From myeloma precursor disease to multiple myeloma: New diagnostic concepts and opportunities for early intervention

Abstract

Since MGUS was first described over 30 years ago, the definition of the entity has evolved. Today, three distinct clinical MGUS subtypes have been defined: non-IgM (IgG or IgA) MGUS, IgM MGUS, and light chain MGUS. Each clinical MGUS subtype is characterized by unique intermediate stages and progression events. Although we now have strong evidence that multiple myeloma is consistently preceded by a precursor state, at the molecular level, there is urgent need to better understand mechanisms which regulate transformation from precursor to full-blown multiple myeloma. In the future, if such knowledge was available, it would allow clinicians to define high-risk and low-risk precursor patients for a more tailored clinical management. Also it would provide insights on the individual patient's disease biology which in turn can be used for targeted and more individualized treatment strategies. Based on current clinical guidelines, patients diagnosed with MGUS and smoldering myeloma should not be treated outside of clinical trials. In the near future, it seems reasonable to believe that high-risk precursor patients will likely become candidates for early treatment strategies. In this review paper we discuss novel insights from recent studies and we propose future directions of relevance for clinical management and research studies.

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder present in over 3% of the general Caucasian population age 50 and older.(1, 2) On a clinical note, individuals diagnosed with MGUS have a 1% annual risk of progression to multiple myeloma (MM) or related malignancy.(3) Typically, MGUS is found incidentally during the work-up of a variety of symptoms and disorders. It is characterized by abnormal immunoglobulins detectable in the patient's peripheral blood and/or urine, as well as clonal plasma cells present in the bone marrow (Figure 1). Definitions of distinct MGUS subtypes are given in Table 1.

Figure 1.

Bone Marrow Biopsies from A Patient With Non-IgM MGUS (Panel A; H&E and Panel B; CD138) and from A Patient with Multiple Myeloma (Panel C; H&E and Panel D; CD138); Magnification 200X

Table 1. Disease Definitions for the Monoclonal Gammopathies: Monoclonal Gammopathy of Undetermined Significance (MGUS) and Related Disorders.

Type of Monoclonal Gammopathy	Premalignancy with a low risk of progression (1-2% per year)	Premalignancy with a high risk of progression (10 % per year)	Malignancy
IgG and IgA (Non-IgM) monoclonal gammopathies*	Non-IgM MGUS All 3 criteria must be met: Serum monoclonal protein <3gm/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	Smoldering Multiple Myeloma Both criteria must be met: Serum monoclonal protein (IgG or IgA) ≥3gm/dL and/or clonal bone marrow plasma cells ≥10%, 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	Multiple Myeloma All 3 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 non-secretory multiple myeloma), and 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 > 2mg/dL or estimated creatinine clearance less than 40ml/minute ○ 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 or severe osteopenia attributed to a plasma cell proliferative disorder or pathologic fractures
IgM Monoclonal gammopathies	IgM MGUS** All 3 criteria must be met: Serum monoclonal protein <3gm/dL Clonal bone marrow lymphoplasmacytic cells <10%, and Absence of end-organ damage such as anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.	Smoldering Waldenström's Macroglobulinemia Both criteria must be met: Serum IgM monoclonal protein ≥3gm/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.	Waldenström's 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 (eg., 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. IgM Myeloma All criteria must be met: Symptomatic monoclonal plasma cell proliferative disorder characterized by a serum IgM monoclonal protein regardless of size Presence of 10% plasma cells on bone marrow biopsy Presence of lytic bone lesions related to the underlying plasma cell disorder and/or translocation t(11;14) on fluorescent in situ hybridization.
Light Chain monoclonal gammopathies	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 FLC in patients with ratio > 1.65 and increased lambda 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	Idiopathic Bence Jones Proteinuria All criteria must be met: Urinary monoclonal protein on urine protein electrophoresis ≥500 mg/24 hours and/or clonal bone marrow plasma cells ≥10% No immunoglobulin heavy chain expression on immunofixation 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 Multiple Myeloma** Same as multiple myeloma except no evidence of immunoglobulin heavy chain expression

^*Occasionally patients with IgD and IgE monoclonal gammopathies have been described and will be considered to be part of this category as well.

^**Note that conventionally IgM MGUS is considered a subtype of MGUS, and similarly light chain multiple myeloma is considered as a subtype of multiple myeloma. Unless specifically distinguished, when the terms MGUS and multiple myeloma are used in general, they include IgM MGUS and light chain multiple myeloma respectively.

