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)

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 patients with a risk of or significant disease. to as or is a monoclonal immunoglobulin by an of in an can be by of serum and/or M-proteins can be and immunoglobulin or immunoglobulin protein be is clinical of an related or the of other the of the presence of an or or or or immunoglobulin are It be levels of immunoglobulins are in such as and other of or immunoglobulin and of M-proteins is usually by M-proteins are not by and is a of of the of be of and of from a individual and from a of protein a of patient serum have by of the the serum which have then for protein or for or or or is serum with immunoglobulins. is serum a level of monoclonal immunoglobulin with monoclonal and little the patient with is serum a is serum an Monoclonal serum are usually by of from by is The of is serum are usually not by of serum urine be as are in urine their level in the to are not detected urine is as as The of to levels of in serum et al, and as as immunoglobulin and an can be used as a for the of monoclonal is the for of not and so no monoclonal can be detected by of and of or AL may not be detected levels are also is of immunoglobulin in patients with or and during following It also be may be detected in urine their is in with and/or is by in in urine are not of a in the or be to an and identify and investigation of the be for of monoclonal by protein and of monoclonal no urine is serum levels can be and urine for the serum is of and Appendix for M-proteins for clinical is not of serum and urine be where is clinical of the clinical of an is the of a then be is required to and of AL and urine is not of serum and urine be in all patients with a of or with no other The serum protein are or serum levels of immunoglobulin or individual with serum immunoglobulin levels and no serum the levels or urine for The of of M-proteins on the to which is used in the investigation of patients, the of the and the to which or are a large of studies in and the of M-proteins in the population and in patients in and in The of M-proteins in these studies is to in the of the patient population and also in the of a health in a in which of of of the population were to have an detected by protein (Axelsson et al, this was in a of members of a health et al, reports have used the of screening a population of MGUS was in et al, an and The was in and in and monoclonal were detected in the urine in et al, are in M-proteins were in and of patients in studies in and et al, Monoclonal gammopathy of undetermined significance is the of and the with (Axelsson et al, et al, et al, Kyle et al, the population MGUS was in of in their in their to in their et al, of of a in monoclonal were in the of et al, the of patients for a newly detected will be are in the of with as as to have an as in a in of of et al, studies have the of identified in patients with an in studies in and the studies are to the population of and of newly detected M-proteins of the of the of MGUS macroglobulinaemia other lymphoproliferative 1% of a of newly detected M-proteins in a in were classified as as and as other et al, from the Mayo a of patients with M-proteins in to be myeloma, myeloma, 1% other and other & Rajkumar, are in serum is by in approximately of patients with in a of patients for grade M-proteins of are associated with and Monoclonal the following MGUS or AL grade and other related disorders. It is very important not to of the significant associated with an However, the of to have an will have MGUS Group a of monoclonal based on the of serum of and the presence or of or tissue Myeloma The for and myeloma, the serum be in the and be no evidence of The and on the presence or of and the are in level M-proteins are and will be most for by MGUS it is very important to this group will be patients with important such as AL amyloidosis, or The investigation and of AL and of have reviewed in et al, et al, Waldenström macroglobulinaemia is by by and monoclonal gammopathy (reviewed by & The are and are by of the in the and and by of the disease and and a of the clinical of and have and are in et al, reports have made the a monoclonal gammopathy and et al, Kyle et al, Kyle & et al, large and The in these is usually of the The serum level is not a in and is no in and clinical in and those an et al, are a of the presence of an and other conditions and in of these a The in monoclonal gammopathy can be and and of monoclonal immunoglobulins or monoclonal with is the of and the other it is the of the to in monoclonal and & these conditions may be the of myeloma, and other also in with as these the term & these are and the clinical the is The of an may be an important to a and It is the of these to recommendations on the and management of these disorders. an important group of clinical are in patients with a monoclonal gammopathy & from the clinical may the need for are in the presence of an gammopathy or et al, and in of the identified and associated with clinical However, in the is patients with gammopathy may with such as or associated with and on may not a to the the monoclonal gammopathy and the It is important to the of other such as and which may with a monoclonal and for appropriate management et al, Guidelines for the management