UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M‐proteins and the management of monoclonal gammopathy of undetermined significance (MGUS)

Abstract

The objective of this guideline is to provide healthcare professionals with clear guidance for the effective clinical investigation of patients with newly detected M-proteins and the practical management of patients with monoclonal gammopathy of undetermined significance (MGUS). The guidance may not be appropriate to all patients and individual patient circumstances may dictate an alternative approach. The members of the joint guideline group of the UK Myeloma Forum (UKMF) and the Nordic Myeloma Study Group (NMSG) were selected to be representative of UK-based and Nordic based medical experts and patient representatives. MEDLINE and EMBASE were searched systematically for publications in English from 1950 to October 2008. The writing group produced the draft guideline, which was subsequently revised by consensus by the UK Myeloma Forum Executive, regional coordinators of the NMSG and members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 100 UK haematologists, the BCSH, the British Society for Haematology Committee and the comments incorporated where appropriate. Criteria used to quote levels and grades of evidence where specified are as outlined in Appendix III of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#appendix7). However, as these levels and grades of evidence usually relate to patient treatment that, by definition, is not required in these patients, levels and grades of evidence are not quoted for most of the recommendations made in this guideline. Clinical trials have provided very little evidence to inform these guidelines. Most of the recommendations which follow are based on the outcomes of large observational studies and evidence from expert committee reports and/or the clinical experiences of respected authorities and are therefore grade C, level IV. Monoclonal gammopathy of undetermined significance (MGUS) is a term originally coined by the Mayo Clinic group (Kyle, 1978) and is defined as the presence of a monoclonal protein in the serum or urine of an individual with no evidence of multiple myeloma, AL amyloidosis, Waldenström macroglobulinaemia (WM) or other related disorders. Monoclonal immunoglobulins (M-proteins or paraproteins) can be detected in the serum of about 1% of the population overall (Axelsson et al, 1966) and most will be classified as MGUS (reviewed in detail in Rajkumar et al, 2007 and Kyle & Rajkumar, 2006) following the exclusion of other conditions associated with monoclonal immunoglobulins. M-proteins are frequently identified during investigation of unrelated symptoms or during health screening and their identification presents clinicians with the challenge of whom and how far to investigate. Clinicians need to be able to identify and treat promptly those patients with multiple myeloma, other lymphoproliferative disease and conditions in which the monoclonal immunoglobulin itself directly causes tissue damage, such as AL amyloidosis. It is also important to identify those patients at highest risk of progression to significant disease. Conversely, it is important to have a strategy to identify and manage patients with MGUS so as to avoid unnecessarily over-investigating patients with a low risk of current or future significant disease. An M-protein (also referred to as paraprotein or M-component) is a monoclonal immunoglobulin secreted by an abnormally expanded clone of plasma cells in an amount that can be visualised by immunofixation of serum and/or urine. M-proteins can be whole (heavy and light chain) immunoglobulin (Ig) or just immunoglobulin free light chain (FLC). Serum protein electrophoresis (SPEP) should be performed if there is clinical suspicion of an M-protein related disorder or when the results of other tests raise the possibility of the presence of an M-protein. Abnormal test results include: raised erythrocyte sedimentation rate (ESR) or plasma viscosity; unexplained anaemia, hypercalcaemia or renal failure; raised total protein/globulin or immunoglobulins, particularly if one or more immunoglobulin classes (IgG, IgA, IgM) are reduced. It should be noted that raised levels of polyclonal immunoglobulins are commonly seen in disorders such as liver disease, infection, rheumatological and other autoimmune conditions; reduction of one or more immunoglobulin class (IgG, IgA and IgM) levels. 3.3.1. Laboratory methods. Identification of M-proteins is usually carried out by SPEP but some M-proteins are not visible by electrophoresis alone and so, when there is a high index of suspicion of B-cell malignancy, the more sensitive method of immunofixation should be requested. 