Furthermore, MGUS has confirmed and reported associations with numerous diseases that are commonly encountered in clinical practice such as osteoporosis and venous thrombosis.(4) Given the fact that MGUS is easily detected in peripheral blood and it can be monitored noninvasively, MGUS represents a readily accessible model to study the conversion of premalignancy to malignancy.(5)

Race and ethnicity play a role in the pathogenesis of MGUS. African Americans, and blacks from Africa, have a 2- to 3-fold higher prevalence of MGUS compared with whites.(6, 7) In contrast, the risk is lower in Asians from Japan,(8)and in Mexicans.(9) Increasing age,(1) male gender, family history of MGUS and/or multiple myeloma,(10) immunosuppression, and exposure to certain pesticides(11) all increase the risk of MGUS. Clearly, future studies are needed to improve our understanding on underlying mechanisms of these associations.

A more advanced premalignant stage of plasma cell proliferation in non-IgM MGUS is termed smoldering myeloma and is characterized by a much higher risk of progression to multiple myeloma (on average, about 10% per year during the first 5 years of follow-up).(12)

During recent years, new concepts and advances have emerged concerning the diagnosis, classification, risk-stratification, and management of myeloma precursor disease (MGUS and smoldering myeloma). In this review paper we discuss novel insights from recent studies and we propose future directions for clinical management and research studies.(13)

Distinct Clinical MGUS Subtypes

Since MGUS was first described in 1978 (14), the definition of the entity has evolved.(15) Today, three distinct clinical MGUS subtypes have been defined: non-IgM (IgG or IgA) MGUS, IgM MGUS, and light chain MGUS (Table 1). Each clinical MGUS subtype is characterized by unique intermediate stages and progression events. For example, as mentioned above, the more advanced premalignant stage of plasma cell proliferation in non-IgM MGUS is smoldering myeloma; it has an average 10% annual risk of progression to multiple myeloma (versus 1% per year collectively for all forms of MGUS).(12) IgM MGUS is associated with a predisposition mainly to Waldenström's macroglobulinemia and rarely to IgM multiple myeloma.(16, 17) Recently, a new disease entity termed “light chain MGUS” was defined. It represents the premalignant precursor of a subtype of multiple myeloma called “light chain multiple myeloma” which accounts for almost 20% of all new multiple myeloma cases.(18) The equivalent of smoldering myeloma and smoldering Waldenström's macroglobulinemia in the spectrum of light chain monoclonal gammopathies is called idiopathic Bence Jones proteinuria (Table 1).(19, 20) At this time, at least one large cohort including patients meeting each of the above listed clinical subtypes has been assembled. These cohorts have allowed clinicians and researchers to study and define the natural history for each MGUS subtype.(3, 12, 16, 18, 19, 21-23) Consequently, we now know how to diagnose each of these entities accurately, and we also know the outcome of patients meeting the specific subtype definition to assist with management and counseling. In Table 1 we have summarized the main features and results from the largest epidemiologic and clinical studies focusing on MGUS subtypes to date.(3, 12, 16, 18, 19, 21-23) More specifically, we have listed and commented on prevalence, risk of progression, and natural history of non-IgM MGUS, IgM MGUS and light chain MGUS.

It should be emphasized that in patients diagnosed with clonal proliferation of plasma cells consistent with a precursor state, the biology and natural history is very different compared with patents diagnosed with multiple myeloma. Importantly, patients with a precursor state should be reassured rather than labeled as having a cancer. For example, patients with less than 10% infiltration of the bone marrow by lymphoplasmacytic cells have an overall survival similar to that of the general population, and should therefore not be labeled as having a lymphoma or Waldenström's macroglobulinemia merely because the bone marrow pathology shows clonal proliferation of lymphoid cells.(22) Furthermore, on a clinical note, increasingly better sensitivity for diagnostic methods will continue to challenge clinical management and the line between malignancy and premalignancy will most likely continue to blur. As our understanding of disease progression improves, it will become more and more important to recognize that well-designed epidemiologic studies and clinicopathologic disease definitions will be required to separate patients who need treatment such as chemotherapy or stem cell transplantation for cancer like myeloma,(24) from those who call for no therapy and need reassurance.(5)

From Precursor to Multiple Myeloma: Current Clinical Risk Models

It is important to keep in mind that the vast majority of MGUS patients will never progress to multiple myeloma. Currently, we do not have access to any reliable markers to predict risk of multiple myeloma progression for individual MGUS patients. At the present time, the risk of progression of MGUS is assessed by a few selected risk factors. Two major models for risk stratification have been proposed: one model by the Mayo Clinic and the other by the Spanish study group (PETHEMA, Programa para el Estudio de la Terapéutica en Hemopatía Maligna)(Figure 2).

