The number of patients with progression to a plasma cell disorder (115 patients) was 7.3 times the number expected on the basis of the incidence rates for those conditions in the general population (Table 97.4). The risk of MM developing was increased 25-fold; WM, 46-fold; and AL amyloidosis, 8.4-fold. The risk of development of lymphoma was only modestly increased at 2.4, but this risk was underestimated because only lymphomas associated with an IgM protein counted in the observed number, whereas the incidence rates for lymphomas associated with IgG, IgA, and IgM proteins were used to calculate the expected number. The risk of development of chronic lymphocytic leukemia was only slightly increased.

FIGURE 97.5. Probability of disease progression among 1,384 residents of southeastern Minnesota in whom monoclonal gammopathy of undetermined significance (MGUS) was diagnosed from 1960 through 1994. The top curve shows the probability of progression to a plasma cell cancer (115 patients) or of an increase in the monoclonal protein concentration to more than 3 g/dl or in the proportion of plasma cells in the bone marrow to more than 10% (32 patients). The bottom curve shows only the probability of progression of MGUS to multiple myeloma, IgM lymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma (115 patients). The error bars indicate 95% confidence intervals. (From Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis of monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-569. Used with permission.)

FIGURE 97.6. The risk of progression to myeloma or related disorder in 1,148 patients with monoclonal gammopathy of undetermined significance. The upper curve illustrates risk of progression of all patients without taking into account competing causes of death. The lower curve illustrates risk of progression after accounting for other competing causes of death. (From Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance (MGUS) Blood 2005;106;812—817. © the American Society of Hematology.)

The 75 patients in whom MM developed accounted for 65% of the 115 patients who had progression to a plasma cell disorder. The mode of development of MM among the patients with MGUS was variable. The M-protein level increased within 2 years of the recognition of MGUS in 11 patients, whereas the serum M-protein level was stable for more than 2 years and then increased within 2 years in 19 patients; in 9 others, the M-protein level increased gradually after having been stable for at least 2 years. In 9 patients, the M-protein level increased gradually during
follow-up until the diagnosis of symptomatic MM was made.

In 10 patients, the serum M-protein level remained essentially stable; the diagnosis of MM was unequivocal in these 10 patients because of an increase in bone marrow plasma cells, development of lytic lesions, or occurrence of anemia, renal insufficiency, or an increased level of urine M protein. Seventeen patients had an insufficient number of serum M-protein measurements to determine the pattern of increase. In patients with WM, the M-protein level showed a gradual increase in 3, stable levels were followed by a sudden increase in 2, and data were insufficient in 2.

TABLE 97.4 RISK OF PROGRESSION AMONG 1,384 RESIDENTS OF SOUTHEASTERN MINNESOTA IN WHOM MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE WAS DIAGNOSED, 1960-1994

	No. of Patients		Relative Risk
Type of progression	Observed	Expected^a	(95% CI)
Multiple myeloma	75	3.0	25.0 (20-32)
Lymphoma^b	19	7.8	2.4 (2-4)
Primary amyloidosis	10	1.2	8.4 (4-16)
Macroglobulinemia	7	0.2	46.0 (19-95)
Chronic lymphocytic leukemia^c	3	3.5	0.9 (0.2-3)
Plasmacytoma	1	0.1	8.5 (0.2-47)
Total	115	15.8	7.3 (6-9)
CI, confidence interval.
^aExpected numbers of cases were derived from the age- and sex-matched white population of the Surveillance, Epidemiology, and End Results program in Iowa except for primary amyloidosis. ^bAll 19 patients had serum IgM monoclonal protein. If the 30 patients with IgM, IgA, or IgG monoclonal protein and lymphoma were included, the relative risk would be 3.9 (95% CI, 2.6-5.5). ^cAll 3 patients had serum IgM monoclonal protein. If all 6 patients with IgM, IgA, or IgG monoclonal protein and chronic lymphocytic leukemia were included, the relative risk would be 1.7 (95% CI, 0.6-3.7).
From Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis of monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-569. (Used with permission.)

Spontaneous disappearance of M protein after the diagnosis of MGUS was rare.² The M protein disappeared without an apparent cause in 27 patients (2%), and only 6 of these 27 patients (0.4% of all patients) had a discrete spike on the densitometer tracing of the initial electrophoresis (median, 1.2 g/dl); the rest had small M proteins detected on immunofixation only.

