Monoclonal gammopathy of uncertain significance (MGUS)

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

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 home^ref >= 70 294 3.1 paper electrophoresis
immunoelectrophoresis no

southern Sweden^ref >= 25 6,995 0.9 paper electrophoresis
immunoelectrophoresis no

Finistère, France^ref >= 50 17,968 1.7 cellulose acetate immunoelectrophoresis no

Ragiora, New Zealand^ref > 21 2,192 0.5 cellulose acetate no

Northern Minnesota, USA^ref >= 50 1,200 1.2 cellulose acetate immunoelectrophoresis no

North Carolina (1 urban and 4 rural counties), USA^ref >= 70 816 3.6 agarose gel immunofixation no

Large city hospital, USA^ref not given 73,630 1.2 agarose gel immunoelectrophoresis no (inpatient)

general hospital, Italy^ref not given 102,000 0.7 cellulose acetate immunoelectrophoresis no (inpatient)

provincial hospital, Italy^ref 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 patients^ref. 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 :

monoclonal gammopathy occasionally occurs secondary to another disease process, such as AIDS or immunodeficiency after organ transplantation . In such patients, further evaluation is generally unwarranted, since the monoclonal gammopathy disappears with the recovery of the immune system. By contrast, the disappearance of a monoclonal protein in patients with MGUS is exceedingly rare^ref. Secondary monoclonal gammopathies have also been reported in patients who have chronic liver disease (due to HCV , in particular), rheumatologic diseases such as rheumatoid arthritis , and other conditions, such as chronic myelomonocytic leukemia , chronic neutrophilic leukemia , lichen myxedematosus, or pyoderma gangrenosum (Kyle RA, Bladé J, Rajkumar SV. Monoclonal gammopathies of undetermined significance. In: Malpas JS, Bergsagel DE, Kyle RA, Anderson KC, eds. Myeloma: biology and management. 3rd ed. Philadelphia: Saunders, 2004:315-52)
up to 25% of patients with Gaucher's disease ^ref
up to 15% of patients with the AIDS ^ref
genetic factors^ref1,
ref2
infection from Citrobacter spp., Proteus spp. or Campylobacter spp.. Transplant recipients with HHV-8 / KSHV infection are more likely to develop MGUS : however, this risk is much lower than the risk conferred by HHV-5 / CMV infection and ALG , arguing against a major role of HHV-8 infection in the pathogenesis of clonal plasma cell proliferation^ref. Awareness of the frequency of MGUS in the elderly may limit the number of diagnostic tests to investigate the abnormality, because in most cases, the presence of a small monoclonal protein will be unrelated to the patient's medical problem. In fact, the presence of such a monoclonal immunoglobulin can be coincidental even among patients in whom a plasma-cell disorder is suspected. For example, elderly patients in whom systemic amyloidosis is diagnosed may have senile systemic amyloidosis and an unrelated MGUS, rather than a monoclonal protein associated with primary systemic amyloidosis. Nevertheless, all patients with MGUS must be monitored indefinitely for progression to a malignant condition.

Pathogenesis :

IgH translocated MGUS/SMM (50%) : primary translocations in the clonal plasma cells involving the IgH locus on chromosome 14q32^ref1,
ref2. The most common partner chromosome loci and genes dysregulated in these translocations are:

11q13 (CCND1 [cyclin D1 gene])
4p16.3 (FGFR-3 and MMSET)
6p21 (CCND3 [cyclin D3 gene])
16q23 (c-maf)
20q11 (mafB)^{ref1,
ref2,
ref3}

^ref

IgH non-translocated MGUS/SMM (40-50%) : pathogenesis is unclear. Karyotyping is of no value in determining the risk of progression, because cells in metaphase are rare in MGUS. The early results of FISH are abnormal in more than half of patients with MGUS, but the prognostic significance of these findings is under investigation^ref

deletion of chromosome 13, a major prognostic factor in multiple myeloma, is seen in up to 50% of patients with MGUS by interphase FISH; hence, the presence of this abnormality cannot be used to differentiate MGUS from MM^ref.

Increased bone absorption occurs in early myeloma but not in MGUS^ref
Symptoms & signs : associated to autoimmune peripheral polyneuropathy

Laboratory examinations :

presence of a serum monoclonal (M) protein < 3 g/dL

Ig class :

IgG (68%^ref-68.9%^ref-70%^ref)

systemic capillary leak syndrome (CLS) (SCLS) / vascular leak syndrome (VLS) / Clarkson's disease

IgM (8%^ref-15%^ref-17.2%^ref-24%^ref)