1, 2 show examples of SPEP and immunofixation of samples from a normal individual and from a variety of patients. Serum protein electrophoresis showing a range of different patient samples. Four serum samples have been processed by immunofixation. In each of the four panels the same serum has migrated along six tracks, which have then been stained for protein (ELP) or for IgG (G), IgA (A) or IgM (M) heavy chains or kappa (K) or lambda (L) light chains. Panel 1 is normal serum with polyclonal immunoglobulins. Panel 2 is serum containing a high level of IgG lambda monoclonal immunoglobulin with monoclonal lambda free light chains and little polyclonal immunoglobulin; the patient had myeloma with renal failure. Panel 3 is serum containing a low concentration IgA kappa M-protein. Panel 4 is serum containing an IgM lambda M-protein. Monoclonal serum FLCs are usually only detectable by immunofixation when removal of FLC from blood by glomerular filtration is compromised. The limit of immunofixation sensitivity is >10× normal serum FLC levels. Consequently, plasma cell dyscrasias secreting only FLC are usually not detectable by immunofixation of serum alone; urine must be assessed as well. FLC are detectable in urine only when their level in the glomerular filtrate exceeds renal tubular capacity to reabsorb them. Consequently, some plasma cell disorders secreting only FLC are still not detected even when urine is examined as well as serum. The introduction of methods to measure low levels of FLC in serum (SFLC) (Bradwell et al, 2003) has confirmed that both normal and neoplastic plasma cells secrete FLC as well as whole immunoglobulin and that an abnormal kappa/lambda SFLC ratio can be used as a surrogate marker for the secretion of monoclonal FLC. This SFLC ratio is often abnormal even when the renal threshold for reabsorption of FLC has not been exceeded and so no monoclonal FLC can be detected by immunofixation of urine. Thus ‘non-secretory’ myeloma and some cases of oligosecretory myeloma or AL amyloidosis may not be detected unless SFLC levels are measured. However abnormal SFLC ratios also occur when there is dysregulation of immunoglobulin production e.g. in patients with systemic lupus erythematosus (SLE) or human immunodeficiency virus (HIV) infection and during immune reconstitution following stem cell transplantation. It should also be noted that polyclonal FLC may be detected in urine when their production is greatly increased (usually in association with hypergammaglobulinaemia) and/or renal reabsorption is reduced by renal tubular damage e.g. in SLE. Polyclonal FLC in urine are not indicative of plasma cell dyscrasia. When SPEP demonstrates a narrow band in the beta or gamma region, immunofixation should always be performed to confirm an M-protein and identify its class and light chain type. Further investigation should include quantification of the M-protein. Urine should be examined for secretion of monoclonal FLC by urinary protein electrophoresis, immunofixation and quantification of monoclonal FLC. Alternatively, if no urine is available, serum FLC levels can be measured and urine only requested for immunofixation if the serum FLC ratio is abnormal. For details of recommended laboratory methods and references, see Appendix I. Screening normal populations for M-proteins for clinical purposes is not recommended. Electrophoresis of serum and urine should always be requested where there is clinical suspicion of plasma cell dyscrasia/B-cell malignancy. If the clinical suspicion of an underlying plasma cell dyscrasia is strong despite the absence of a detectable M-protein, then immunofixation should be performed. SFLC measurement is required to detect non-secretory myeloma and some cases of AL amyloidosis and light chain only myeloma when urine is not available. Electrophoresis of serum and urine should be requested in all patients with a persistent elevation of ESR above 30 mm/h, anaemia, renal failure or hypercalcaemia with no other obvious explanation. The laboratory should perform serum protein electrophoresis when there are abnormally high or low serum levels of total immunoglobulin or individual Ig classes. In cases with low serum immunoglobulin levels and no detectable serum M-protein, the laboratory should measure SFLC levels or request urine for immunofixation. The frequency of detection of M-proteins depends on the extent to which SPEP is used in the investigation of patients, the sensitivity of the SPEP methods and the extent to which laboratories direct or suggest further investigations. There are a large number of population-based studies in Europe and North America describing the prevalence of M-proteins in the general population and in patients in community/general practise and in hospitals. The incidence of M-proteins in these studies is generally similar but some variation does occur due to differences in the composition of the patient population and also in the frequency of performing SPEP. In a health survey in a county in Sweden, which included 79% of people above 25 years of age, 0·9% of the population were found to have an M-protein detected