Risk factors for progression
It is not possible to predict which patients with MGUS will remain stable and which will experience progression at a subsequent time. However, a number of parameters are helpful in predicting the likelihood of progression of MGUS to MM.
Size of the M protein. The size of the M protein at the time of recognition of MGUS is the most important predictor of progression. Twenty years after recognition of MGUS, the risk of progression to MM or a related disorder was 14% for patients with an initial M protein value of ≤ 0.5 g/dL, 25% for those in whom the value was 1.5 g/dL, 41% for those in whom the value was 2.0 g/dL, and 49% in those with an M spike of 2.5 g/dL. The risk of progression in a patient with an M protein of 1.5 g/dL was almost double that of a patient with an M protein of 0.5 g/dL. The risk of progression with an M protein of 2.5 g/dL was 4.6 times that of a patient with an M protein of 0.5 g/dL. Also, a progressive increase in the size of the M protein during the first year of follow-up is an important risk factor for progression.
Type of serum M protein. In our series of 1,384 patients, those who had an IgM or an IgA monoclonal protein had an increased risk of progression compared with patients who had an IgG protein.
Bone marrow plasma cells. The presence of more than 5% bone marrow plasma cells was an independent risk factor for progression in one series. Baldini et al recognized a malignant transformation rate of 6.8% during follow-up when the bone marrow plasma cell was less than 10%; however, the rate was 37% for those with bone marrow plasmacytosis of 10% to 30%.
Serum FLC ratio. In a study of 1,148 of the 1,384 MGUS patients from southeastern Minnesota, we found an abnormal FLC ratio in 33%. Progression occurred in 7.6% of these patients at 15 years of follow-up. The risk of progression in patients with an abnormal FLC ratio was higher than in patients with a normal ratio (HR, 3.5) and was independent of the concentration and type of serum M protein.
Role of flow cytometry and cytogenetics
Perez-Persona et al reported that a marked preponderance of abnormal plasma cells in the bone marrow as assessed by flow cytometry was associated with a significantly higher risk of progression to MM in a cohort of 407 patients with MGUS and 93 with SMM. The most important risk factors were the presence of ≥ 95% aberrant plasma cells together with DNA aneuploidy. Although fluorescence in situ hybridization (FISH) reveals almost the same number and type of abnormalities as in MM, there is little evidence that this has a role in assessing the risk of the progression of MGUS to MM. No convincing evidence exists at present, but the gene expression profile may be of benefit in predicting the risk of progression.
In a study of 1,400 patients with MGUS over the past 3 decades, Varettoni et al found a significant reduction in the size of the M protein and number of bone marrow plasma cells in those diagnosed more recently. They concluded that more recently diagnosed MGUS had more favorable presenting features and probably a better outcome. Rossi et al also reported that patients with an M protein ≤ 1.5 g/dL, absence of light chain proteinuria, and normal serum levels of uninvolved immunoglobulins had a more favorable prognosis.
Risk stratification model for MGUS
A risk stratification model for predicting the risk of progression of MGUS using simple laboratory markers has been developed. Those with risk factors consisting of an elevated serum M protein value (≥ 1.5 g/dL), IgA or IgM MGUS, and an abnormal serum FLC ratio had an absolute risk of progression at 20 years of 58% (high risk), compared with a risk of only 5% when none of these risk factors were present (low risk) (Table 5). Plasma cell disorders developed in 10% of our southeastern Minnesota MGUS patients after 20 years of follow-up, whereas 72% had died of other causes.
