Routine screening for monoclonal gammopathy of undetermined significance (MGUS) is not indicated. Despite this fact, MGUS is a common finding in medical practice. Almost all individuals diagnosed with MGUS represent incidental cases diagnosed when physicians order serum protein electrophoresis, immunofixation, or both, as part of the work-up of a number of common symptoms and laboratory abnormalities. In the absence of reliable molecular predictors of outcome, the detection of an early precursor state typically imposes a complex situation for the patient and the responsible physician—usually, it leads to a lot of questions that lack clear answers. In the past years, several novel insights have been gained in the area of multiple myeloma (MM) precursor disease. This review focuses on results from recent investigations and discusses implications for diagnostic work-up, clinical management, and patient counseling. More specifically, it sheds light on the following commonly asked questions by patients and physicians: i) what is the risk of progression from precursor to full-blown MM, and are there ways to risk-stratify patients?; ii) is MM always preceded by a precursor state, and is there anything that could or should be done to delay or prevent progression?; and iii) why do some individuals develop MM precursor diseases, and is there a reason to screen the family?

From ‘Benign Monoclonal Protein’ to Monoclonal Gammopathy of Undetermined Significance

The concept of monoclonal versus polyclonal gammopathies was initially raised in 1960 by Jan Waldenström,1  who described patients with a narrow band of hypergammaglobulinemia on electrophoresis as having a monoclonal—or M—protein. Many of these patients had multiple myeloma (MM) or macroglobulinemia, while others had no evidence of malignancy. Waldenström considered these patients to have “essential hypergammaglobulinemia” or a “benign monoclonal protein.”

Based on the observation that otherwise healthy individuals with these protein abnormalities turned out to have an excess risk of developing MM, Waldenström's macroglobulinemia, light-chain amyloidosis, or related disorders, Robert Kyle coined the term “monoclonal gammopathy of undetermined significance” (MGUS) in 1978.2  According to diagnostic criteria provided by the International Myeloma Working Group (IMWG) in 2010,3  MGUS is defined as follows (and all three criteria must be met): i) serum monoclonal protein under 3 g/dL; ii) clonal bone marrow plasma cells under 10%; and iii) absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions that can be attributed to the plasma-cell-proliferative disorder.

Screening studies have found MGUS to be present in approximately 3.2% of Caucasians above the age of 50 years.4  Prevalence appears to be roughly twice as high among African men, African-American women, and obese individuals.5,6  Chronic antigen stimulation7–11  and pesticide exposure have also been associated with an excess risk of MGUS/MM.12,13  Recently, a large population-based study found a 2-fold increased relative risk for MM among 37,838 first-degree relatives of 13,896 MM patients (compared with 151,068 first-degree relatives of 54,365 matched controls).14  Similarly, a 3-fold-increased relative risk for both MGUS and MM was found among 14,621 first-degree relatives of 4458 MGUS patients (compared with 58,387 first-degree relatives of 17,505 matched controls).15  These observations support a role for both susceptibility genes and immune-related factors in the causation of MGUS and MM.6–17 

Although MGUS is commonly referred to as single entity in the literature, lymphoid (or lymphoplasmacytoid) MGUS and plasma-cell MGUS have distinct differences both in the clinic and in the laboratory. About 15% to 20% of MGUS tumors secrete IgM, and mostly they have a lymphoid or lymphoplasmacytoid phenotype; non-IgM (IgG>IgA>light chain Ig only>IgD>IgE) MGUS tumors have a plasma-cell phenotype.18  Primary amyloidosis belongs to the plasma-cell MGUS category, although it is characterized by pathological deposits in various tissues of monoclonal Ig light-chain fragments produced by MGUS tumors, which often include only a small number of premalignant tumor cells.18 

Typically, plasma-cell MGUS tumors can progress to MM or related plasma-cell disorders, whereas lymphoid MGUS tumors progress to Waldenström's macroglobulinemia, lymphoma, or other malignant lymphoproliferative disorders.19,20  Furthermore, there is virtually no overlap of the molecular genetic events responsible for the molecular pathogenesis of the two kinds of MGUS, suggesting that lymphoid and plasma-cell MGUS are distinct biological entities.21 

From ‘Multiple Myeloma Without a Progressive Course’ to Smoldering Multiple Myeloma

In 1980, Kyle was the first to describe smoldering MM (SMM) as a distinct entity—an “illness that met the criteria of MM but has not had a progressive course,” a corollary to smoldering leukemia.22  Based on six patients, he found all cases to have ≥10% bone marrow plasma cells and ≥3 g/dL of M protein without progression to MM for at least 5 years.22  Since this initial description, the diagnostic criteria for SMM have evolved. In fact, several studies of SMM have been completed using criteria ranging from including patients with mild anemia, requiring M protein less than 4.5 g/dL, marrow plasma cells above 15%, ignoring percent marrow plasma cells entirely, and requiring Bence-Jones proteinuria.23–25  Furthermore, many studies have included separate definitions of SMM and indolent MM (IMM), with IMM being described as either a “mildly symptomatic” form of MM or a form of MM in which minimal end-organ damage was clinically evident even though the patient did not report any symptoms. For example, in some studies, patients with lytic bone lesions noted on imaging who had not yet suffered a pathologic fracture were classified as having IMM.23,26  Commonly, SMM and IMM patients have been combined into the entity of asymptomatic MM, while in some studies SMM and asymptomatic MM were considered equivalent.23,24,27  Due to these varying definitions, one has to be cautious when assessing results across different studies. In fact, it is very problematic to compare SMM data collected prior to 2003, the year that the International Myeloma Working Group (IMWG) released a consensus on the specific diagnostic criteria for the known monoclonal gammopathies.28 