by paper protein electrophoresis (Axelsson et al, 1966); this percentage was 1·1% in a French study of 30 279 members of a health care programme (Saleun et al, 1982). Later reports have used the more sensitive technique of agarose gel electrophoresis. In screening a normal Minnesota population of 21 463 people aged over 50 years, MGUS was found in 694 individuals (3·2%) (Kyle et al, 2006). Of these, 68·9% had an IgG M-protein, 17·2% IgM and 10·8% IgA. The light chain was kappa in 62% and lambda in 38% and monoclonal light chains were detected in the urine in 21·5% (Kyle et al, 2006). Similar figures are obtained in hospitalised patients. M-proteins were found in 0·7% and 1·2% of hospitalised patients screened in studies in Italy and North America respectively (Malacrida et al, 1987; Vladutiu, 1987). Monoclonal gammopathy of undetermined significance is uncommon below the age of 50 years and the prevalence increases with advancing age (Axelsson et al, 1966; Fine et al, 1972; Saleun et al, 1982; Kyle et al, 2006). In the Minnesota population study, MGUS was present in 1–2% of people in their sixth decade, 2–4% in their seventh decade, rising to 4–5% in their eighth decade (Kyle et al, 2006). In one study of 111 residents of a retirement home in Carolina, monoclonal bands were found in 14% over the age of 90 years (Crawford et al, 1987). Thus, the majority of patients being investigated for a newly detected M-protein will be elderly. There are racial differences in the prevalence of M-proteins, with black people more than twice as likely as white people to have an M-protein, as demonstrated in a community-based study in North Carolina of 1732 subjects over 70 years of age (Cohen et al, 1998). Several studies have reported the percentages of different diagnoses identified in patients presenting with an M-protein in studies in Sweden, Italy and America. Differences between the studies are likely to reflect the different referral population of secondary and tertiary centres. In 930 cases of newly detected M-proteins among residents of the City of Malmö (1975–89) the distribution of subsequent diagnoses was: MGUS 72%, macroglobulinaemia 2%, myeloma 19%, other lymphoproliferative disease/disorder (LPD) 6%, AL-amyloidosis 1% (I. Turesson, Department of Medicine, Malmö University Hospital, Malmö, Sweden, personal communication). In a study of 375 newly detected M-proteins in a general district hospital in Italy, 69·6% were classified as MGUS, 26·6% as myeloma and 4·8% as other lympho-proliferative diseases (Malacrida et al, 1987). A study from the Mayo clinic, a tertiary referral centre, of 1510 patients with new M-proteins in 2005 reported 51% to be MGUS, 18% myeloma, 6% smouldering myeloma, 1% plasmacytoma, 3% WM, 4% other LPDs, 11% AL-amyloidosis and 6% other diseases (Kyle & Rajkumar, 2006). These results are summarised in Table I. A serum M-protein is detectable by electrophoresis in approximately 80% of patients with myeloma but in only a small proportion of patients with, for example, low grade B-cell non-Hodgkin lymphoma (NHL). M-proteins of IgM subclass are more commonly associated with WM and lymphoplasmacytoid lymphoma than myeloma. Monoclonal gammopathies include the following conditions: MGUS Multiple myeloma Solitary plasmacytoma (skeletal or extra-medullary) AL amyloidosis WM Low grade B-lineage non-Hodgkin’s lymphoma and other B-lineage LPD Other M-protein related disorders. It is clearly very important not to miss any of the clinically significant diseases associated with an M-protein that require treatment. However, the majority of individuals found to have an M-protein will have MGUS (see Epidemiology section above). An International Working Group has recently recommended a new classification of monoclonal gammopathies, based on the level/concentration of serum M-protein, percentage of bone marrow plasma cells and the presence or absence of myeloma-related organ or tissue impairment (ROTI) (The International Myeloma Working Group, 2003). The classification defines criteria for MGUS, asymptomatic myeloma and symptomatic myeloma (see Table II). To exclude myeloma, the serum M-protein concentration should be <30 g/l, plasma cells in the marrow <10% and there must be no evidence of myeloma-ROTI (see Table II). The distinction between symptomatic and asymptomatic myeloma depends on the presence or absence of myeloma-ROTI and the relevant criteria are shown in Table III. Low level M-proteins are common and will be most commonly accounted for by MGUS but it is very important to recognise that within this group there will be some patients with clinically important disease, such as AL amyloidosis, light chain myeloma or solitary plasmacytoma. The investigation and diagnosis of AL amyloidosis and of solitary plasmacytoma have been reviewed in recent UKMF/BCSH guidelines (Bird et al, 2004; Soutar et al, 2004). Waldenström macroglobulinaemia is characterised by bone marrow infiltration