Clinical and laboratory findings are helpful in differentiating a patient with MGUS from one with MM. A bone marrow aspirate and biopsy as well as a radiographic bone survey are indicated in all patients with an M protein value ≥ 1.5 g/dL and in all patients who have an abnormality in their complete blood cell count (CBC), creatinine level, or calcium level. The reduction of uninvolved immunoglobulins in serum or the presence of an M protein in the urine (Bence Jones proteinuria) is of little help in distinguishing between patients with MGUS and those with MM because these abnormalities may be present in both MGUS and MM. Those with a serum M protein ≥ 3 g/dL or bone marrow plasma cells ≥ 10% without CRAB features are considered to have SMM. The presence of osteolytic lesions or pathologic fractures strongly suggests MM, but metastatic carcinoma may also produce lytic lesions and be associated with an unrelated monoclonal protein and plasmacytosis. Abnormalities were found in magnetic resonance imaging (MRI) in 86% of 44 patients with MM, but none were present in those patients with MGUS. Although an elevated plasma cell labeling index usually indicates symptomatic MM, one-third of patients with symptomatic MM have a normal labeling index. Symptomatic MM is often associated with circulating monoclonal plasma cells in the peripheral blood. FISH is not helpful in distinguishing between MGUS and MM because abnormalities detected with FISH may be found in both conditions. Conventional cytogenetic studies rarely reveal an abnormal karyotype in MGUS because of the low proliferative rate and the small number of plasma cells.
The differentiation of symptomatic MM from MGUS or SMM depends mainly on the presence or absence of end-organ damage due to the underlying plasma cell proliferative disorder. MGUS and SMM are distinguished from each other by the size of the serum M protein and the number of bone marrow plasma cells.
Management of MGUS
At follow-up, after MGUS has first been recognized, a complete history and physical examination should be performed with emphasis on symptoms and findings that might suggest AL amyloidosis or MM. The physician should obtain a CBC and serum calcium and creatinine measurements, and should perform a qualitative test for the presence of urine protein. If proteinuria is found, a 24-hour collection of urine is needed, followed by electrophoresis and immunofixation of a concentrated aliquot. After 3 to 6 months, serum protein electrophoresis should be repeated to exclude MM and WM, since the M protein is usually recognized by chance and may represent an early MM or WM. It is important to detect MM before complications such as renal failure or pathologic fractures occur.
Low-risk MGUS. These patients have a serum M spike < 1.5 g/dL, IgG isotype, and a normal FLC ratio. Their absolute risk of progression at 20 years is 5%, compared to 58% for the high-risk group. Patients with low-risk MGUS do not require a bone marrow examination or skeletal radiography if the clinical evaluation, CBC, and serum creatinine and calcium values suggest only MGUS. On the other hand, a bone marrow examination is required if the patient has any CRAB features, such as unexplained anemia, renal insufficiency, hypercalcemia, or bone lesions. A patient with low-risk MGUS should be followed with serum protein electrophoresis 6 months after the diagnosis of MGUS to exclude the possibility of early MM or WM, and if stable, can be followed until symptoms suggestive of a plasma cell malignancy arise.
Intermediate- and high-risk MGUS. Patients with intermediate-risk MGUS have one or two abnormal risk factors, while all three risk factors are abnormal in those with high-risk MGUS—ie, the serum M protein is > 1.5 g/dL, the protein type is IgA or IgM, and the FLC ratio is abnormal. Intermediate-risk and high-risk patients should have a bone marrow aspirate and biopsy with both conventional cytogenetics and FISH. If available, a plasma cell labeling index and a search for circulating plasma cells in the peripheral blood using flow cytometry are useful. Intermediate- or high-risk MGUS patients with the IgM isotype should have a CT scan of the abdomen since asymptomatic retroperitoneal lymph nodes may be present. If there is evidence of MM or WM, lactate dehydrogenase, β2-microglobulin, and C-reactive protein levels should be measured. If the results of these tests are satisfactory, patients should be followed with serum protein electrophoresis and CBC in 6 months and then annually for life. In addition, patients must be instructed to contact their physician if there is any change in their clinical condition. Treatment is not indicated unless it is part of a clinical trial.
