Diana Samson

Multiple myeloma (MM) is a malignant plasma cell disorder accounting for about 10% of haematological malignancies. The disease is characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin heavy and/or light chain (paraprotein, M-protein or M-component). This patient-specific paraprotein is present in the serum and/or urine of all patients except in the 1–2% of patients with non-secretory myeloma. Typical clinical and laboratory features in patients with MM include bone pain (due to lytic lesions or osteoporosis), anaemia, renal insufficiency, hypercalcaemia, increased susceptibility to infection and constitutional symptoms resulting in poor performance status. Less common complications include cord compression due to extramedullary plasmacytomas or vertebral collapse, peripheral neuropathy, amyloidosis and hyperviscosity syndrome ( Malpas, 1998). Prior to the introduction of alkylating agents, the median survival of patients with MM was less than a year ( Korst et al, 1964 ; Holland et al, 1966 ). Approximately 60% of patients respond to initial treatment with conventional chemotherapy, but although survival is prolonged by treatment the median survival remains approximately 3 years ( Bergsagel, 1998). Complete remissions are rare and all patients ultimately relapse, resulting in c 25% survival at 5 years and <10% survival at 10 years. Criteria by which different treatment regimens can be evaluated include the proportion of patients achieving an objective response, the duration of response, and survival. Over the past 10–15 years high-dose therapy followed by haemopoietic stem-cell rescue, either allogeneic or autologous, has been increasingly employed in the treatment of multiple myeloma. For a number of reasons the existing criteria for the assessment of disease response have not proved entirely satisfactory for the analysis of disease outcome after high-dose therapy. In particular, there has been no generally agreed definition of complete response. Agreed definitions of response and progression are essential to ensure consistency of reporting within the transplant registries and to enable comparison of results from different studies and/or different treatment centres. New criteria for response and progression have therefore been developed as a result of discussions between representatives of the Myeloma Subcommittee of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) and representatives of the Myeloma Working Committee of the Autologous Blood and Marrow Transplant Registry (ABMTR) and the International Bone Marrow Transplant Registry (IBMTR). These criteria will now form the working definitions of response and progression for the purposes of data collection and registry-based studies. Currently none of the registries include specific diagnostic criteria, although all record the relevant investigations performed at diagnosis. However, we wish to emphasize that all patients undergoing high-dose therapy should have proven myeloma which requires treatment. At present high-dose therapy is not recommended for patients with equivocal myeloma or those with stage I disease. We have not at this stage reviewed the criteria for the diagnosis of myeloma, but there may be a requirement for this in the future. For example, because of the increasing use of high-dose therapy for the treatment of primary amyloidosis, it will be important to establish clear guidelines for the differential diagnosis between this condition and multiple myeloma with amyloid. Changes in the level of the serum paraprotein and/or urinary light chain excretion form the basis of assessing the response to therapy and monitoring the progress of the disease. In a minority of patients disease progression will be manifested by increasing marrow or skeletal involvement, or development of other complications, without a rise in paraprotein. In non-secretory myeloma it is difficult to monitor disease accurately. Serial bone marrow examinations are helpful, although the patchy nature of marrow involvement in myeloma makes it difficult to accurately interpret small changes in the percentage of plasma cells present. The currently used response criteria are shown in Tables I. Response criteria were first developed by the Committee of the Chronic Leukemia and Myeloma Task Force (CLMTF) of the U.S. National Cancer Institute in 1968 and were reviewed by the same group in 1973 ( Chronic Leukemia and Myeloma Task Force, 1968, 1973). The main response parameter is a reduction in the paraprotein of at least 50% ( Table I). In 1972 the Southwest Cancer Chemotherapy Study Group, now the Southwest Oncology Group (SWOG), defined ‘objective response’ as a reduction of at least 75% in the calculated serum paraprotein synthetic rate (rather than paraprotein concentration) and/or a decrease of at least 90% in urinary light-chain excretion, sustained for at least 2 months ( Alexanian et al, 1972 ). Patients with