by lymphoplasmacytoid lymphoma and IgM monoclonal gammopathy (reviewed by Fonseca & Hayman, 2007). The presenting features are heterogeneous and are caused both by infiltration of the neoplastic cells in the bone marrow and peripheral lymphoid tissues and by biological effects of the M-protein. These latter include hyperviscosity, cryoglobulinaemia, peripheral neuropathy, cold agglutinin disease and bleeding diathesis. Diagnostic criteria and a description of the clinical features, cytomorphology, pattern of bone marrow infiltration and immunophenotype have been published and are summarised in Table IV (Owen et al, 2003). Numerous reports have made the association between a monoclonal gammopathy and B-lineage LPDs (Azar et al, 1957; Kyle et al, 1960; Alexanian, 1975; Kyle & Gahrton, 1987;Lin et al, 2005) including chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma and angioimmunoblastic T-cell lymphoma. The M-protein in these disorders is usually of the IgM class. The serum M-protein level is not a reliable discriminator in differential diagnosis and there is no apparent difference in clinico-pathological features and clinical outcome in CLL/SLL between M-protein-associated cases and those without an M-protein (Yin et al, 2005). There are a number of recognised associations between the presence of an M-protein and other conditions and in some of these a causal relationship has been established. The M-protein secreted in any monoclonal gammopathy can sometimes be damaging and cause serious symptoms. Aggregation and deposition of monoclonal immunoglobulins or monoclonal light chains with subsequent organ damage is the cardinal feature of AL-amyloidosis, light chain deposition disease, adult Fanconi syndrome and type I cryoglobulinaemia. On the other hand, it is the antibody activity of the M-protein that leads to organ damage in monoclonal cold agglutinin disease, mixed cryoglobulinaemia and M-protein-related neuropathy (Merlini & Stone, 2006). All these conditions may be seen within the setting of myeloma, WM and other LPD but also in association with M-protein-producing clones that behave biologically as MGUS. For these latter cases the term M-protein-related disorders has been introduced (Table V) (Merlini & Stone, 2006). As these diseases are uncommon and the clinical manifestations protean, the diagnosis is often delayed. The finding of an M-protein may be an important clue to establishing a correct diagnosis and instigating early treatment. It is however beyond the scope of these guidelines to give detailed recommendations on the diagnosis and management of these disorders. Polyneuropathies (PNs) form an important group of clinical disorders that are frequent in patients with a monoclonal gammopathy (Dispenzieri & Kyle, 2005). Their importance stems from the potentially damaging clinical course that may occur, raising the need for therapeutic intervention. They are more common in the presence of an IgM gammopathy than either IgA or IgG (Nobile-Orazio et al, 1992), and in some cases, anti-neuronal antibody activity of the M-protein against carbohydrate antigenic targets has been identified and associated with distinct clinical presentations. However, in many cases, the association is less clear; patients with IgM gammopathy may present with typical sensory symptoms, such as parasthesiae, dysasthesiae or neuropathic pain associated with ataxia and gait disturbance, but on investigation, may not possess a specific antibody to confirm the causal association between the monoclonal gammopathy and the PN. It is thus important to consider the possibility of other PNs, such as chronic inflammatory demyelinating polyneuropathy (CIDP), paraneoplastic, metabolic and toxic neuropathies, which may co-exist with a monoclonal protein, and arrange for appropriate management (Hughes et al, 2006). Guidelines for the management of M-protein-associated neuropathies have recently been published (Hadden et al, 2006). An increased prevalence of M-proteins has also been reported in various systemic conditions without clear evidence for a pathogenetic role of the M-protein. Owing to its increasing prevalence in older age groups, MGUS frequently co-exists with other conditions, many of which also have increasing prevalence with age and the finding of an M-protein is only coincidental. In the following section some of these associations will be addressed and recommendations made on how to manage MGUS within the stated clinical context. Monoclonal gammopathy of undetermined significance has also been described in the setting of numerous other clinical situations. MGUS has been reported in patients with connective tissue disorders such as rheumatoid arthritis (RA) (Hardiman et al, 1994), SLE, scleroderma, polymyositis and ankylosing spondylitis. A number of skin disorders have been described in association with plasma cell dyscrasias and neoplasms, (Daoud et al, 1999). The prevalence of