According to the 2010 IMWG diagnostic criteria, SMM is defined as follows (and both criteria must be met): i) serum monoclonal protein (IgG or IgA) ≥3g/dL and/or clonal bone marrow plasma cells ≥10%, and ii) 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. The IMWG guidelines do not include a definition of IMM, and the term has fallen out of use; instead, such patients meet IMWG criteria for MM.28  In the current literature, asymptomatic MM is now synonymous with SMM.28 

Interestingly, excess bone resorption measured by quantitative bone biopsy and biomarkers of bone turnover suggest that bone disease not detectable by skeletal survey is present even in some MGUS patients.29,30  This finding may explain the previously reported excess risk of bone fractures in MGUS patients independent of malignant transformation.31–33  Along the same lines, smaller studies have used magnetic resonance imaging (MRI) in patients otherwise defined as having SMM, and found occult bone lesions in some patients.34  Based on a hospital-based series of 72 SMM patients showing that those with an abnormal MRI of the spine had a shorter time to MM progression, the 2010 IMWG guidelines state the following: “an MRI of the spine and pelvis is recommended because it can detect occult lesions and, if present, predict for a more rapid progression to symptomatic myeloma.”28 

It is important to keep in mind that clinical criteria for end-organ damage are highly dependent on the sensitivity and specificity of the methods used to detect the damage. Most likely, the definition of end-organ damage will change in the coming years as imaging technology and molecular markers improve, and this will have a direct impact on the clinical management of patients diagnosed with MM precursor disease in the future.

Risk of Progression to Multiple Myeloma

Although for the individual patient it is currently not possible to predict whether the underlying MGUS will remain benign or transform to MM, from a population standpoint the significance of MGUS has been well characterized. Based on data from the Mayo Clinic, long-term follow-up of MGUS patients reveals an average 1% annual risk of developing a lymphoproliferative malignancy.19,20  Given these facts, once diagnosed, patients must be appropriately counseled that MGUS is a premalignant entity with a relatively low risk of progression to MM or related malignancies. In addition to malignant transformation, MGUS patients also have a higher risk of several pathologic conditions, including fractures31–33  and deep vein thrombosis.35,36  In fact, these recent findings suggest that osteoclastic activation and hypercoagulation occur early in the pathogenesis of plasma-cell neoplasia rather than abruptly in early MM,31–33,35,36  supporting the development of future clinical studies aimed at developing prophylaxis for fractures and thrombosis among MGUS patients at high risk. Furthermore, recent data suggest that MGUS patients (compared with the general population) have a significantly reduced life expectancy and an excess risk of dying from bacterial infections and heart, liver, and renal diseases,37  although this may be related to the various underlying medical conditions that led to the detection of the MGUS in the first place.

In the first and largest systematic study focusing on SMM, retrospective data from 276 patients seen at the Mayo Clinic between 1970 and 1995 were collected. In that study, SMM patients had a 10% average annual risk of progression to MM for the first 5 years following diagnosis, decreasing to 3% annually for the following 5 years, and then lowering to the same 1% annual rate of progression as MGUS thereafter.38 

As already mentioned, we lack reliable, biological predictors of progression from MGUS/SMM to MM. In the absence of such markers, MGUS and SMM patients are currently being risk-stratified based on a few selected clinical variables that have been identified in epidemiological studies. To date, two major models have been proposed: the Mayo Clinic38,39  and the Spanish PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatía Maligna)40  risk-stratification models (Table 1).

The Mayo Clinic model focuses largely on serum protein abnormalities. For MGUS patients, the following features are considered to be adverse risk factors: non-IgG isotype, M-protein concentration over 1.5 g/dL, and an abnormal serum free light chain (FLC) ratio (normal reference 0.26–1.65).39  In this model, at 20 years of follow-up, MGUS patients with all three risk factors have, on average, an absolute risk of MM progression of 58%; for MGUS patients with two, one, and none of these risk factors, the corresponding absolute risk is 37%, 21%, and 5%, respectively.39  For SMM patients, the following features are considered to be adverse risk factors: ≥3 g/dL M-protein, an FLC ratio outside the reference range of 0.125 to 8, and ≥10% bone marrow plasma cells.38,41  At 5 years of follow-up, SMM patients with all three risk factors have, on average, a cumulative risk of MM progression of 76% (median time-to-progression [TTP] was 1.9 years); for patients with two or one risk factors, the corresponding risk was 51% (median TTP, 5.1 years) and 25% (median TTP, 10 years), respectively.38,41 