Figure 2. Risk Stratification Schemes for MGUS (Left) and Smoldering Myeloma (RIGHT).

Footnote: Two major models for risk stratification have been proposed: one model by the Mayo Clinic and the other by the Spanish study group (PETHEMA). The Mayo Clinic model focuses largely on serum protein abnormalities. For MGUS patients, the following features are considered as adverse risk factors: non-IgG isotype, M-protein concentration ≥ 1.5 g/dL, and an abnormal serum free light chain (FLC)-ratio (normal reference 0.26-1.65) (25). For smoldering myeloma 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 (12, 26). The Spanish model uses multiparametric flow cytometry of bone marrow aspirates to differentiate aberrant from normal plasma cells (27). Plasma cells characteristically express CD138 and intense (bright) CD38. The features of aberrant plasma cells included decreased CD38 expression, expression of CD56, and the absence of CD19 and/or CD45. In their study, MGUS and smoldering myeloma patients with ≥95% phenotypically aberrant plasma cells (aPC) of total bone marrow plasma cells (BMPC) (i.e. ≥95% aPC/BMPC) at diagnosis had a significantly higher risk of multiple myeloma progression (27). Furthermore, on multivariate analysis, ≥95% aPCs/BMPC, DNA aneuploidy, and immunoparesis were found to be independent predictors of multiple myeloma progression from MGUS/smoldering myeloma. More specifically, for MGUS patients ≥95% aPCs/BMPC and DNA aneuploidy were found to be risk factors for progression. For smoldering myeloma patients the risk factors were ≥95% aPCs/BMPC and immunoparesis (27).

The Mayo Clinic model focuses largely on serum protein abnormalities. For MGUS patients, the following features are considered as adverse risk factors: non-IgG isotype, M-protein concentration ≥1.5 g/dL, and an abnormal serum free light chain (FLC)-ratio (normal reference 0.26-1.65) (Figure 2) (25). In the Mayo Clinic model, at 20 years of follow-up, MGUS patients with all three risk factors, on average, have an absolute risk of multiple myeloma progression of 58%; for MGUS patients with 2, 1, and 0 of these risk factors, the corresponding absolute risk is 37%, 21% and 5%, respectively (25). For smoldering myeloma 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 (Figure 2) (14, 26). In the Mayo Clinic model, at 5 years of follow-up, smoldering myeloma patients with all three risk factors, on average, have a cumulative risk of multiple myeloma progression of 76% (median time-to-progression (TTP) was 1.9 years); for patients with 2 or 1 risk factors the corresponding risk was 51% (median TTP 5.1 years) and 25% (median TTP 10 years), respectively (12, 26).

The Spanish model uses multiparametric flow cytometry of bone marrow aspirates to differentiate aberrant from normal plasma cells (27). Plasma cells characteristically express CD138 and intense (bright) CD38. The features of aberrant plasma cells included decreased CD38 expression, expression of CD56, and the absence of CD19 and/or CD45. In 93 smoldering myeloma and 407 MGUS patients, the percentage of phenotypically aberrant plasma cells (aPC) of total bone marrow plasma cells (BMPC) at diagnosis allowed risk stratification of MGUS and smoldering myeloma patient's progression to overt multiple myeloma. In their study, MGUS and smoldering myeloma patients with ≥95% aPCs/BMPC at diagnosis had a significantly higher risk of multiple myeloma progression (27). Furthermore, on multivariate analysis, ≥95% aPCs/BMPC, DNA aneuploidy, and immunoparesis were found to be independent predictors of multiple myeloma progression. More specifically, for MGUS patients with 0, 1, or 2 risk factors (≥95% aPCs/BMPC and DNA aneuploidy) the risk of progression at 5 years was 2%, 10%, and 46%, respectively (Figure 2). For smoldering myeloma patients (risk factors: ≥95% aPCs/BMPC and immunoparesis) the corresponding risks at 5 years were 4%, 46%, and 72%, respectively (Figure 2) (27).