a reduction in serum paraprotein synthetic rate of between 50% and 74% were considered to have improved ( Table II). A review of the literature indicates that the CLMTF or SWOG criteria have been used in most subsequent clinical trials, albeit frequently with some modifications of the original proposals. The relative merits of these two sets of criteria in defining outcomes has never been formally assessed, i.e. there is no evidence to indicate whether a 75% reduction in paraprotein synthetic rate has a better prognostic significance than a 50% reduction in serum paraprotein level. Most groups have used paraprotein concentration to define response because of simplicity. The terms partial response or partial remission are also frequently used. Some groups have added additional response categories, such as good or very good partial response and minimal response, again based on the degree of paraprotein reduction. An exception is the United Kingdom Medical Research Council (MRC) Myelomatosis trials, which have evaluated the efficacy of treatment not by the degree of paraprotein reduction but by the proportion of patients achieving plateau ( Table III) ( MacLennan et al, 1992 ). Plateau phase consists of a period of stability after chemotherapy in which tumour progression does not occur despite the persistence of measurable disease. The definition of plateau does not require any specific degree of paraprotein reduction. The minimum period of stable observation required to define plateau was 6 months in the early MRC trials but more recently has been reduced to 3 months ( MacLennan et al, 1992 ). Although the concept of plateau phase was introduced almost 20 years ago ( Durie et al, 1980 ), it has not been extensively used for the evaluation of response in multiple myeloma. Neither the CLMTF nor the SWOG response criteria include a definition of complete response/complete remission (CR), since CR was rarely observed with existing treatments. With the introduction of new regimens such as VAD (vincristine, adriamycin and dexamethasone) and high-dose melphalan (140 mg/m2) without stem cell support, measurable paraprotein disappeared in a significant proportion of patients and criteria for complete remission were formulated ( Selby et al, 1987 ; Gore et al, 1989 ; Samson et al, 1989 ). As the use of high-dose therapy has increased there has been a consequent increase in the number of patients entering CR, and other groups have published their own definitions of CR; as shown in Table IV ( Gahrton et al, 1991 ; Anderson et al, 1993 ; Dimopoulos et al, 1993 ; Bjorkstrand et al 1995b ; Attal et al, 1996 ; Vesole et al, 1996 ; Barlogie et al, 1997 ; Ballester et al, 1997 ; Joshua et al, 1997 ; Schiller et al, 1998 ). All groups agreed that there should be no detectable paraprotein in serum or urine together with a normal number of plasma cells in the marrow (i.e. <4–5%), but differed according to whether the absence of paraprotein is based on routine electrophoresis (EP) alone or whether a more sensitive method such as immunoelectrophoresis (IEP) or immunofixation (IF) was required. In the earliest reports either no method was specified or only EP was required. More recently there has been a trend towards a more stringent definition of CR requiring a negative IF. Some groups have also required the plasma cells in the marrow to be of normal morphology whereas others have not included morphological assessment, and some groups have included factors such as transfusion independence and lack of symptoms. It is perhaps surprising that many groups do not exclude transient responses by specifying a minimum duration of time for which the paraprotein must remain undetectable to fulfil the definition of CR. CR has hitherto been defined by the EBMT Myeloma Transplant Registry as absence of detectable paraprotein in serum and urine and < 5% plasma cells in marrow, without specifying the method to be used for excluding the presence of paraprotein, nor the time period for which results must remain negative. The IBMTR and ABMTR have not hitherto used a standard definition of CR. The current North American National Cancer Institute Intergroup (SWOG, INT, CALGB and ECOG) Myeloma Trial, comparing conventional versus high-dose therapy, defines CR as absence of paraprotein in serum and urine by EP and IF on at least two measurements for a minimum of 6 weeks, and <4% plasma cells in the bone marrow. There are also currently no generally accepted criteria for the definition of disease progression or relapse and papers reporting the results of different treatment regimens do not always specify the criteria used to define progression ( MacLennan et al, 1992 ; Ballester et al, 1997 ; Barlogie et al, 1997 ). Bergsagel et al (1979 ) defined progression as a progressive increase in serum paraprotein of at least 10 g/l or a 100% increase in urinary light chain excretion. Belch et al (1988 ) also used a minimum