The Spanish model uses multiparametric flow cytometry of bone marrow aspirates to differentiate aberrant from normal plasma cells.40  Plasma cells characteristically express CD138 and intense (bright) CD38. The features of aberrant plasma cells include decreased CD38 expression, expression of CD56, and the absence of CD19 and/or CD45. In 93 SMM and 407 MGUS patients, the percentage of phenotypically aberrant plasma cells and total bone marrow plasma cells at diagnosis allowed risk stratification of MGUS and SMM patient's progression to overt MM. In their study, MGUS and SMM patients with ≥ 95% aberrant plasma cells/bone marrow plasma cells at diagnosis had a significantly higher risk of MM progression.40  Furthermore, on multivariate analysis, ≥95% aberrant plasma cells/bone marrow plasma cells, DNA aneuploidy, and immunoparesis were found to be independent predictors of MM progression. More specifically, for MGUS patients with no, one, or two risk factors (≥95% aberrant plasma cells/bone marrow plasma cells and DNA aneuploidy), the risk of progression at 5 years was 2%, 10%, and 46%, respectively. For SMM patients (risk factors: ≥95% aberrant plasma cells/bone marrow plasma cells and immunoparesis) the corresponding risks at 5 years were 4%, 46%, and 72%, respectively.40 

Overall it seems reasonable to argue that MGUS cases with higher risk may benefit from annual follow-up of the M protein in addition to their usual medical care. Although the value of this has not been proven, the test is simple and worth doing, considering that MM can present with devastating bone complications that may be preventable in some patients if a significant rise in the M protein is detected in time. For SMM patients, the annual risk of MM progression is high and close monitoring has been the standard for several years.

Clearly, we need better markers to define high-risk (versus low-risk) MGUS/SMM and to better predict individual risk of MM progression. Until such markers are available, the 2010 IMWG guidelines suggest up-front risk stratification and more individualized clinical follow-up based on the above-mentioned Mayo Clinic risk-stratification model.28 

In brief, the 2010 IMWG guidelines state that “low-risk MGUS” patients (M protein under 1.5 g/dL, IgG isotype, and a normal FLC ratio) should be followed with serum protein electrophoresis in 6 months, and if stable can be followed every 2 to 3 years or if symptoms arise.28  For “intermediate-/high-risk MGUS” patients (M protein above 1.5 g/dL, IgA or IgM isotype, or an abnormal FLC ratio), the guidelines state that a bone marrow aspirate and biopsy should be done at baseline to rule out underlying plasma cell malignancy; the patient should be followed with serum protein electrophoresis and a complete blood count in 6 months and then annually for life.28 

For SMM patients, the IMWG guidelines state that a skeletal survey and a bone marrow aspirate and biopsy should be carried out at baseline.28  Laboratory tests and clinical work-up should be done at diagnosis and in 2 to 3 months after the initial recognition of SMM. If the results are stable, the studies should be repeated every 4 to 6 months for 1 year and, if stable, evaluation intervals can be lengthened to every 6 to 12 months; a skeletal survey should be performed if there is evidence of progression.28  Treatment is not indicated unless it is part of a clinical trial.42  For full details regarding the 2010 IMWG guidelines, please see the reference.28 

Using standard chemotherapy in SMM, early treatment has not been found to delay progression to active disease and overall survival.43  The first randomized phase III study using novel drugs (lenalidomide/dexamethasone vs. surveillance) in SMM was presented by the Spanish study group at ASH 2009.44  After a median of about 1.5 years of follow-up, their interim analysis showed the following: in the surveillance arm, the progression rate was similar to historical controls, while in the treatment arm, only two patients had progressed to MM (p < 0.0001). Importantly, due to the short follow-up, the interim analysis was unable to determine if early treatment improves overall survival. Until we know the answer to this important question, we can only speculate whether early treatment has the potential to cure SMM, or if SMM should be classified as a chronic, asymptomatic disease state requiring maintenance therapy (Figure 1). At the same time, we do not know if early treatment may facilitate selection of aggressive clones that are more capable of competing in the treatment-altered microenvironment (Figure 1). Because none of these scenarios has been proven true, it is very important to conduct well-designed correlative studies in clinical trials aimed at treating SMM patients.43 

Figure 1.

Theoretically possible scenarios resulting from early treatment of smoldering myeloma. Progression of untreated high-risk SMM to full-blown MM is shown on the left. SMM patients with two or three risk factors (see Table 1) have a median TTP of 5 and 2 years, respectively. Scenarios 1 to 3 illustrate possible scenarios resulting from early treatment of SMM: Scenario 1 (center left) represents a complete cure of MM, which has not yet been reliably achieved by any current treatment modalities. This would likely require more intense treatment, necessitating improved risk-stratification of patients. Ultimately, targeted therapies may be able to achieve cure. Scenario 2 (center right) represents the generation of a chronic, asymptomatic disease state requiring ongoing maintenance therapy. This is a likely outcome of using immunomodulatory and targeted agents available in the near future. Scenario 3 (right) illustrates the theoretical possibility of the selection of a particularly aggressive, resistant clone. While TTP is extended in this scenario, overall survival may not be improved, because symptomatic disease might progress unchecked if available treatments become less effective following early treatment. Future studies are needed to fully explore these possibilities. Taken together, we do not know which, if any, of these scenarios are true. Therefore, clinical trials aimed at developing treatments for SMM should incorporate well-designed correlative studies to examine the biology of treatment response. (Reprinted with permission from Waxman et al., 2010.43 )

Figure 1.

