MONOCLONAL GAMMOPATHY OF UNCERTAIN (OR UNDETERMINED) SIGNIFICANCE (MGUS) / "BENIGN" MONOCLONAL GAMMOPATHY
(first reported by Kyle in 1978ref)

Epidemiology : prevalence increases with age. In large referral centers, half the patients with a monoclonal gammopathy have MGUS, whereas only 15 to 20% have multiple myeloma.
age (yr)
no. of persons studied
prevalence of MGUS (%)
test used to identify monoclonal protein
geographically defined population based
Swedish nursing homeref >= 70 294 3.1 paper electrophoresis
immunoelectrophoresis
no
southern Swedenref >= 25 6,995 0.9 paper electrophoresis
immunoelectrophoresis
no
Finistère, Franceref >= 50 17,968 1.7 cellulose acetate immunoelectrophoresis no
Ragiora, New Zealandref > 21 2,192 0.5 cellulose acetate no
Northern Minnesota, USAref >= 50 1,200 1.2 cellulose acetate immunoelectrophoresis no
North Carolina (1 urban and 4 rural counties), USAref >= 70 816 3.6 agarose gel immunofixation no
Large city hospital, USAref not given 73,630 1.2 agarose gel immunoelectrophoresis no (inpatient)
general hospital, Italyref not given 102,000 0.7 cellulose acetate immunoelectrophoresis no (inpatient)
provincial hospital, Italyref 11 to >= 75 35,005 2.9 cellulose acetate immunofixation no (inpatient and outpatient)
Olmsted county, Minnesota, USA (new residents had rates similar to long-time residents)ref >= 50 21,463 3.2% of persons > 50 years of age and 5.3% of persons > 70 years. Age-adjusted rates were higher in men (4.0 per 100) than in women (2.7 per 100); this finding corresponds to that in multiple myeloma, in which men account for almost 60% of patientsref. The rate among men was similar to that among women a decade older. In both sexes, the prevalence increased with advancing age and was almost four times as high among persons 80 years of age or older as among those 50 to 59 years of age. The prevalence leveled off after 85 years of age in men and after 90 years of age in women. In persons older than 85 years of age, the prevalence of MGUS was 8.9% in men and 7.0% in women (total, 7.5%). There was no significant difference in the concentration of the monoclonal protein among the age groups agarose gel immunofixation yes
Aetiology :

Pathogenesis : Increased bone absorption occurs in early myeloma but not in MGUSref
Symptoms & signs : associated to autoimmune peripheral polyneuropathy
Laboratory examinations : Therapy : the current standard of care for both MGUS and SMM is observation alone, without therapyref1, ref2. Patients with MGUS may benefit from risk-stratification to guide follow up. Patients with low-risk MGUS can be rechecked in 6 months and then once every 2 years or only at the time of symptoms for evidence of progression. All other subsets of patients need to be rechecked in 6 months and then yearly thereafter on an indefinite basis. In addition to history and examination, laboratory tests required at follow-up include a complete blood count, serum calcium, serum creatinine, and serum protein electrophoresis. Chemo-prophylactic trials with agents such as dehydroepiandrosterone (DHEA), anakinra, and celecoxib are underway.