Follow-up in Other Series

The risk of progression of MGUS has been estimated in several other studies, and the results mirror those seen in the Southeastern Minnesota study. For example, Baldini et al. noted that 6.8% of 335 patients with MGUS had progression during a median follow-up of 70 months.⁷³ In the Danish Cancer Registry, 64 new cases of malignancy (5 expected; relative risk, 12.9) were found among 1,229 patients with MGUS.⁷⁴

Prognostic Factors

No findings at 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.

Size of M Protein

The size of the M protein at recognition of MGUS is one of the most important predictors for the risk of progression. In the study of 1,384 patients from Southeastern Minnesota, the risk of progression to MM or a related disorder 10 years after diagnosis of MGUS was 6% for patients with an initial M-protein level of 0.5 g/dl or less, 7% for 1 g/dl, 11% for 1.5 g/dl, 20% for 2 g/dl, 24% for 2.5 g/dl, and 34% for 3.0 g/dl.²

Corresponding rates for progression at 20 years were 14%, 16%, 25%, 41%, 49%, and 64%, respectively. The risk of progression in a patient with an M-protein level of 1.5 g/dl was almost twofold greater than that in a patient with an M-protein level of 0.5 g/dl, and the risk of progression in a patient with an M-protein level of 2.5 g/dl was 4.6 times that of a patient with a 0.5-g/dl spike.

Type of M Protein

Patients with an IgM or IgA M protein have a higher risk of progression compared with those with an IgG M protein.² IgM MGUS is a unique subtype of MGUS in which patients are at risk of progression to WM rather than MM.⁷⁵ Due to a confusion in terminology, some patients with WM are referred to as having non-Hodgkin lymphoma or lymphoplasmacytic lymphoma (a term commonly used by pathologists to describe the bone marrow findings of patients with WM). Rarely do patients with IgM MGUS evolve into IgM MM.⁷¹ Among 213 patients in the Southeastern Minnesota MGUS study, 23 developed “non-Hodgkin lymphoma” or WM, 3 developed chronic lymphocytic leukemia, and 3 developed AL amyloidosis.⁷⁵ The risk of progression was 1.5% per year. The risk of progression of light chain MGUS relative to IgA, IgG, or IgM MGUS is not known.

Bone Marrow Plasma Cells

Cesana et al. have found that patients with MGUS who have 5% to 9% bone marrow plasma cells have a higher risk of progression compared with those with <5% bone marrow plasma cells.⁷⁶ Of 1,104 patients with MGUS in this study, at a median follow-up of 65 months, 64 MGUS cases (5.8%) evolved to MM or related plasma cell disorder. Patients with greater than 5% marrow plasmacytosis had a significantly higher risk of progression compared to those with 5% or fewer plasma cells, 1.35 versus 0.64 per 100 person years, respectively, P = 0.004.

Abnormal Serum-Free Light Chain Ratio

An abnormal FLC ratio is an independent risk factor for progression of MGUS. In a study of 1,148 patients with MGUS, 379 (33%) had an abnormal FLC ratio.¹⁹ The risk of progression in patients with an abnormal FLC ratio was significantly higher than that in patients with a normal ratio (hazard ratio 3.5; P < 0.001) and was independent of the size and type of serum M protein (Fig. 97.7). The production of excess monoclonal FLC in MGUS may be a biomarker for plasma cells bearing a higher degree of cytogenetic abnormalities thereby serving as a biomarker for a higher risk of progression.

Risk Stratification

A risk-stratification model can be used to predict risk of progression in MGUS, and is useful for management.¹⁹ The model is based on the size and type of the M protein and the FLC ratio (Table 97.5). Patients with all three risk factors consisting of an abnormal serum FLC ratio, IgA or IgM MGUS, and an increased serum M-protein value (≥1.5 g/dl) have a risk of progression at 20 years of 58%, whereas the risk is 37% with any two risk factors present, 21% with one risk factor present, and 5% when none of the risk factors are present. When competing causes of death were
taken into account, the risk of progression in the low risk group is only 2% at 20 years.

FIGURE 97.7. Risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to myeloma or related disorder. The top curve illustrates the risk of progression with time in patients with three risk factors: abnormal serum κ:λ free light chain (FLC) ratio (<0.26 or >1.65), a high serum monoclonal (M)-protein level (≥1.5 g/dl), and non-IgG MGUS. The second curve is the risk of progression in patients with any two of these risk factors. The third curve illustrates the risk of progression with one of these risk factors. The bottom curve is the risk of progression for patients with none of the risk factors. (From Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance (MGUS) Blood 2005;106;812—817. © the American Society of Hematology.)

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