Schnitzler's syndrome (SS), initially described in 1974 (around 70 cases reported to date^ref), is a rare clinical condition characterized by chronic urticaria, intermittent fever, elevated ESR, bone pain, arthralgia or arthritis, and monoclonal IgM gammopathy. Antiphospholipid syndrome and hyperhomocysteinemia^ref and sensitive chronic inflammatory demyelinating polyradiculoneuropathy^ref have been reported. Most patients have a chronic and indolent course, but 9 patients have progressed to develop lymphoplasmacytic neoplasias, particularly Waldenstrom's macroglobulinemia (WM)^ref. Responses to pulse cyclophosphamide ^ref, cyclosporin A ^ref, IFN-a_2b ^ref1,
ref2, PUVA therapy ^ref, and thalidomide ^ref. At least 4 cases with similar symptoms but with monoclonal IgG instead of IgM paraproteinaemia have been reported^ref1,
ref2 : histological examination showed perivascular neutrophil and lymphocytic infiltration into the upper dermis and diffuse neutrophilic infiltration in the middle dermis.
scleromyxedema

IgA (10.8%^ref-12%^ref)
IgE (only one case reported^ref)
biclonal (3.0%^ref1,
ref2)

serum light-chain type^ref :

k (61%^ref-62.0%^ref) => found in urine in only 16.5%^ref-21%^ref of MGUS cases
l (37.9%^ref-39%^ref) => found in urine in only 5%^ref-10%^ref of MGUS cases

^ref

monoclonal Ig concentration :

too low to measure (13.1%)
< 1.00 g/dl (63.5%)
1.00-1.49 g/dl (16.6%)
1.50-1.99 g/dl (15.4%)
2.00-3.00 g/dl (4.5%)

concentration of uninvolved (normal, polyclonal, or background) Ig is reduced in 27.7%^ref-29%^ref-38%^ref

1 of the 2 measured isotypes of polyclonal immunoglobulins was reduced in 21.9%, median :

IgA : 40 mg/dl
IgM : 50 mg/dl
IgG : 580 mg/dl

both were decreased in 5.8%

urine protein immunofixation
dosage of serum IgA, IgG, IgM

IgA (n.v : 70-400 mg/dl)
IgG (n.v. : 700-1600 mg/dl)
IgM (n.v. : 40-280 mg/dl)
IgD (n.v. 0.3-14 mg/dl)
IgE (n.v. : < 0.025 mg/dl or < 150 E/l)

dosage of l and k L chains in :

serum :

k (n.v. 1.7-3.7 g/l)
l (n.v. 0.9-2.1 g/l)
k/l ratio (n.v. 1.35-2.65)

urine :

k (n.v. : 0.0-7.1 mg/l)
l (n.v. : 0.0-3.9 mg/l)

ESR, b₂-microglobulin, uricemia, sideremia, transferrin, ferritin, bilirubin, SGOT, SGPT, g-GT, alkaline phosphatase, LDH, fibrinogen, total serum proteins; IL-6, IL-6R, TDK
bone marrow plasma cells < 10% (bone marrow examination is not necessary unless the monoclonal protein value is more than 2 g per deciliter or the patient has unexplained anemia, renal insufficiency, hypercalcemia, or bone pain). Some patients who seem to have a monoclonal gammopathy of undetermined significance at the time of their first evaluation actually have indolent multiple myeloma. Such patients have plasma cells with abnormal morphologic features^ref that proliferate^ref in the bone marrow (increased labeling index)^ref1,
ref2, aneuploidy with chromosomal abnormalities^ref, and histologic evidence of abnormal bone remodeling^ref. These features may suggest an early diagnosis of multiple myeloma, but it will be important to standardize them if they become part of new diagnostic criteria.
CBC : absence of anemia , hypercalcemia , lytic bone lesions, or renal failure (creatinine) attributable to the plasma cell proliferative disorder (multiple myeloma , Waldenström's macroglobulinemia )
at diagnosis : mosaic HAV, HBV , HCV antigens/serology
idiopathic or pure Bence Jones proteinuria, resulting from a plasma-cell dyscrasia involving the excretion of monoclonal light chains into the urine. From a pathophysiological point of view, it is reasonable to include light-chain disease in MGUS, since it clearly also represents a gammopathy^ref. Although the disorder is clinically relevant, there is astonishingly little information in the literature on the prognosis for patients with pure, idiopathic Bence Jones proteinuria^ref1,
ref2. Before 1980, it was not recognized that there are indolent cases in which Bence Jones proteinuria remains stable for years^ref, thus representing a benign counterpart of light-chain myeloma with its poor prognosis. In 1982, 7 patients with idiopathic Bence Jones proteinuria, five of whom had progression to myeloma, were described in detail by Kyle and Greipp^ref

Therapy : the current standard of care for both MGUS and SMM is observation alone, without therapy^ref1,
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 year^{ref1,
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-up^ref1,
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 malignancy^ref. 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 cells^ref. Clearly the bone marrow microenvironment undergoes marked changes with progression, including induction of angiogenesis