Taken together, these studies emphasize the fact that the risk of multiple myeloma progression varies greatly among individuals diagnosed with myeloma precursor disease. As discussed in detail below, we need better markers to define high-risk (versus low-risk) MGUS/smoldering myeloma and to better predict individual risk of multiple myeloma progression.

From Precursor to Multiple Myeloma: Current Knowledge from The Research Laboratory

Two independent studies have shown that multiple myeloma is consistently preceded by MGUS.(28, 29) In the first study, based on a large cancer screening trial including 77,469 volunteers prospectively followed for up to 10 years in a cancer screening trial, 71 individuals were found to develop multiple myeloma. Using stored pre-diagnostic serum samples obtained annually from these subjects, evidence of MGUS was demonstrated prior to multiple myeloma in all participants. (28) In 82% of multiple myeloma cases, evidence of MGUS was present in pre-diagnostic blood collected ≥8 years prior to multiple myeloma diagnosis.(28) The other study was based on a large U.S. Army serum repository. In brief, that study reported that 27 of 30 multiple myeloma cases with available pre-diagnostic serum samples had evidence of a preceding MGUS diagnosis; the other 3 patients either had IgD multiple myeloma or lacked samples ≤8 years prior to multiple myeloma diagnosis.(29)

Of great relevance from a clinical perspective, in approximately half of the 71 multiple myeloma patients from the large cancer screening trial (28), based on the systematically collected pre-diagnostic blood samples, the M-protein concentration increased annually following initial detection; among the remaining patients, serum M-protein was stable until multiple myeloma diagnosis (30). Similar patterns of gradual evolution and sudden increase prior to diagnosis were also observed in the serum free light chain (FLC)-ratio (around 85% had a skewed FLC ratio 2 years prior to multiple myeloma diagnosis).(28) Importantly, these findings emphasize the fact that clinicians must be alert in monitoring patients for myeloma-related end-organ damage regardless of the stability of serum protein markers.

At the molecular level, based in our current knowledge, transformation from precursor to full-blown multiple myeloma does not appear to be a sudden, discontinuous process with specific immunophenotypic markers differentiating plasma cells in patients with MGUS, smoldering myeloma, and multiple myeloma.(31, 32) Instead, several overlapping oncogenic events within plasma cells and the marrow microenvironment accumulate from normal plasma cells through precursor disease to full-blown multiple myeloma. Indeed, early cytogenetic changes are seen amongst almost all patients at the level of MGUS. (31, 32) These potentially overlapping, enduring changes are seen from MGUS onward and include hyperdiploidy and primary immunoglobulin translocations at the 14q32 locus.(33-35) In both states, Cyclin D dysregulation is a very common early event.(36) Importantly, at this time, MGUS from smoldering myeloma cannot be differentiated using conventional cytogenetics or fluorescent in situ hybridization.(37)

Abnormal plasma cells in MGUS, smoldering myeloma as well as multiple myeloma produce a broad range of immunoreceptors which are stimulated by both exogenous molecules and microenvironmental paracrine signals such as interleukin-6, contributing to the clonal proliferation observed in patients' bone marrow biopsies.(38) In contrast, many secondary oncogenic events have been implicated in the transition from MGUS/smoldering myeloma to full-blown multiple myeloma and from newly diagnosed multiple myeloma to advanced/refractory disease. These secondary genetic events may, in part, be dependent on the primary lesion.(39, 40) Furthermore, complex alterations to microenvironmental interactions occur in the transition from MGUS to multiple myeloma.(41) An apparent manifestation in myeloma-genesis is the interaction between abnormal plasma cells, cells in the bone marrow microenvironment as well as the bone (41), which ultimately lead to characteristic lytic lesions in approximately 80% of multiple myeloma patients.(42) While osteoclastic activation and osteoblastic inactivation leading to lytic lesions is a criterion for progression from MGUS/smoldering myeloma to multiple myeloma, studies using quantitative bone biopsy and levels of biomarkers for bone turnover (e.g. RANK ligand), have revealed excess bone resorption in patients with MGUS. (43-45) Future studies are needed to better define the role of activated osteoclasts in the pathogenesis of multiple myeloma.