Prognosis : risk of progression to MM = 1% per yearref1, ref2, ref3 (Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma. Blood. 2003;102:687a). Malignant evolution has been observed even after 30 years of follow-upref1, ref2. The constant rate of progression of MGUS to MM in a recent epidemiologic study over a period spanning 30-35 years is very suggestive, if not one of the best examples of a simple, random, 2-hit genetic model of malignancyref. The risk of progression is similar regardless of the known duration of antecedent MGUS, suggesting that the second hit responsible for progression is a random event, not cumulative damage. The specific second hit that initiates the cascade of events associated with progression is unknown and may even be different in IgH translocated versus non-translocated MGUS/SMM, even within IgH translocated MGUS depending on the partner chromosome involved. Several abnormalities have been detected with progression in both the plasma cell and its microenvironment that likely play a role in the progression of MGUS/SMM, but little is known about the sequence of events. Ras mutations, p16 methylation, abnormalities involving the myc family of oncogenes, secondary translocations, and p53 mutations have been identified in the clonal plasma cellsref. Clearly the bone marrow microenvironment undergoes marked changes with progression, including induction of angiogenesis, which is markedly different in MGUS than in MMref, suppression of cell-mediated immunityref, and paracrine loops involving cytokines such as IL-6 and VEGFref. The transition from MGUS to MM may involve an angiogenic switch as in solid tumors. In solitary plasmacytoma, which is the closest analogy to a solid tumor among the spectrum of plasma cell disorders, induction of angiogenesis at the time of diagnosis has been shown to be a predictor of progression to MM, suggesting a pathogenetic role for the process in disease progressionref. Angiogenesis is a striking characteristic of MM and has prognostic importance. Increased angiogenesis in MM is correlated with disease activity, bone marrow plasma cell involvement, and plasma cell proliferative capacity. The formation of new blood vessels is induced by the malignant plasma cells and may contribute to disease progression by ensuring an adequate tumor nutrient supply as well as by paracrine stimulation of tumor growth. There is a gradual increase in degree of bone marrow angiogenesis along the disease spectrum from MGUS to SMM to newly diagnosed myeloma (NMM) and relapsed myeloma (RMM). In a study of 400 patients, the median microvessel density (MVD) was 1.3 (range, 0-11) in controls, 1.7 (0-10) in amyloidosis, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in NMM, and 20 (6-47) in RMM, P < 0.001ref. In another study, 61% of MM bone marrow plasma samples stimulated angiogenesis in an in vitro angiogenesis assay, compared to 0% of SMM and 7% of MGUS, P < 0.001.18 The increased angiogenesis seen in MM may be related to expression of proangiogenic cytokinesref. However, no significant difference was seen in expression of VEGF, bFGF, or their receptors between MGUS, SMM and MM. Recently, we have described loss of angiogenesis inhibitory activity with disease progression from MGUS to MM, which may in part account for the increase in angiogenesis that occurs in MMref. In an in vitro human angiogenesis assay, 63% of MGUS bone marrow plasma samples inhibited angiogenesis, compared to SMM (43%) and NMM (4%), P < 0.001. The inhibitory activity was heat stable, not overcome by addition of VEGF and studies are ongoing to determine the nature and identity of angiogenesis inhibitors in MGUS. The role of angiogenesis in MM has triggered an interest in anti-angiogenic therapy for the disease. Studies show that while increased MVD in MM may not regress following conventional dose or high-dose chemotherapy, regression has been noted in responders with thalidomide, an agent with known anti-angiogenic propertiesref. Clinical trials have been initiated to test the hypothesis that therapy with antiangiogenic agents may inhibit angiogenesis and delay progression in SMM. The development of bone lesions in MM is caused by an imbalance between the activity of osteoclasts and osteoblasts. There is an increase in RANKL expression by osteoblasts (and possibly plasma cells) accompanied by a reduction in the level of its decoy receptor, OPGref1, ref2. This leads to an increase in RANKL/OPG ratio, which causes osteoclast activation and bone resorption. In addition, increased levels of MIP-1a, IL-3 and IL-6 produced by marrow stromal cells contribute to the overactivity of osteoclasts. At the same time, increased levels of IL-3, IL-7 and DKK1 produced by marrow stroma inhibit osteoblast differentiation. These changes lead to osteoclast activation and bone resorption without any repair activity by osteoblasts. Thus, the risk of malignancy for a 50-year-old patient with a 25-year life span is 25%. However, because of the relatively low annual risk of progression, one needs to take into consideration other competing causes of death such as heart disease and unrelated malignancies. In fact, the true life-time probability of progression is substantially lower when these competing causes of death are taken into account, 11.2% at 25 yearsref. The risk of progression with MGUS does not diminish even after 25-35 years, making lifelong follow-up necessary in all persons diagnosed with MGUSref1, ref2 : the upper curve illustrates risk of progression of all patients without taking into account competing causes of death. The lower curve illustrates risk of progression after accounting for other competing causes of death.