Theoretically possible scenarios resulting from early treatment of smoldering myeloma. Progression of untreated high-risk SMM to full-blown MM is shown on the left. SMM patients with two or three risk factors (see Table 1) have a median TTP of 5 and 2 years, respectively. Scenarios 1 to 3 illustrate possible scenarios resulting from early treatment of SMM: Scenario 1 (center left) represents a complete cure of MM, which has not yet been reliably achieved by any current treatment modalities. This would likely require more intense treatment, necessitating improved risk-stratification of patients. Ultimately, targeted therapies may be able to achieve cure. Scenario 2 (center right) represents the generation of a chronic, asymptomatic disease state requiring ongoing maintenance therapy. This is a likely outcome of using immunomodulatory and targeted agents available in the near future. Scenario 3 (right) illustrates the theoretical possibility of the selection of a particularly aggressive, resistant clone. While TTP is extended in this scenario, overall survival may not be improved, because symptomatic disease might progress unchecked if available treatments become less effective following early treatment. Future studies are needed to fully explore these possibilities. Taken together, we do not know which, if any, of these scenarios are true. Therefore, clinical trials aimed at developing treatments for SMM should incorporate well-designed correlative studies to examine the biology of treatment response. (Reprinted with permission from Waxman et al., 2010.43 )

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MM is consistently preceded by a precursor state (MGUS). Although it has been known for some time now that MGUS patients have an increased risk of progression to MM and other related malignancies,19,20  it has only been recently that two independent studies have provided convincing evidence to show that virtually all cases of MM are preceded by a precursor state (MGUS).

A recent study based on 77,469 healthy adults enrolled in a U.S. nationwide population-based prospective cancer screening trial identified 71 individuals who developed MM during the course of the study. Median age at MM diagnosis was 70 years; 4.3% were African-Americans. Using serially collected, prediagnostic serum samples obtained up to almost 10 years prior to MM diagnosis, all MM cases were found to be preceded by MGUS.45  In accord with recent observations,46  the median M-protein concentration for the group exhibited a year-by-year increase over time. Two years prior to MM diagnosis, the proportion of MGUS cases with an abnormal FLC ratio was 85%, supporting a role for FLC assays in routine MGUS follow-up. Importantly, when we assessed protein abnormalities in individual patients, the following patterns were observed: in about half the study population, the M-protein concentration and involved FLC ratios showed a year-by-year increase prior to MM diagnosis, while the other half maintained largely stable abnormal serum protein level up to the diagnosis of MM (Figure 2).45  Thus, stable M-protein or FLC levels do not exclude the development of MM. Until better molecular markers for progression to MM are available, clinicians must synthesize clinical measures with routine blood tests (including renal function, hemoglobin, and serum calcium) and serum and urine M-protein markers to monitor MGUS cases.47  Although it remains to be confirmed, it has been speculated that “evolving MGUS” could potentially be an independent marker for an early myeloma with a slow rate of progression.45 

Figure 2.

M-protein concentrations year-by-year over time prior to multiple myeloma. Two major patterns of MGUS prior to multiple myeloma: “evolving MGUS” and “non-evolving MGUS.” In about half the study population, the M-protein concentration and involved FLC-ratio levels showed a year-by-year increase prior to MM diagnosis, while the other half maintained largely stable abnormal serum protein levels up to the diagnosis of MM.45  Currently, we do not know if this represents a genetic switch in the tumor cells, a change in the host, or a combination; neither do we know if these different M-protein concentration patterns represent different biology when MM arises. One might speculate that there could be differences in response to therapy and survival. Future studies need to address these and other related questions. On a clinical note, one has to keep in mind that stable M-protein or FLC levels do not exclude the development of MM development. Until better molecular markers for progression to MM are available, clinicians have to use clinical measures in combination with routine blood tests (including renal function, hemoglobin, and serum calcium) and serum and urine M-protein markers in their monitoring of MGUS patients. (Adapted from Landgren et al., 2009.45 )

Figure 2.