monoclonal gammopathies in patients with hepatitis C virus (HCV)-related chronic liver disease is striking, may be accompanied by mixed cryoglobulinaemia (Idilman et al, 2004) and has been reported to be more prevalent in the context of HIV infection than would be expected in HIV-negative individuals (Amara et al, 2006). Infection by Helicobacter pylori has been linked to MGUS and eradication of the former has been associated with resolution of the latter in a proportion of cases (Malik et al, 2002). MGUS is frequent after autologous stem cell transplantation (Zent et al, 1998) and a higher prevalence of MGUS has been noted also following solid organ transplantation (Radl et al, 1985; Renoult et al, 1988; Caforio et al, 2001). Haematological associations of MGUS include acquired von Willebrand disease, lupus anticoagulant, pernicious anaemia, refractory anaemia, pure red cell aplasia, polycythaemia vera, myelofibrosis, congenital dyserythropoietic anaemia type III and Gaucher disease (Kyle & Rajkumar, 2006). There is little evidence that the occurrence of an M-protein in these disorders influences the natural history or treatment outcome of the disease. A detailed review of M-protein-associated disorders has been published (Kyle & Rajkumar, 2006). The finding of an M-protein in any patient with polyneuropathy, signs of systemic vasculitis or evidence of cardiac, renal or hepatic abnormalities and no other explanation should alert the physician to look for an M-protein-related disorder. For the diagnosis and treatment of these disorders the reader is referred to specific clinical practise guidelines. There is no evidence that MGUS in patients with RA and other connective disorders, dermatological disorders, infections, primary hyperparathyroidism, or following autologous or allogeneic transplantation should be managed differently to patients with isolated MGUS. The M-protein level is usually low in MGUS. In 1065 consecutive cases of MGUS diagnosed in inhabitants of the City of Malmö, Sweden the level was <10 g/l in 754 (70·8%) (I. Turesson, Department of Medicine, Malmö University Hospital, Malmö, Sweden, personal communication) (Figure 3 and Table VI). This is in contrast to 329 and 109 consecutive cases of IgG and IgA myeloma among inhabitants of Malmo in which the proportion of cases with M-protein level <10 g/l was 6·4% and 11%, respectively (Figure 4 and Table VII). M-protein concentration in individuals with MGUS (I. Turesson, personal communication). M-protein concentration in myeloma patients (I. Turesson, personal communication). Of 2836 patients entered into UK Medical Research Council myeloma trials, one-third of IgG and IgA M-proteins were <30 g/l at diagnosis 5% were <10 g/l (Drayson et al, 2006 and M. Drayson, Division of Immunity and Infection, University of Birmingham, personal communication). Nineteen per cent of all patients in these trials had no serum M-protein. Immune paresis. Between 30% and 40% of patients with MGUS have a reduction in polyclonal immunoglobulins (Blade et al, 1992; Baldini et al, 1996; Kyle et al, 2002) whereas a reduction of one or more polyclonal immunoglobulins is seen in more than 90% of patients with myeloma (Kyle et al, 2003). Presence of urinary Bence-Jones protein (BJP). In a study of 1384 individuals diagnosed with MGUS in south-eastern Minnesota between 1960 and 1994, monoclonal light chain was detected in the urine in 31% patients (10% lambda; 21% kappa) by immunofixation (Kyle et al, 2002). Sixty-nine per cent were negative for monoclonal light chain and only 17% had a urinary monoclonal protein value >150 mg/24 h. Because of the low proliferation rate of MGUS, plasma cells with abnormal karyotypes are rarely detected in MGUS by conventional cytogenetic techniques. However the introduction of fluorescence in situ hybridization (FISH), a technique not dependent upon the presence of dividing cells, has demonstrated that cytogenetic abnormalities typical in multiple myeloma can also be found in a high proportion of patients with MGUS. This applies to translocations involving the IgH locus (IGH@, 14q32), to other structural changes and also to the numerical changes which usually result in hyperdiploidy. Hence there are no unequivocal genetic markers that distinguish MGUS from myeloma. It has been suggested that 14q translocations and monosomy 13 observed in MGUS delineate a multi-step process for the oncogenesis of multiple myeloma. Bone marrow plasma cells from myeloma patients and other monoclonal gammopathies display an aberrant phenotype by flow cytometry and restricted immunoglobulin light chain expression at the cytoplasmic level. Based on these features, unequivocal identification and enumeration of aberrant and normal plasma cells co-existing in a bone marrow sample can be performed. There is correlation between neoplastic plasma cell phenotype and cytogenetic abnormalities but it is not possible to distinguish between myeloma