increase of 10 g/l in serum paraprotein but required an increase of 2.0 g/24 h in urinary light chain excretion. In recent reports most groups have defined progression as an increase in serum paraprotein or urinary light chain excretion by 25% ( Oivanen et al, 1997 ) or 50% ( Samson et al, 1989 ; Bjorkstrand et al 1995a ; Attal et al, 1996 ; Joshua et al, 1997 ). Other indicators of progressive disease such as increasing marrow infiltration or an increase in the number of lytic bone lesions are also included in the definition of disease progression by most groups. For patients in CR a reappearance of paraprotein, by whatever method, is generally accepted to constitute relapse. The EBMT has hitherto defined progression as a 50% increase of measurable paraprotein levels ( Bjorkstrand et al, 1995b ; Gahrton et al, 1995 ). The IBMTR and ABMTR have not previously utilized any defined criteria, but a number of groups recently reporting results of high-dose therapy studies have used a 25% increase for defining progression ( Attal et al, 1996 ; Schiller et al, 1998 ; Barlogie et al, 1997 ) and the current North American Intergroup trial adopts the same definition. In the pioneer study dealing with response to treatment in multiple myeloma, the median survival of patients who responded to melphalan was 41 months compared with 9 months in patients who did not respond ( Bergsagel, 1975) and Alexanian et al (1972 ) reported that the survival of patients treated with combination chemotherapy was directly correlated with the extent of reduction of paraprotein synthesis. This has been a frequently quoted reference supporting the relationship between the degree of response and subsequent survival. However, a similar survival analysis carried out by Palmer et al (1989 ) failed to show such a correlation. Several other studies have also reported a lack of correlation between response and survival ( Baldini et al, 1991 ; Marmont et al, 1991 ; Joshua et al, 1991 ; Blade et al, 1994 ). Even with regimens such as high-dose melphalan 140 mg/m2 and VAD, which produced CR in up to 25% of newly diagnosed patients, duration and survival were not prolonged in patients reaching CR as compared with those achieving PR ( Selby et al, 1987 ; Samson et al, 1989 ). With conventional chemotherapy, stabilization of tumour load is a more powerful prognostic factor than the degree of tumour reduction in predicting survival ( Durie et al, 1980 ; Joshua et al, 1991 ; MacLennan et al, 1992 , 1994; Blade et al, 1994 ; Oivanen, 1996). Since the survival of patients who achieve a partial or minimal response is similar to that of those fulfilling more stringent response criteria, all patients attaining a stable state should be considered in plateau phase regardless of the level of paraprotein. The MRC has been unique among those carrying out clinical trials in multiple myeloma in using stable plateau phase to define treatment efficacy rather than response criteria based on a given degree of paraprotein reduction. In some patients the paraprotein does not fall with treatment but does not increase and may remain stable for months or years. These patients have non-responding but non-progressive disease and may be considered to be in plateau phase at diagnosis. Although these patients are classified as non-responders according to the CLMTF and SWOG criteria, the disease does not progress and such patients in fact usually have a long survival ( Blade et al, 1986 ; Joshua et al, 1991 ). This situation is similar to that observed in patients with smouldering myeloma ( Kyle & Greipp, 1980). In summary, few patients treated with conventional chemotherapy enter CR and the correlation between the degree of tumour response and survival is In up to 50% of patients enter CR after high-dose therapy CR defined on the basis of negative after high-dose therapy a correlation between the degree of tumour response and survival has been myeloma patients who enter CR have a and survival than those who enter or remain in PR or who to respond ( Gahrton et al, 1991 , Bjorkstrand et al, 1995a ; Attal et al, 1996 ; Barlogie et al, 1997 ). This be entirely by the increasing use of more stringent criteria for CR in more recent studies of high-dose therapy since in some of these reports CR was based on negative EP without negative IF ( Gahrton et al, 1991 , Bjorkstrand et al, 1995a ). It more that there is a in the of CR after conventional chemotherapy and after high-dose in other the level of minimal disease is in patients in CR than in those who are in CR after therapy. The new criteria are shown in Table are based on existing criteria, with As will form the basis for data reporting from a number of the a was the investigations required are therefore those which are to be the minimum to response and to progression or relapse. paraprotein levels and urinary light chain excretion form the basis for the assessment of response, progression and