, which is markedly different in MGUS than in MM^ref, suppression of cell-mediated immunity^ref, and paracrine loops involving cytokines such as IL-6 and VEGF^ref. 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 progression^ref. 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 < 0.001^ref. 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 cytokines^ref. 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 MM^ref. 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 properties^ref. 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, OPG

^ref1,
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 years^ref. The risk of progression with MGUS does not diminish even after 25-35 years, making lifelong follow-up necessary in all persons diagnosed with MGUS^ref1,
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.

size and type of M protein (IgM and IgA subtypes) were predictive of progression^ref
bone marrow plasma cell percentage of 6-9% carried twice the risk of progression compared to marrow involvement that is <= 5%^ref
abnormal serum free light chain (FLC) ratio at baseline has been shown to be an important risk factor for progression of MGUS to malignancy in a large population-based study of 1148 patients^ref. In this study, the risk of progression in MGUS patients with an abnormal FLC ratio was significantly higher compared to patients with a normal ratio (hazard ratio, 3.5; 95% CI, 2.3-5.5; P < 0.001) and was independent of the size and type of the serum M protein. The risk of progression to MM or related malignancy at 10 years was 17% with an abnormal ratio compared to 5% with a normal ratio; corresponding rates at 20 years were 35% and 13%, respectively. An abnormal serum FLC ratio is interpreted as evidence of free monoclonal light chains in the serum. The mechanisms by which presence of monoclonal free light chains increase risk of progression in MGUS are not understood, but they may either represent clonal evolution of the neoplastic plasma cell or function as a surrogate marker for cytogenetic subtypes of MGUS that possess an inherently higher tendency progression. The mechanism of the imbalance in H and L chain production is more likely related to suppression of heavy chain expression rather than overexpression of light chains. Risk of progression of MGUS to MM based on the serum FLC ratio :

^ref

The normal FLC ratio (free k/free l) is 0.26 to 1.65

^ref

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 MGUS^ref.
A new risk stratification system has been developed to predict the risk of progression of MGUS based on 3 risk factors^ref :

size of the serum M protein (threshold 1.5 g/ml) : the risk of progression to multiple myeloma or a related cancer 10 years after the diagnosis of MGUS was 6% for an initial monoclonal protein value < 0.5 g/dl, 7% for a value of 1 g/dl, 11% for 1.5 g/dl, 20% for 2 g/dl, 24% for 2.5 g/dl, and 34% for 3.0 g/dl (P<0.001).
type of immunoglobulin (IgG vs. non-IgG)
serum FLC ratio (normal value 0.26-1.65)

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)

the presence of circulating plasma cells detected by a sensitive slide-based immunofluorescent assay is an adverse predictor of progression in MGUS^ref. This suggests that alterations in expression of adhesion molecules may be involved in the progression of MGUS to MM; alternatively the presence of circulating plasma cells may be a marker of plasma cell proliferative rate. The clinical application of this finding is presently limited by the lack of widespread availability of the test in clinical practice.

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

6 of these 27 patients (0.4% of all patients) had a discrete spike, or peak, on the densitometer tracing that could be measured on the initial electrophoresis (median, 1.2 g/dl),

the remaining 21 had a small monoclonal protein that could not be measured by the densitometer.

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 :

multiple myeloma (RR = 25). Patterns of increase in M component :

stable with sudden increase : 19 pts
stable with gradual increase : 9 pts
gradual increase : 9 pts
sudden increase : 11 pts
stable : 10 pts
indeterminate : 17 pts

IgM lymphoma (RR = 2.4)
primary amyloidosis (RR = 8.4)
macroglobulinemia (RR = 46)

stable with sudden increase : 2 pts
stable with gradual increase : 0 pts
gradual increase : 3 pts
sudden increase : 0 pts
stable : 0 pts
indeterminate : 2 pts

chronic lymphocytic leukemia (RR = 0.9)
plasmacytoma (RR = 8.5)

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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	age (yr)	no. of persons studied	prevalence of MGUS (%)	test used to identify monoclonal protein	geographically defined population based
Swedish nursing home^ref	>= 70	294	3.1	paper electrophoresis immunoelectrophoresis	no
southern Sweden^ref	>= 25	6,995	0.9	paper electrophoresis immunoelectrophoresis	no
Finistère, France^ref	>= 50	17,968	1.7	cellulose acetate immunoelectrophoresis	no
Ragiora, New Zealand^ref	> 21	2,192	0.5	cellulose acetate	no
Northern Minnesota, USA^ref	>= 50	1,200	1.2	cellulose acetate immunoelectrophoresis	no
North Carolina (1 urban and 4 rural counties), USA^ref	>= 70	816	3.6	agarose gel immunofixation	no
Large city hospital, USA^ref	not given	73,630	1.2	agarose gel immunoelectrophoresis	no (inpatient)
general hospital, Italy^ref	not given	102,000	0.7	cellulose acetate immunoelectrophoresis	no (inpatient)
provincial hospital, Italy^ref	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 patients^ref. 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