and MGUS on the basis of phenotype. Monoclonal gammopathy of undetermined significance is a clinical diagnosis based on the exclusion of B cell/plasma cell malignancy and made after finding an M-protein in blood and/or urine. The decision on which patients should be referred and how far to investigate a patient who has been found to have an M-protein also requires a knowledge of the evolution of MGUS (see below). People with MGUS have an increased risk of developing malignant disorders, most often multiple myeloma from IgG and IgA MGUS, and other malignant LPDs from IgM MGUS. A large study from the Mayo Clinic of 1384 patients with MGUS who resided in SE Minnesota detected 115 cases of malignant transformation during 11 009 person-years of follow-up (median 15·4 years) (Kyle et al, 2002). The cumulative risk of progression to myeloma or other LPDs was 10% at 10 years; 21% at 20 years and 26% at 25 years. The overall risk of progression was 1% per year and the risk remained even after 25 years or more. Because of the high median age at detection of the M-protein and the existence of diseases not associated with the M-protein, the risk that a patient with MGUS in his/her lifetime will develop myeloma or related disorders is considerably lower (Rajkumar et al, 2005). Another population-based study of 1324 Danish patients with MGUS found similar risks of malignant transformation, with 107 observed cases versus 6·0 expected yielding a standardised incidence ratio of 17·9 (95% confidence interval, 14·7–21·7) (Gregersen et al, 2001a). The few studies that have compared the survival of MGUS patients with the general population have indicated a reduced life expectancy for MGUS. (Kyle et al, 2004; Gregersen et al, 2001b; Van de Poel et al, 1995). Although malignant transformation is an important cause of death in MGUS it only explained 20% of an excess mortality in a Danish cohort of MGUS patients (Fig 5, Gregersen et al, 2001b). In reality, given the limited life expectancy in this elderly population, a greater proportion of patients will die from causes other than transformation. The probability of survival in a cohort of 1324 Danish patients with monoclonal gammopathy of undetermined significance. The probability of survival in the entire cohort, the subgroup of patients dying of malignant transformation and the subgroup of patients dying of other causes (Reproduced from Gregersen, H., Ibsen, J.S., Mellemkjær, L., Dahlerup, J.F., Olsen, J.H. & Sørensen, H.T. (2001b) Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance. British Journal of Haematology, 112, 353–357. With permission of Wiley-Blackwell.). The cumulative risks of malignant transformation in the two studies were, in general, lower than the risks reported from studies of MGUS patients from haematological centres (Giraldo et al, 1991; Blade et al, 1992; Van de Poel et al, 1995; Baldini et al, 1996; Pasqualetti et al, 1997; Cesana et al, 2002). The difference in risk between studies is most likely to reflect differences in referral patterns. Patients with MGUS are at increased risk of certain other clinical events other than malignant transformation. Recent published studies found lower bone mineral density measurements in MGUS patients than in patients without MGUS (Pepe et al, 2006; Dizdar et al, 2008). This might explain an increased risk of fractures in patients with MGUS (Melton et al, 2004; Gregersen et al, 2006). In addition, two uncontrolled studies have indicated that the risk of venous thrombo-embolism is increased in MGUS (Sallah et al, 2004; Srkalovic et al, 2004). The clinical implications of these findings are yet to be clarified in terms of the risk-benefit of therapeutic intervention. Risk factors for transformation of MGUS to malignant conditions have been addressed in several studies. A major shortcoming of most of these studies has been their relative small size and the inclusion of patients who today would be classified as asymptomatic multiple myeloma. The data are conflicting but the initial concentration of M-protein and type of M-protein are consistent risk factors for progression. 8.2.1. Type of M-protein. In the Mayo Clinic study, M-proteins of IgA and IgM class were associated with an increased risk of progression (Kyle et al, 2002). The higher risk of non-IgG MGUS was also found in an Italian study (Cesana et al, 2002). Other studies have confirmed that IgA MGUS carries a higher risk of transformation than the other types of MGUS (Blade et al, 1992; Gregersen et al, 2001a; Rosiñol et al, 2007). 8.2.2. Level of M-protein. The Mayo Clinic study also found a strong association between the level of M-protein and risk of progression (Kyle et al, 2002) – see Table VIII. The impact of initial M-protein concentration on the risk of malignant transformation has been confirmed in a number of other studies (Van de Poel et al, 1995; Baldini et al, 1996; Gregersen et al, 2001a; Van De Donk et al, 2001;Rosiñol