Risk factors for progression of MGUS : given the baseline risk of progression of MGUS, the potential adverse effects of prophylactic approaches and the duration for which such interventions will be needed, only patients at a high risk for progression can be considered candidates for testing preventive strategies. Similarly it is also important to identify low-risk patients who can be reassured and should not be subjected to potentially harmful or expensive tests or preventive interventions. It is therefore important to identify risk factors that can accurately predict the subset of patients with the greatest likelihood of progression. In a series, the variables associated with a higher risk of progression in the multivariate analysis were the kappa light chain (as compared with the lambda light chain, RR = 4.1), the serum monoclonal protein concentration (<1.5 vs. 1.5 g/dl, RR = 2.6), and the % of bone marrow plasma cells (<5% vs. 5%, RR = 2.2). These findings indicate that the initial plasma-cell burden, as reflected by the serum monoclonal protein concentration and the proportion of bone marrow plasma cells, is the critical risk factor for malignant transformation in MGUSref.
A new risk stratification system has been developed to predict the risk of progression of MGUS based on 3 risk factorsref :
risk group
% of the cohort
no. of patients relative risk absolute risk of progression at 20 years absolute risk of progression at 20 years accounting for death as a competing risk
monitoring
low-risk (no risk factors) 40% 449 1 5% 2% less frequently than once a year, perhaps only if symptoms of MM or related disorder become apparent
low-intermediate-risk (any 1 factor abnormal) 420 5.4 21% 10%
high-intermediate-risk (any 2 factors abnormal) 226 10.1 37% 18%
high-risk (all 3 factors abnormal) 53 20.8 58% 27% more closely and will serve as the base from which additional risk factors can identify a suitable cohort for chemo-prevention trials (Lust JA, Donovan KA. Chemoprevention: a new paradigm for managing patients with smoldering/indolent myeloma and high-risk MGUS. In: Kelloff GJ, Hawk ET, Sigman CC, eds. Cancer chemoprevention: strategies for cancer chemoprevention. Vol. 2. Totowa, N.J.: Humana Press, 2005:519-28)
During 11,009 person-years of follow-up of 1384 patients, MGUS .. :
  • disappeared during follow-up in 66 patients (5%). All these patients had low initial concentrations of monoclonal protein; only 17 had a value > 0.5 g/dl at diagnosis
  • in 39 cases, treatment of patients who had progression to lymphoma or multiple myeloma or who had other disorders, such as idiopathic thrombocytopenic purpura and vasculitis unrelated to the monoclonal gammopathy, caused the disappearance of the monoclonal protein.
  • in 27 patients (2%) the monoclonal protein disappeared without a known cause
  • in 19 additional patients, the results of immunofixation or immunoelectrophoresis were initially thought to represent a monoclonal protein, but subsequent studies showed no evidence of monoclonal protein, suggesting that it was not present initially. Nevertheless, patients with a small monoclonal protein (< 0.5 g/dl) had a 14% risk of progression at 20 years.
  • progressed to smoldering multiple myeloma in 32 patients (0.02%)
  • progressed in 115 of the 1384 patients (RR = 7.3; 0.08%) to :
  • The cumulative probability of progression was 12% at 10 years, 25% at 20 years, and 30% at 25 years.
    However, it is important to keep in mind that patients with MGUS are more likely to die of an unrelated disease than to have progression to a malignant plasma-cell disorder. Indeed, the actual risk of death from multiple myeloma and related disorders is overstated when one ignores the greater risk of death from other causes in these mostly elderly patients. Although we do not have evidence that monitoring improves survival, we believe that patients with MGUS should be monitored annually with serum protein electrophoresis to detect multiple myeloma before complications such as renal failure or pathologic fractures occur. Averting these events would improve the patient's quality of life and reduce the cost of long-term dialysis or surgical intervention for skeletal complications.


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