M-protein concentrations year-by-year over time prior to multiple myeloma. Two major patterns of MGUS prior to multiple myeloma: “evolving MGUS” and “non-evolving MGUS.” In about half the study population, the M-protein concentration and involved FLC-ratio levels showed a year-by-year increase prior to MM diagnosis, while the other half maintained largely stable abnormal serum protein levels up to the diagnosis of MM.45  Currently, we do not know if this represents a genetic switch in the tumor cells, a change in the host, or a combination; neither do we know if these different M-protein concentration patterns represent different biology when MM arises. One might speculate that there could be differences in response to therapy and survival. Future studies need to address these and other related questions. On a clinical note, one has to keep in mind that stable M-protein or FLC levels do not exclude the development of MM development. Until better molecular markers for progression to MM are available, clinicians have to use clinical measures in combination with routine blood tests (including renal function, hemoglobin, and serum calcium) and serum and urine M-protein markers in their monitoring of MGUS patients. (Adapted from Landgren et al., 2009.45 )

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Another study evaluated 30 MM cases with available prediagnostic serum stored in the U.S. Department of Defense Serum Repository.48  Because this study took advantage of stored samples from individuals who served in the Army, the patients were younger (median age 48 years); 97% were males and 47% were African Americans. Although there were differences between the two studies with regard to the patients' characteristics, the results were very similar. The military study found that 27 of the 30 (90%; 95% confidence interval 73%–98%) MM patients had had a preceding MGUS diagnosis. Of the three patients with no detectable MGUS preceding the diagnosis of MM, one had only one prediagnostic serum sample available more than 5 years before the MM diagnosis and the other two were found to have IgD MM (a MM subtype with very low levels of monoclonal immunoglobulin secretion) with serum samples available only 3 and 5 years before the diagnosis.

This novel observation from two independent studies45,48  establishes an essential role for MGUS in the pathway to MM. Indeed, the finding that MM is consistently preceded by a precursor state is very important in that it emphasizes the scientific need and clinical potential for future studies designed to define high-risk versus low-risk MM precursor disease, and, importantly, to define underlying mechanisms of progression. Ultimately, such insights will identify novel targets that may be used to delay and prevent MM progression.

On a clinical note, the following is important to keep in mind: while MGUS, SMM, and MM can be differentiated based on clinical diagnostic parameters,28  it is unfortunate that, at this time, there are no definitive molecular or immunophenotypic markers to differentiate the plasma cells of these three different types (Figure 3).49,50  Likewise, none of the known MM genetic abnormalities defined by karyotyping or interphase fluorescence in situ hybridization (FISH) been found to predict progression from MGUS/SMM to MM. Furthermore, two prior FISH-based studies were unable to find any significant cytogenetic differences between MGUS and SMM patients.51,52  Indeed, in 2003, an international workshop reviewed various studies and determined that some cytogenetic anomaly is present in virtually all cases of MGUS and SMM; often these changes cannot differentiate MM from its precursors, although some events, such as p53 deletions and mutations or homozygous deletions of p18, are far more prevalent in highly aggressive, refractory, or extramedullary MM.49,53 

Figure 3.

The clinical dilemma of smoldering myeloma. (Reprinted with permission from Waxman et al., 2010.43 )

Figure 3.

The clinical dilemma of smoldering myeloma. (Reprinted with permission from Waxman et al., 2010.43 )

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In research studies designed to uncover myelomagenesis, point-mutation analysis has been valuable. Indeed, it has led to the identification of N-RAS and K-RAS mutations with much higher frequencies in patients with MM compared with MGUS, although they are overrepresented in tumors expressing cyclin D1. This indicates that the second, transformational event may vary depending on the initial oncogenic event.54,55  Interestingly, a case report of five annual FISH studies and genomic microarrays performed on a patient who progressed from SMM to MM found a deletion of chromosomal band 1p23 that was correlated with the transformation.56  While other studies have shown a correlation between a gain of chromosomal band 1q and the development of MM,57,58  this finding may open an avenue for future research in this area. Furthermore, karyotype and FISH in this patient displayed a MYC oncogene translocation in the transition from SMM to MM.56  This has previously been found to occur in 15% of MM cases, but only in 3% to 4% of MGUS/SMM cases.59  In further support, gene-expression profiling has shown that MYC RNA expression is significantly higher in MM versus MGUS versus normal plasma cells.60  Thus, there may be an early increase in MYC expression due to epigenetic factors, followed by a further increase due to chromosomal rearrangements.

Research studies focusing on complex interactions in the bone marrow have been carried out using flow cytometry. As discussed above in the section on the Spanish PETHEMA risk-stratification model, characteristic changes in aberrant plasma cells include absent CD19, lack of CD45, decreased CD38, and/or overexpression of CD56.61  A prior investigation found that almost all cases of MM have ≥95% abnormal plasma cells, compared with 60% and 18% of SMM and MGUS cases, respectively.40  Furthermore, a recent gene-expression profiling analysis of bone marrow endothelial cells found differences in gene-expression patterns between MGUS and MM.62  Differences with regard to cellular and secreted components of the microenvironment have also been observed in MGUS compared with MM patients.63  Conversion from precursor to full-blown disease has been proposed to be related to an “angiogenic switch” resulting from an alteration in the milieu of pro- and anti-angiogenic cytokines allowing for malignant proliferation64–66 . Finally, microRNAs, short, noncoding RNA sequences that modulate many biological processes by pairing with target mRNAs and regulating their expression,67  have been implicated as playing a role in myelomagenesis.68 

Based on the above, we currently lack reliable biological markers to either differentiate plasma cells of MGUS, SMM, or MM or to predict progression from MGUS/SMM to MM.49  As discussed above, our current understanding is that progression from precursor to MM is due to both intrinsic changes of plasma cells and the extrinsic influence of bone marrow stromal cells, angiogenesis, and immunologic factors. Malignant transformation is believed to be mediated, at least in part, through antigenic stimulation.69  Much future work is needed to elucidate the role of the microenvironment in the progression from precursor to MM. Studies focusing on the cells of the microenvironment will be challenging, because they require careful sorting of the numerous cell types that reside in the marrow.50  Adding to this complexity, it is likely that alterations in the microenvironment may allow for both enhanced growth of malignant plasma cells and expansion of the overall plasma-cell niche.50  Importantly, due to heterogeneity of plasma-cell neoplasia, there is a great need for future studies based on prospectively collected, paired samples from the same patient. Such efforts will provide insights that are unattainable from studies comparing populations of patients in different disease states at a single point in time.