relapse. levels must remain stable for a minimum of 6 to fulfil the criteria for a given of response. The response criteria for serum paraprotein and urinary light chain must be in patients in are present. Bone marrow examinations are essential only to complete response or to response in non-secretory myeloma. It is that there are patients who increasing bone marrow despite a paraprotein level or non-secretory but this is not common to marrow examinations in all patients and will on In patients to have non-secretory myeloma, marrow is essential to response. In these patients it was also to require a to ensure that the response is not transient and because of the patchy nature of myeloma of the marrow is not but is performed the marrow plasma cell percentage must the skeletal are not required for the definition of response, but performed there must be no evidence of progression of bone disease. to response are also not although examinations are examinations are performed as of routine or for other clinical and show evidence of progressive this will constitute relapse or progression in the absence of any other It is recommended therefore that a skeletal be performed to in to ensure that any new lesions were not in fact present at the time of the It is also that the development of a new vertebral compression may result from bone lesions or and does not response nor constitute relapse. data have not been included in the definitions of response and progression because with this is and the significance of different is not CR is defined on the basis of negative IF on serum and for a minimum of 6 Patients who have no detectable paraprotein on EP without a negative IF result either or not will no be classified as CR. A bone marrow plasma cells is also required for the of CR. Although it is that in patients with myeloma it be very to have of the paraprotein with marrow it was important to exclude this morphology of the plasma cells is not specified because morphological assessment was to be It is not essential to a but a is performed this must also plasma In non-secretory myeloma the marrow must be after a to CR. The main requirement in the definition is the absence of detectable paraprotein by IF as as by Since CR is a for in myeloma, it is that CR should require absence of paraprotein by the most sensitive method in routine of minimal disease at the or level may in patients without detectable paraprotein ( et al, 1993 ; Bjorkstrand et al, 1995b ) but the results of such studies are not and are not in and data at present be included in the criteria for CR. There are in the use of IF to remission status. The requirement for monitoring by IF additional laboratory and and many do not IF EP is negative. it is the to that IF be performed EP is negative. A is classified as in CR only a negative IF has been on at a minimum of 6 In patients achieving CR, IF must also be performed at all subsequent in to the time of disease relapse. Most IF months in these using IF rather than EP to define CR will relevant will on the evaluation of outcomes CR as a prognostic this the EBMT and will record EP and IF results and will outcomes in patients in CR and those who are but or A 50% decrease in serum paraprotein is required for as in the CLMTF However, a 50% decrease in urinary light chain excretion was not considered to define Most light are by the and the urinary excretion therefore only the that renal a given degree of tumour reduction has a more on urinary light chain excretion than on serum paraprotein level. & Alexanian observed that in a of patients with serum paraprotein and urinary light a 50% decrease in serum paraprotein level was always by a decrease of in urinary light chain excretion. We have therefore used the SWOG of 90% decrease in urinary light chain excretion to define However, in to the SWOG criteria, it is not for urinary light chain excretion to fall h there has been a 90% reduction. urinary light chain excretion may decrease by and for PR it to < since it is difficult to accurately of light chain excretion which be to a reduction of in patients with an initial light chain excretion of 2 g/24 h or a transient response as CR or PR a minimum period of negative results or stable paraprotein level to be although this is than that required to fulfil the criteria for plateau It has been agreed that 6 will be the minimum required this assessment of response to be at which with the initial data collection Some patients will their response after and in this the response will be on the first The paraprotein level must be compared with a reference in to accurately response. A is to use the paraprotein level to transplant as the reference However, this may to the of a as of a remission a the paraprotein level does not decrease by a Patients in CR who remain in CR be classified as transplant has been performed as of a remission the response will be by comparing the and paraprotein levels