of have et al, of M-proteins also in conditions clear evidence for a of the to in MGUS frequently with other of which also have with and the of an is the following of these will be and recommendations made on how to manage MGUS the clinical Monoclonal gammopathy of undetermined significance also in the of other clinical MGUS in patients with tissue such as et al, and of have in with and et al, The of monoclonal in patients with disease is may be by et al, and to be in the of be in et al, by to MGUS and of the associated with of the in a of et al, MGUS is et al, and a of MGUS also following et al, et al, et al, of MGUS III and disease & Rajkumar, is little evidence the of an in these the or treatment of the disease. of & Rajkumar, The of an in patient with of or evidence of or and no other the to for an the and treatment of these the is to clinical guidelines. is no evidence MGUS in patients with and other or following or be to patients with The level is usually in of MGUS in of the of the level was in of and is in to and of and of in which the of with level was and and in with MGUS in patients patients UK of and M-proteins were at were et al, and of and of of all patients in these trials no serum and of patients with MGUS have a in immunoglobulins et al, et al, Kyle et al, a of or immunoglobulins is in of patients with et al, of protein a of with MGUS in and monoclonal was detected in the urine in patients by et al, were for monoclonal and a monoclonal protein of the of with are detected in MGUS by the of in a not the presence of in multiple can also be in a of patients with to the to other and also to the which usually in are no MGUS from It and in MGUS a for the of multiple from patients and other monoclonal an by and immunoglobulin at the on these identification and of and in a can be is and it is not to and MGUS on the of Monoclonal gammopathy of undetermined significance is a clinical based on the exclusion of and made an in and/or The on which patients be and how far to a patient to have an also a of the of MGUS with MGUS have an risk of most multiple from and and other from large from the Mayo Clinic of patients with MGUS in detected of during of et al, The risk of progression to or other was at at and at The overall risk of progression was 1% and the risk or of the at of the and the of not associated with the the risk a patient with MGUS in will or related is et al, of patients with MGUS of with a of et al, The studies have the of MGUS patients with the population have a for et al, et al, et al, is an important of in MGUS it of an in a of MGUS patients et al, the in this a of patients will from causes other The of in a of patients with monoclonal gammopathy of undetermined The of in the the of patients of and the of patients of other causes from & and causes of in patients with monoclonal gammopathy of undetermined British of of The of in the studies in the from studies of MGUS patients from et al, et al, et al, et al, et al, et al, The in risk studies is most to in with MGUS are at risk of other clinical other studies in MGUS patients in patients MGUS et al, et al, an risk of in patients with MGUS et al, et al, studies have the risk of is in MGUS et al, et al, The clinical of these are to be in of the of for of MGUS to conditions have in of most of these studies their and the of patients be classified as multiple The are the of and of are risk for of the Mayo Clinic M-proteins of and were associated with an risk of progression et al, The risk of MGUS was also in an et al, studies have MGUS a risk of the other of MGUS et al, et al, et al, of The Mayo Clinic also a the level of and risk of progression et al, The of on the risk of in a of other studies et al, et al, et al, et al, et al, associated with risk of studies have the level of is with an risk of progression et al, et al, et al, with of the risk of those with et al, of other have to be of in studies the need in other the presence of et al, and et al, The of detected by is also a risk for et al, these are to clinical as on or on be to in which are The significance of an serum The levels of in serum of of MGUS patients in the were et al, of and levels was detected in of the a of in patients The risk of progression in patients with an was in patients with a and was of the and of serum The a based on of the serum the of immunoglobulin and the presence of an with risk of an serum MGUS and an serum a risk of progression at of with with risk with risk and of the risk was may very in MGUS patients with a risk of progression as for and of the other it also in patients with a very risk of and no need for However, these need to be by other studies this can be for all not associated with risk of such as the presence of and have not to have et al, are no have to have with to progression of MGUS to is not in progression of MGUS to as are in MGUS of the of and are in MGUS and is used et al, et al, The presence of not have and is not The of patients in whom an is detected will be the of a or other a The following the of an to a the of the immunoglobulin of the may Myeloma is associated with M-proteins of and or M-proteins are associated with such as or grade and on the the patient a or lymphoproliferative and and associated with myeloma, or AL are in and be the of an may be associated with or have no to