From a clinical standpoint, there are emerging data supporting up-front risk stratification and a model for tailored clinical follow-up for MGUS patients. Until we have more reliable biological markers that allow us to predict the individual patient's risk for MM progression, the 2010 IMWG guidelines advocate the application of the Mayo Clinic risk-stratification model to define low-risk versus intermediate-/high-risk MGUS patients.28 The guidelines recommend that SMM patients be considered candidates for chemoprevention trials28 ; however, off-study observation is still the standard in this group.42 

From a research perspective, the development of better biologic and molecular markers will improve our understanding of the molecular pathways involved in myelomagenesis.43,50  This will help us not just in understanding the biology of plasma-cell dyscrasia, but also in identifying newer therapeutic targets and novel treatments for these diseases. The recent finding that MM is consistently preceded by a precursor state (MGUS)45,48  has opened an avenue for future research, and highlights the need for upcoming studies based on prospectively collected, paired samples from the same patient with the aim of distinguishing benign (low-risk) from progressive (high-risk) precursor disease and uncovering the underlying mechanisms of progression. Such insights will allow us to define novel targets that can be used to delay and prevent MM progression.43,50 

Finally, it is important to consider the clinical implications of recently reported familial aggregation patterns for MGUS and MM.15,17  First-degree relatives of patients with MGUS and MM are at an increased relative risk of MGUS/MM.15,17  However, because of the low baseline risk in the general population (0.2–0.3% of men and women in the United States will develop MM between their 50th and 70th birthdays),70  the absolute risk of a first-degree relative developing MM is still low. At our institution, relatives of MGUS/MM patients are informed that they have a higher relative risk of developing MGUS and MM (compared with family members of unaffected individuals). However; we emphasize that the absolute risk of developing MM is low and, outside of clinical studies, observation is still the standard for MM precursor disease.42  At this time, no therapy has been found to prolong survival for MGUS/SMM patients, so we do not currently recommended screening for plasma-cell diseases among family members outside of clinical research studies.

Conflict-of-interest disclosure: Author declares no competing financial interests.

Off-label drug use: Len/Dex for smoldering myeloma.

Funding: This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health.

Dr. Ola Landgren, Multiple Myeloma Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bldg 10/Room 13N240, Bethesda, MD, 20892, USA; Phone: 301-496-0670; Fax: 301-402-0172; e-mail: landgreo@mail.nih.gov