Smoldering (Asymptomatic) Multiple Myeloma (SMM)
Smoldering (asymptomatic) multiple myeloma is characterized by the presence of an M protein level of ≥ 3 g/dL and/or ≥ 10% monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. SMM must be distinguished from MGUS because of the higher risk of progression to MM or a related disorder associated with the former. The risk of progression for SMM is 10% per year vs 1% per year for MGUS.
Clinical course and prognosis
In a cohort of 276 patients fulfilling the criteria for SMM, 163 (59%) developed symptomatic MM or AL amyloidosis during follow-up. The cumulative probability of progression to active MM or AL amyloidosis was 51% at 5 years, 66% at 10 years, and 73% at 15 years (Figure 4). The median time to progression was 4.8 years. The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the last 10 years. The risk of progression to symptomatic MM was 522 times the risk of developing MM in a normal population. The risk of AL amyloidosis was increased by a factor of 50-fold. Symptomatic MM accounted for 97% of those who progressed. The risk of progression in patients with SMM is much greater than the fixed 1% per year risk of progression in patients with MGUS. During 2,131 cumulative person-years of follow-up (median, 6.1 years; range, 0 to 29 years), 85% of the patients died.
The cumulative probability of progression at 15 years was 87% for the patients with ≥ 10% plasma cells in the bone marrow and ≥ 3 g/dL of M protein, 70% for the patients with ≥ 10% plasma cells and < 3 g/dL of M protein, and 39% for those with < 10% plasma cells and ≥ 3 g/dL of M protein. The median times to progression were 2 years, 8 years, and 19 years, respectively, for the three groups. The type of serum heavy chain (IgA) had a significant effect on the multivariate model containing the number of bone marrow plasma cells and size of the serum M protein.
Risk factors for progression
The size of the serum M protein and the number of plasma cells in the bone marrow are the most important factors for progression. The FLC ratio (≤ 0.125 and ≥ 8) is an independent additional risk factor for progression. Gender, hemoglobin level, type of serum heavy chain, serum albumin level, presence and type of urinary light chain, and reductions in levels of uninvolved immunoglobulins are not significant risk factors for progression. The presence of occult bone lesions on MRI increases the risk of progression in patients with SMM. In another report, the median time to progression in 72 patients with SMM was 1.5 years in the presence of an abnormal MRI vs 5 years for those with a normal MRI.
Risk stratification model
A risk model incorporating the three risk factors (abnormal FLC ratio, bone marrow plasma cells ≥ 10%, and serum M protein ≥ 3 g/dL) predicted for survival. Patients with one, two, or three risk factors had 5-year progression rates of 25%, 51%, and 76%, respectively. The presence of more than 95% aberrant plasma cells detected by flow cytometry together with immunoparesis can identify three prognostic groups in SMM, with progression rates at 5 years of 72%, 46%, and 4% if a patient has two, one, or none of the above risk factors.
A CBC, measurement of calcium and creatinine levels, serum protein electrophoresis, and a 24-hour urine collection for electrophoresis and immunofixation should be performed at diagnosis. A bone marrow biopsy and skeletal survey are essential. An MRI of the spine and pelvis is recommended because the presence of occult lesions predicts a more rapid progression. The blood tests should be repeated 2 to 3 months after the initial recognition of SMM to exclude the possibility of symptomatic MM. If the results are stable, testing should be repeated every 4 to 6 months for 1 year, and if still stable, the interval between evaluations can be lengthened to every 6 to 12 months. A skeletal survey and bone marrow examination should be performed if there is evidence of progression in the above-mentioned studies.
Observation is the standard of care. There are no data to show that early treatment at the smoldering myeloma stage can prolong survival. However, clinical trials are ongoing to determine whether early therapy with newer agents can prolong the time to progression—and most importantly, prolong survival. In the United States, the Eastern Cooperative Oncology Group has recently activated a trial testing the role of lenalidomide (Revlimid) in SMM; this agent has shown promise in this setting in recent studies.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
The work reflected in this article has been supported in part by Research Grants CA-62242 and CA-107476 from the National Institutes of Health, Bethesda, Maryland.