Treatment Studies for Smoldering Myeloma: Future Challenges and Opportunities

Based on the International Myeloma Working Group 2010 guidelines, patients diagnosed with MGUS and smoldering myeloma should not be treated outside of clinical trials. (2) Overall, treatment trials for MGUS patients are complicated, as these individuals are relatively healthy and the majority has a low life-time risk of progression, especially when other causes of death are taken into account. (3) Therefore, it seems reasonable to propose that an ideal treatment would be effective, non-toxic, and directed towards patients with a high risk of progression. At this time, we do not have access to any such drug.

In contrast to MGUS, early treatment strategies for smoldering myeloma are particularly attractive, as the rate of progression to multiple myeloma is substantially higher. Prior to the advent of novel therapies, a randomized-controlled trial of melphalan-prednisone given initially versus at progression to multiple myeloma found no difference in response rate or overall survival.(46) Furthermore, a single-arm trial using thalidomide and pamidronate in 76 patients with smoldering myeloma failed to show a clear benefit for treatment, with a quite unexpected shorter time to progression among treatment responders versus non-responders.(47) In their report, the authors speculated that their observation perhaps was reflecting greater drug sensitivity of more aggressive disease. (47) Another randomized trial (zoledronic acid versus surveillance during one year) found reduced skeletal complications at progression from smoldering myeloma to multiple myeloma but without impact on the risk of progression.(48) It is unknown whether a more extended bisphosphonate treatment influences the risk of progression. The study based on zoledronic acid versus surveillance was prematurely stopped by the safety committee due to development of osteonecrosis of the jaw in a smoldering myeloma patient in the treatment arm. (48) Currently, a randomized, multicenter phase III trial for patients with high-risk smoldering myeloma is ongoing in Spain (lenalidomide-dexamethasone versus active surveillance). An interim analysis at 19 months of follow-up shows that about 50% of patients in the surveillance arm experienced progression to multiple myeloma while only 2 patients in the treatment arm had progression.(49) A collaborative ECOG/SWOG study based on lenalidomide versus active surveillance just opened in the U.S. Furthermore, at the NCI in Bethesda, MD, novel treatment strategies (designed to facilitate the patient's own immune system, to achieve anti-myeloma effects) are under development and the first treatment study opened in December 2010. Importantly, it is currently unknown whether treating smoldering myeloma patients improves overall survival and/or quality of life, as such data are not yet available. As stated above, in accord with the International Myeloma Working Group 2010 guidelines, smoldering myeloma patients should not be treated outside of clinical trials. (2)

While the above discussed trials underscore the value of ongoing treatment trials for smoldering myeloma patients, one can envision several scenarios resulting from treatment of smoldering myeloma. Aimed at preventing progression, smoldering myeloma could be treated as a chronic disease, with an extended dosing schema used to control the malignant clone (Figure 3). Alternately, in the future, highly active therapy could be used with the goal of cure. However, to responsibly perform any such trial, well-designed correlative studies must be performed to assess for the theoretical possibility of unexpected long-term adverse events or selecting for more aggressive disease (Figure 3).

Figure 3. Treatment Goals in Smoldering Myeloma.

Footnote: Under active surveillance, patients with high-risk SMM have a >84% lifetime risk of progression to full-blown myeloma (52). One can envision several scenarios resulting from treatment of SMM. Aimed at preventing progression, SMM could be treated as a chronic disease, with relatively benign maintenance therapy used to control the malignant clone. Alternately, highly active therapy could be used with the goal of cure, though this may prove challenging in the context of current treatment options. However, to responsibly perform any such trial, well-designed correlative studies should be performed to assess for the theoretical possibility of unexpected long-term adverse events or selecting for more aggressive disease.

Future Directions

In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and smoldering myeloma represents an ongoing challenge. Clearly, we need future prospective studies based on clinical monitoring and extensive correlative science. The ultimate goal is to develop better molecular markers which will allow (i) clinicians to define high-risk and low-risk precursor patients for a more tailored clinical management, and (ii) to provide insights on the individual patient's disease biology which in turn can be used for targeted and more individualized treatment strategies. In the near future, it seems reasonable to believe that high-risk precursor patients will likely become candidates for early treatment strategies. As discussed in detail in this review paper, future studies need to assess the role of early treatment in relation to overall survival and quality of life (50-52). High response rates among smoldering myeloma patients receiving treatment may not correlate with survival (50, 52). In fact, one may speculate that prolonged “stable disease” may provide key benefit to patients. Currently, the answers to these important questions remain unknown.