The Spanish Group risk stratification model13 is based on 2 risk factors: a high proportion of abnormal plasma cells (aPC) within the bone marrow plasma cell (BMPC) compartment (ie, ≥95% CD56+/CD19-); and an evolving subtype of the disease (defined as an increase in the level of serum M-protein by at least 10% during the first 6 months of follow-up, or a progressive and constant increase of the M-protein until overt MM develops). The 7-year cumulative probability of progression of MGUS to MM: 2% for patients with neither risk factor, 16% with one risk factor, and 72% with both risk factors.13
SMM. Classification of this progressive state is defined by a serum level of monoclonal protein (IgG, IgA, IgD, or IgE) ≥3 g/dL or a concentration of clonal bone marrow plasma cells ≥10%; and by an absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to a plasma cell proliferative disorder (TABLE 2).3 Both laboratory and clinical criteria must be met.
According to the Mayo Clinic risk stratification model, likelihood of progression reflects combinations of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.14 Using this stratification scheme, the risk over 10 years of progressing from SMM to MM is 84% for those with all 3 risk factors, 65% with 2 factors, and 52% with one factor.14 As SMM is defined, there is no upper limit of bone marrow involvement. However, Rajkumar et al15 found that progression time was significantly shorter (P<.001) among patients with ≥60% bone marrow involvement, compared with those having <60% involvement.
The Spanish Group risk stratification model13 uses the same model applied to MGUS: a proportion of abnormal plasma cells in the BMPC compartment ≥95% CD56+/CD19-; and an evolving subtype of disease. The 3-year cumulative probability of progression of SMM to MM is 46% for those with both risk factors, 12% for those with one factor, and <1% for those with no risk factors.13
LC-MGUS. The classification of LC-MGUS (TABLE 4)3 is primarily from a Mayo Clinic study6 and research on risk stratification is underway at 2 other institutions. False-positive results are possible in patients with renal16 and inflammatory17 disorders.
Applying risk stratification to patient management
The current approach to a patient with clearly defined MGUS is a prudent “watch and wait” strategy that specifies monitoring details based on risk category (ALGORITHM).1,18
MGUS. In the low-risk MGUS group (IgG subtype, M-protein <1.5 g/dL, and normal FLC ratio)3 there is no need for bone marrow examination or skeletal radiography. Repeat the serum protein electrophoresis (SPE) in 6 months, and if there is no significant elevation of M-protein, repeat the SPE every 2 to 3 years.1,19,20 However, if other findings are suggestive of plasma cell malignancy (anemia, renal insufficiency, hypercalcemia, or bone lesions), bone marrow examination and computed tomographic (CT) scan are advised. Further evaluation of an incidental detection of MGUS is also important since it is occasionally associated with bone diseases,21 arterial and venous thrombosis,22 and an increased risk (P<.05) of developing bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis) and viral (influenza and herpes zoster) infections.23
Patients in the intermediate- and high-risk MGUS groups with serum monoclonal protein ≥1.5 g/dL, IgA or IgM subtype or an abnormal FLC ratio should undergo tests for CRAB and have bone marrow aspirate and biopsy with cytogenetics, flow cytometry, and fluorescence in situ hybridization (FISH). Patients with IgM MGUS should also undergo a CT scan of the abdomen to rule out the presence of asymptomatic retroperitoneal lymph nodes.1,19 If the BM examination and CT scan yield negative results, repeat SPE and complete blood count (CBC) after 6 months and annually thereafter for life. IgD or IgE MGUS is rare, and patients exhibit a progression similar to the 20-year risk seen with MGUS generally.
SMM. Given the increased risk of progression from SMM to MM compared with MGUS (all risk groups), the 2010 International Myeloma Working Group (IMWG) has suggested monitoring SMM patients more frequently—ie, SPE every 2 to 3 months in the first year following diagnosis.1 Repeat SPE in the second year every 4 to 6 months, and, if results are clinically stable, every 6 to 12 months thereafter. In addition to a baseline bone marrow examination (including cytogenetics, flow cytometry, and FISH studies), consider ordering magnetic resonance imaging of the spine and pelvis to detect occult lesions, as their presence predicts a more rapid progression to MM.24 During the course of the follow-up, evaluate any unexplained anemia or renal function impairment for its origin. A report of MGUS progression over more than a decade to SMM and then to MM illustrates prudent monitoring of a patient.25