Monoclonal gammopathy of undetermined significance (MGUS) is the most prevalent of the plasma cell dyscrasias and is characterized by a low level of production of serum monoclonal (M) protein (classically less than 3 g/dL), less than 10% clonal plasma cells in the bone marrow, and the absence of symptoms and signs associated with end-organ injury.[1,2] It is estimated that the prevalence of MGUS is approximately 3% in Caucasian Americans, and is two times higher than this in African Americans. MGUS is a clonal premalignant condition that may progress to malignancy (including multiple myeloma, AL amyloidosis, Waldenstrm macroglobulinemia, or lymphoma) in approximately 1 in 4 patients affected. The risk of progression is thus approximately 1% per year, but importantly the risk continues for 25 years or more. In recent years, risk factors for progression have been identified and include the size of the serum M protein at the time of presentation, the type of serum M protein, the extent of plasmacytosis in the marrow, and the presence of an abnormal serum free light chain ratio.
Smoldering multiple myeloma (SMM) is classically asymptomatic and is characterized by the presence of serum M protein > 3 g/dL with at least 10% or more monoclonal plasma cells identified in the bone marrow, but again no evidence of significant end-organ injury. In this disorder, which in essence constitutes an early stage of myeloma, the overall risk of progression is up to 10% per year for the first 5 years, with risk of progression diminishing in likelihood during the next decade; however, the disease almost always becomes symptomatic over time. Thus, patients with SMM typically do progress, with some demonstrating an evolving picture and becoming symptomatic within the first 5 years after diagnosis, and with a second group who have a non-evolving pattern and who remain stable for much longer.
The cornerstone of management for both entities is observation. In the population of patients affected by SMM, early intervention with novel agents holds promise, and use of bisphosphonates in patients with documented osteopenia appears justified, provided careful consideration is given to potential side effects, including renal dysfunction, osteonecrosis of the jaw, and brittle bones (recognizing that each of these is relatively uncommon and usually manageable). In contrast, strategies in MGUS remain almost wholly investigational at this time, and relatively few studies have been performed in this group—although this is something that hopefully will change in the future.[5,6]
Dr. Kyle and colleagues present a succinct and very useful review of MGUS, its definition, and strategies for recognizing the syndrome, as well as a discussion of its prevalence, etiology and risk factors. The clinical course and prognosis of MGUS are well described and the risk factors for progression are comprehensively reviewed, with the management of both low-risk and intermediate- and high-risk MGUS clearly defined.
At a practical level, patients with intermediate-risk MGUS have one or two abnormal risk factors, while those with high-risk MGUS have at least three risk factors, including an elevated M protein (in excess of 1.5 g/dL), non-IgG isotype, and an abnormal free light chain ratio. In contrast, low-risk MGUS patients have a serum M protein less than 1.5 g/dL, IgG isotype, and a normal free light chain ratio; these patients have a particularly low risk of progression—5% over 10 to 20 years is seen—compared with 58% over 10 to 20 years for the high-risk group. The recommendations provided by Dr. Kyle and colleagues are thus especially useful in terms of the continuous long-term follow-up that is needed regardless of risk category, and which is particularly important in high-risk patients.
In the section on SMM, the clinical course and prognosis are briefly summarized by the authors with a similarly concise and helpful review of risk factors for progression. Important risk factors include the degree of marrow involvement, as well as the size of the serum M protein and the free light chain ratio, with a risk stratification model for SMM having been derived that considers three risk factors (abnormal free light chain ratio, bone marrow plasma cells ≥ 10%, and serum M protein ≥ 3 g/dL) as most consistently predicting for survival. As one might expect, those patients with two or more risk factors are at a high risk for progression by 5 years, with one distinct subgroup being especially prone to more rapid progression; in this latter subgroup, extensive marrow involvement and immunoparesis (as reflected by suppression of uninvolved immunoglobulins), as well as the other high-risk features, are seen.
Interestingly, for patients with smoldering disease but without the three risk factors described above, other factors—such as gender, anemia, type of serum heavy chain, serum albumin level, and presence and type of urinary light chain, as well as reductions in the levels of uninvolved immunoglobulins—have not consistently been identified as risk factors for progression. Conversely, the presence of occult bone lesions on magnetic resonance imaging (MRI) does appear to be associated with an increased risk of progression in patients with SMM.
The authors correctly state that SMM patients should undergo comprehensive evaluation and careful follow-up with additional imaging, including an MRI, as well as consideration for participation in clinical trials. While observation is the standard of care, trials of novel agents in SMM have been encouraging, including a prospective randomized trial of the use of oral lenalidomide and dexamethasone, in which both a response rate and progression-free survival advantage were seen. Other strategies aiming to augment immunity are also being explored to see if such approaches can be beneficial.
Importantly, in patients with early bone disease, trials of aminobisphosphonates have shown clinical benefit, as reflected by a lower incidence of skeletal-related events. Several studies have also shown increased bone density with a reduction in bone turnover, as well as an increase in serum markers suggesting improved bone remodeling.[10,11] While studies in asymptomatic MM have not shown a statistically significant difference in the rate of evolution from asymptomatic to symptomatic myeloma, the largest trial to date of intravenous zoledronic acid administered to patients with newly diagnosed myeloma included a subgroup in whom bone disease was not apparent, and a survival advantage was seen in these patients; this further supports a role for bisphosphonate use in patients with early-stage disease, especially if osteopenia is present.
In terms of the future, strategies aimed at arresting the progression of high-risk SMM as well as improving our understanding of the factors that contribute to disease progression hold promise for this important subgroup, especially those involving novel therapies. Convenient oral therapies such as lenalidomide integrated with either vaccinations or immunotherapeutic strategies (such as monoclonal antibodies), as alluded to above, have particular appeal; however, comprehensive study is clearly required before such approaches can be recommended.
In addition, translational studies of both tumor and tumor-related stroma in patients with SMM (and indeed MGUS) are fertile areas for basic research to help us better understand the natural progression of myeloma. The opportunity to further define mechanisms of disease progression—and most importantly, to better characterize the tumor microenvironment—is particularly important to emphasize. This especially resonates with the point made by Dr. Kyle and colleagues that the cytogenetics and characteristics of the plasma cell clone itself do not appear to be particularly informative in terms of progression and biology in either MGUS or SMM, suggesting that the niches that drive progression lie elsewhere, such as within the marrow milieu and the cortical bone. Rational strategies targeting both of these functional compartments may thus be of special importance going forward and as part of future studies.
Financial Disclosure: Dr. Richardson serves on advisory boards for Millennium, Celgene, Novartis, Johnson & Johnson, and Bristol Myers Squibb. Dr. Mitsiades has served as a consultant to and has received honoraria from Millennium, Novartis, Celgene, Bristol Myers Squibb, Merck, Centocor, Pharmion, and Kasan, and he has received research support from OSI, Amgen, AVEO, EMD Serono, Sunesis, Gloucester Pharma, and Johnson & Johnson. Dr. Ghobrial serves on the advisory boards of Celgene, Millennium, Novartis, and Onyx. Dr. Munshi serves as a consultant and advisory board member for Celgene, Novartis, and Millennium, and is on the advisory board of Onyx. Dr. Anderson serves as a consultant to Celgene, Onyx, Merck, Novartis, Millennium, and Bristol Myers Squibb; he is also a founder of Acetylon. Dr. Laubach and Dr. Schlossman have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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