The of an and the presence of of the or an to to a of MGUS a is associated with or it is to be of the AL is associated with a level and can also with levels of It is for this it is symptoms and associated with and be for in patients with M-proteins at and are et al, and et al, patients in whom an and urine as serum immunoglobulin urine for protein and protein serum and serum The following recommendations to clinicians in how an It is to be that, levels of have to or the risk of is related to the and of the for to the of will with an individual with an of is at risk of progression a with an level of the risk of progression for a with level of is individual is or may be and M-proteins are also associated with a risk of all patients be and patients with levels of M-proteins follow the very with very levels of The following of patients be to a Haematology for with symptoms or of myeloma, other or AL symptoms with investigation or or on with significant or M-proteins of M-proteins or M-proteins patient with a level is not to a will The recommendations have in an as an for and other clinicians to to a is also recommendations for which are in detail in the all patients are and have the to or not for investigation the of MGUS with it is this group will patients with and symptoms from causes other and other It is not to avoid of these patients in of a newly detected in the for patients with or other causes of an It is are clinical which will clinicians with and of these are level clear is a need for investigation to and a to a for investigation of the and is on other or is a need to AL in such a patient so a for evidence of other is is so in the of patients with and be The investigation and of AL reviewed in et al, with associated conditions to the of and an with of the presence of and frequently associated such patients be a to a to disease. also to investigation and of the Clinicians need to disease an and the of the and level such be a for and/or and to for The patient be MGUS in most a with no on health in a of patients is progression to or other for and other clinicians is in Appendix with MGUS be provided with and an to guidance is and patients with a of a or AL a and with will be by the of the and/or and have in detail in other et al, et al, an in patients of a other or AL amyloidosis, the following are to be serum with of level and protein with of and monoclonal serum clinical of AL or for may a of and to in et al, with patients with an of serum and protein with of level and serum and and for and of and is are for a a of of the conditions and have a level not need to investigation of the or or on the these patients a risk group for progression may be from a and/or are not in the of patients with studies have may be in the of associated with myeloma, in the investigation of patients with a newly be a of MGUS is made by conditions need and follow the the patient a risk the patient may be to their for of a may be used to inform the of the of and to is as Appendix IV. The of is to to identify to a myeloma, at an is no significant or other symptoms and at a the patient is to from effective Clinicians for patients be the risk of progression to or other and risk the The of disease progression is The Mayo identified of in patients, the was and then it or in the from in it in and in patients the serum was in or in the level of urine et al, it is patients be not by also and be of and symptoms and the of and other symptoms progression to myeloma, or other lymphoproliferative disease. group can be defined as in which an is at the following levels in whom are no or of of myeloma, other or AL amyloidosis. patients are at risk of have a or It be this the of M-proteins detected in is no evidence on which to recommendations for the of and guidance of to which is about risk for progression and of It be in the with a very and very level follow is not required myeloma, AL and have However, it not be to the the patient other Conversely, the patient with with and with or be It is that, in the identification in this group of patients, for the is to as as are no symptoms of the for patients and clinicians to be of clinical The be at are as of the and immunoglobulin and be to the following the of the by of symptoms with a of or other or or a patient is by the at or symptoms may in the The patient is the to be of the of It is patients are of important symptoms and be to these The risk group can be defined as in which an is at the following levels and in by definition, are no or of of myeloma, other or AL or or this group of patients follow usually the of a is no evidence on which to recommendations may Clinicians be of the of progression as with an or significant are at risk of and disease progression and be for patients be of this and to is no evidence the of in The be at are as of the and immunoglobulin and be a for to investigation to progression or of the a in a be as an individual level clinicians be can be as as be by the in the of term follow in the UK in which of patients is by an which and of and symptoms identified in a with as the on is and is of the by a is very patients as a of the and also this of is at a et al, are no have to or the progression of MGUS to or other of have identified as for investigation in patients with risk MGUS or The associated with such an where