1
Waldenstrom
J
Studies on conditions associated with disturbed gamma globulin formation (gammopathies)
Harvey Lect
1960
56
211
231
2
Kyle
RA
Monoclonal gammopathy of undetermined significance. Natural history in 241 cases
Am J Med
5
1978
64
5
814
826
3
Kyle
RA
Durie
BG
Rajkumar
SV
et al
Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management
Leukemia
2010
6
24
6
1121
1127
4
Kyle
RA
Therneau
TM
Rajkumar
SV
et al
Prevalence of monoclonal gammopathy of undetermined significance
N Engl J Med
3
30
2006
354
13
1362
1369
5
Landgren
O
Katzmann
JA
Hsing
AW
et al
Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana
Mayo Clin Proc
2007
82
12
1468
1473
6
Landgren
O
Rajkumar
SV
Pfeiffer
RM
et al
Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance (MGUS) among African-American and Caucasian women
Blood
2010
116
7
1056
1059
7
Alexander
DD
Mink
PJ
Adami
HO
et al
Multiple myeloma: a review of the epidemiologic literature
Int J Cancer
2007
120
Suppl 12
40
61
8
Gregersen
H
Pedersen
G
Svendsen
N
Thulstrup
AM
Sorensen
HT
Schonheyder
HC
Multiple myeloma following an episode of community-acquired pneumococcal bacteraemia or meningitis
Apmis
2001
109
11
797
800
9
Landgren
O
Rapkin
JS
Mellemkjaer
L
Gridley
G
Goldin
LR
Engels
EA
Respiratory tract infections in the pathway to multiple myeloma: a population-based study in Scandinavia
Haematologica
2006
91
12
1697
1700
10
Linet
MS
Harlow
SD
McLaughlin
JK
A case-control study of multiple myeloma in whites: chronic antigenic stimulation, occupation, and drug use
Cancer Res
1987
47
11
2978
2981
11
Landgren
O
Linet
MS
McMaster
ML
Gridley
G
Hemminki
K
Goldin
LR
Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study
Int J Cancer
2006
118
12
3095
3098
12
Landgren
O
Kyle
RA
Hoppin
JA
et al
Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study
Blood
2009
113
25
6386
6391
13
Rusiecki
JA
Patel
R
Koutros
S
et al
Cancer incidence among pesticide applicators exposed to permethrin in the Agricultural Health Study
Environ Health Perspect
2009
117
4
581
586
14
Kristinsson
SY
Bjorkholm
M
Goldin
LR
et al
Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 patients with multiple myeloma in Sweden
Int J Cancer
2009
125
9
2147
2150
15
Landgren
O
Kristinsson
SY
Goldin
LR
et al
Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden
Blood
2009
114
4
791
795
16
Landgren
O
Weiss
BM
Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis
Leukemia
2009
23
10
1691
1697
17
Vachon
CM
Kyle
RA
Therneau
TM
et al
Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance
Blood
2009
114
4
785
790
18
Swerdlow
SH
Campo
E
Harris
NL
et al
World Health Organization classification of tumours of haematopoietic and lymphoid tissues
4th ed
Lyon, France
IARC Press
2008
19
Kyle
RA
Therneau
TM
Rajkumar
SV
et al
A long-term study of prognosis in monoclonal gammopathy of undetermined significance
N Engl J Med
2002
346
8
564
569
20
Kyle
RA
Therneau
TM
Rajkumar
SV
et al
Long-term follow-up of IgM monoclonal gammopathy of undetermined significance
Blood
11
15
2003
102
10
3759
3764
21
Bergsagel
PL
Kuehl
WM
Molecular pathogenesis and a consequent classification of multiple myeloma
J Clin Oncol
2005
23
26
6333
6338
22
Kyle
RA
Greipp
PR
Smoldering multiple myeloma
N Engl J Med
1980
302
24
1347
1349
23
Alexanian
R
Barlogie
B
Dixon
D
Prognosis of asymptomatic multiple myeloma
Arch Intern Med
.
1988
148
9
1963
1965
24
Dimopoulos
MA
Moulopoulos
A
Smith
T
Delasalle
KB
Alexanian
R
Risk of disease progression in asymptomatic multiple myeloma
Am J Med
1993
94
1
57
61
25
Witzig
TE
Kyle
RA
O'Fallon
WM
Greipp
PR
Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma
Br J Haematol
1994
87
2
266
272
26
Greipp
PR
Smoldering, asymptomatic stage 1, and indolent myeloma
Curr Treat Options Oncol
2000
1
2
119
126
27
Rajkumar
SV
Dispenzieri
A
Fonseca
R
et al
Thalidomide for previously untreated indolent or smoldering multiple myeloma
Leukemia
2001
15
8
1274
1276
28
International Myeloma Working Group
Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group
Br J Haematol
2003
121
5
749
757
29
Bataille
R
Chappard
D
Basle
MF
Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies
Blood
6
1
1996
87
11
4762
4769
30
Politou
M
Terpos
E
Anagnostopoulos
A
et al
Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS)
Br J Haematol
2004
126
5
686
689
31
Melton
LJ
3rd
Rajkumar
SV
Khosla
S
Achenbach
SJ
Oberg
AL
Kyle
RA
Fracture risk in monoclonal gammopathy of undetermined significance
J Bone Miner Res
2004
19
1
25
30
32
Gregersen
H
Jensen
P
Gislum
M
Jorgensen
B
Sorensen
HT
Norgaard
M
Fracture risk in patients with monoclonal gammopathy of undetermined significance
Br J Haematol
2006
135
1
62
67
33
Kristinsson
SY
Tang
M
Pfeiffer
RM
et al
Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study
Blood
2010
7
7
[Epub ahead of print]
34
Dimopoulos
MA
Moulopoulos
LA
Datseris
I
et al
Imaging of myeloma bone disease–implications for staging, prognosis and follow-up
Acta Oncol
2000
39
7
823
827
35
Kristinsson
SY
Fears
TR
Gridley
G
et al
Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma
Blood
2008
112
9
3582
3586
36
Kristinsson
SY
Pfeiffer
RM
Bjorkholm
M
et al
Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study