is and also the the no on overall have identified as in progression have and Most have on patients with this a with a in related at progression not the of the disease et al, in MGUS patients have and can in patients with with the of et al, et al, no progression can be or to identify MGUS patients at risk for and the of for treatment of multiple myeloma, such as and are to trials at to progression in with risk is a of and in patients with at risk of progression no are with in multiple with et al, and may also be in MGUS patients in the of and for patients and their is to in to with and all a as as to about clinical studies and It is important for patients and their to MGUS can to a myeloma, it a approach. The for health professionals is how to provide appropriate the patient to the and of their at the avoid unnecessarily about the appropriate of about MGUS which is and a of progression not be patients with MGUS it as on a not and the disease will and how to their MGUS patients and their therefore need appropriate and on a of and which from a of The to be with the of or is to a patient and or The be in the appropriate and in the of a and the presence of a and their be to have the it may be to this an of a or the of the it is patients and their are on the also be and for patient provide and of these Myeloma UK and the need to be of the of the members of the are in of their and clear on how to and and from the The to be and be in the so the is a be to patients on guidance for the as an However, patients and their be about on the and be of the and in these is to be and at the of to the the UK Myeloma Forum the and Nordic Myeloma the British Society for Haematology the for the of these guidelines. guideline was produced with the of an from Myeloma to provide for the of serum and urine and serum such an can be provided for in the of the recommendations from are provided where and urine be be a a the and or by of serum be is a for an on immunoglobulins are and of with the of the or of immunoglobulin are the of an protein is in the urine an in the is a clinical of a associated with an be with immunoglobulin and and and monoclonal an associated be to with to and of urine for be by urine is or urine as with a protein The for is a of be in all are may not be the urine is very in which or a urine be may be used as the urine be a in to is the is of a of in urine can be used for screening levels and are by and However, of urine be is a clinical of disease and/or serum immunoglobulin levels a of an be made by or the for It be made clear on the a a significant from a or by or immunoglobulin and/or are to to individual M-proteins and the will the immunoglobulin for the immunoglobulin of the may be appropriate the with a or with a of or an or of on a immunoglobulin It can be appropriate to quote the of the immunoglobulin in to the of M-proteins the of be and M-proteins of other the of is usually of of an with be made the and and of the be on by to of for The it clear or not a significant in with be by for a of and to is a significant a of and is the and clinicians be can be as as of is made from of the with is it is not and is to identify the is protein be with are associated with other for of urine monoclonal is no for and and in the are used the of of to be in and monoclonal or as of an immunoglobulin of is as a the in a urine this from in urine can be as a to in a urine Monoclonal serum are usually by of or of from by is are in urine their level in the to for can serum to a of of monoclonal from a will usually the serum is to and be on of to this be is and of as may be in patients with are the of M-proteins for and management of patients with and patients in whom no can be detected by of serum and are a to other in myeloma, and for patient where urine is not to the for for the the is used by the The of for in the of risk of progression of MGUS is in The with the clinical Clinical for which the is It is for the to in with this clinical for appropriate for reports are and the and of comments are to MGUS is defined by a monoclonal immunoglobulin or in the serum of to in the of and is related to the monoclonal and in the It is a to multiple or related and so term clinical The of MGUS is of is in of The of is by and then M-proteins are associated with lymphoproliferative conditions such as or Clinical a of are on the of the patient and of The presence of a and immunoglobulins and the of or related is to be such patients, a and may or may not be at the of the Myeloma where the of as or the patient is or the level is or the most be a and the of an such as a may be to as evidence of an lymphoproliferative of is it may be at a the follow of patients with is no need for follow of levels as this may to of The risk of progression to or related is 1% and this risk not follow of progression to or related in to have a strategy for the follow of The most is of progression to is the level of the The level in is to the risk of progression for patient at following a with an of a of progression to to a for an individual with an of The other risk for progression is the and MGUS are to such as the presence of in the of the and are not for an is it is important to the clinical and of the patient with MGUS and to the Myeloma Clinic evidence for progression is at which will be and recommendations