Blood
2010
115
24
4991
4998
37
Kristinsson
SY
Bjorkholm
M
Andersson
TM
et al
Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study
Haematologica
2009
94
12
1714
1720
38
Kyle
RA
Remstein
ED
Therneau
TM
et al
Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma
N Engl J Med
2007
356
25
2582
2590
39
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
Blood
2005
106
3
812
817
40
Perez-Persona
E
Vidriales
MB
Mateo
G
et al
New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells
Blood
2007
110
7
2586
2592
41
Dispenzieri
A
Kyle
RA
Katzmann
JA
et al
Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma
Blood
2008
111
2
785
789
42
Anderson
KC
Kyle
RA
Rajkumar
SV
Stewart
AK
Weber
D
Richardson
P
Clinically relevant end points and new drug approvals for myeloma
Leukemia
2008
22
2
231
239
43
Waxman
AJ
Kuehl
WM
Balakumaran
A
Weiss
B
Landgren
O
Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future
Clin Lymphoma Myeloma Leuk
2010
10
4
248
257
44
Mateos
MV
Lopez-Corral
L
Hernandez
MT
et al
Multicenter, randomized, open-label, phase III trial of lenalidomide-dexamethasone (Len/dex) vs therapeutic abstention in smoldering multiple myeloma at high risk of progression to symptomatic MM: results of the first interim analysis paper [abstract]
Blood
2009
114
614
45
Landgren
O
Kyle
RA
Pfeiffer
RM
et al
Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study
Blood
2009
113
22
5412
5417
46
Rosinol
L
Cibeira
MT
Montoto
S
et al
Monoclonal gammopathy of undetermined significance: predictors of malignant transformation and recognition of an evolving type characterized by a progressive increase in M protein size
Mayo Clin Proc
2007
82
4
428
434
47
Blade
J
Rosinol
L
Cibeira
MT
de Larrea
CF
Pathogenesis and progression of monoclonal gammopathy of undetermined significance
Leukemia
2008
22
9
1651
1657
48
Weiss
BM
Abadie
J
Verma
P
Howard
RS
Kuehl
WM
A monoclonal gammopathy precedes multiple myeloma in most patients
Blood
2009
113
22
5418
5422
49
Chng
WJ
Glebov
O
Bergsagel
PL
Kuehl
WM
Genetic events in the pathogenesis of multiple myeloma
Best Pract Res Clin Haematol
2007
20
4
571
596
50
Balakumaran
A
Robey
PG
Fedarko
N
Landgren
O
Bone marrow microenvironment in myelomagenesis: its potential role in early diagnosis
Expert Rev Mol Diagn
2010
10
4
465
480
51
Avet-Loiseau
H
Facon
T
Grosbois
B
et al
Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation
Blood
2002
99
6
2185
2191
52
Fonseca
R
Bailey
RJ
Ahmann
GJ
et al
Genomic abnormalities in monoclonal gammopathy of undetermined significance
Blood
2002
100
4
1417
1424
53
Fonseca
R
Barlogie
B
Bataille
R
et al
Genetics and cytogenetics of multiple myeloma: a workshop report
Cancer Res
2004
64
4
1546
1558
54
Rasmussen
T
Kuehl
M
Lodahl
M
Johnsen
HE
Dahl
IM
Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors
Blood
2005
105
1
317
323
55
Chng
WJ
Gonzalez-Paz
N
Price-Troska
T
et al
Clinical and biological significance of RAS mutations in multiple myeloma
Leukemia
2008
22
12
2280
2284
56
Chiecchio
L
Dagrada
GP
Protheroe
RK
et al
Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case
Haematologica
2009
94
7
1024
1028
57
Hanamura
I
Stewart
JP
Huang
Y
et al
Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation
Blood
2006
108
5
1724
1732
58
Rosinol
L
Carrio
A
Blade
J
et al
Comparative genomic hybridisation identifies two variants of smoldering multiple myeloma
2005
130
5
729
732
59
Avet-Loiseau
H
Gerson
F
Magrangeas
F
Minvielle
S
Harousseau
JL
Bataille
R
Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors
Blood
2001
98
10
3082
3086
60
Anguiano
A
Tuchman
SA
Acharya
C
et al
Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma
J Clin Oncol
2009
27
25
4197
4203
61
Mateo Manzanera
G
San Miguel Izquierdo
JF
Orfao de Matos
A
Immunophenotyping of plasma cells in multiple myeloma
Methods Mol Med
2005
113
5
24
62
Ria
R
Todoerti
K
Berardi
S
et al
Gene expression profiling of bone marrow endothelial cells in patients with multiple myeloma
Clin Cancer Res
2009
15
17
5369
5378
63
Podar
K
Richardson
PG
Hideshima
T
Chauhan
D
Anderson
KC
The malignant clone and the bone-marrow environment
Best Pract Res Clin Haematol
2007
20
4
597
612
64
Folkman
J
Watson
K
Ingber
D
Hanahan
D
Induction of angiogenesis during the transition from hyperplasia to neoplasia
Nature
1989
339
6219
58
61
65
Rajkumar
SV
Mesa
RA
Fonseca
R
et al
Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis
Clin Cancer Res
2002
8
7
2210
2216
66
Hillengass
J
Zechmann
C
Bauerle
T
et al
Dynamic contrast-enhanced magnetic resonance imaging identifies a subgroup of patients with asymptomatic monoclonal plasma cell disease and pathologic microcirculation
Clin Cancer Res
2009
15
9
3118
3125
67
Bartel
DP
MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
2004
116
2
281
297
68
Pichiorri
F
Suh
SS
Ladetto
M
et al
MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis
Proc Natl Acad Sci U S A
2008
105
35
12885
12890
69
Rajkumar
SV
Lacy
MQ
Kyle
RA
Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma
Blood Rev
2007
21
5
255
265
70
Ries
LAG
Melbert
D
Krapcho
M
et al
SEER Cancer Statistics Review, 1975–2005, based on November 2007 SEER data submission
Bethesda, MD
National Cancer Institute
2008