with those to the chemotherapy a may from PR to CR, or from PR to or from disease to PR or CR. Patients in CR who remain in CR will be as in complete response. Patients who have not responded to initial chemotherapy nor to subsequent transplant will be classified as no response. For patients who have not chemotherapy within the 6 months to transplant the response to the transplant alone will be by comparing paraprotein levels with those to patients will include some patients with primary disease or in relapse, as as those who have stable for months after of The of plateau is an important prognostic for the outcome of patients treated with conventional It may therefore be important to patients in plateau transplant have a better in to transplant However, this may be difficult to since transplant is now performed as the of a treatment and time may have for stable plateau to be the transplant It may also be important to whether reaching plateau is also of prognostic significance in those patients who do not achieve CR, and whether the of plateau is more important than the degree of partial response It has been agreed that plateau phase will be defined on the basis of stable paraprotein levels for a minimum of 3 as in the current MRC Plateau will require to be within 25% of the response is assessed, a rise 25% of the criteria for disease We have used the progression to a increase in disease in patients in partial remission or plateau whereas the relapse to a of disease in patients previously in CR. is usually defined as an increase of in serum paraprotein or urinary light chain excretion, with reference to the levels at the time of response. However, the paraprotein level or urinary light chain excretion is at a very and it not be to a in serum paraprotein from a level of for example, as evidence of We have therefore defined progression as an increase of in paraprotein or urinary light chain excretion marrow plasma cell percentage in the but in we have minimum in these These criteria have been to a increase in disease it is that many patients will be and may not require treatment at this may also be defined on the basis of increasing marrow infiltration or skeletal as it is not essential to these investigations there is a clinical to do is defined as reappearance of detectable paraprotein or other of disease in patients previously in CR. is a more than progression in these patients as there was no evidence of disease were in CR. Since a negative IF is the for the definition of CR, of on IF on at least relapse, whether or not the paraprotein detectable again by This is a very stringent definition of relapse, since of IF is not always followed by an increase in paraprotein and such patients may remain for a prolonged period ( Bjorkstrand et al, 1995b ). the IF result may only be in some patients, a situation to that of patients with in for may be but not ( et al, 1993 ). In other of IF does not at least in the to clinical disease This sensitive definition of relapse in CR patients at least to a remission duration in CR patients than those who do not enter CR. It will therefore be important to record the time treatment was after progression or relapse, in to whether the criteria are of subsequent disease These criteria for response, progression and relapse have been developed with the of the evaluation of new in multiple myeloma, high-dose therapy with haemopoietic stem cell It is that and subsequent of these criteria, again using an may be in the as are in clinical and as new For the these criteria for complete relapse and progression should a for clinical trials and was by a from the and Gahrton by the Cancer of

Most patients with plasma cell neoplasia have generalized disease at diagnosis, i.e. multiple myeloma (MM). However, a minority (<5%) of patients with plasma cell malignancies present with either a single bone lesion, or less commonly, a soft tissue mass, of monoclonal plasma cells: solitary bone plasmacytoma (SBP) or extramedullary plasmacytoma (SEP). SBP has a high risk of progression to MM and on magnetic resonance imaging (MRI) examination at least 25% of patients with an apparent solitary lesion have evidence of disease elsewhere (Moulopoulos et al, 1993). In contrast, SEP is nearly always truly localized and has a high cure rate with local treatment. The diagnosis and management of patients with solitary plasmacytoma requires the same range of clinical and laboratory expertise as for patients with MM (UK Myeloma Forum, 2001). The primary treatment for most patients will be radiotherapy, but surgery may also be required, where close liaison among the haematologist, radiotherapist and surgeon is crucial for planning optimum care. A literature search was performed by a professional librarian using MEDLINE and EMBASE from 1996 to March 2002. A search was made for randomized-controlled trials involving plasmacytoma, papers where plasmacytoma was the major focus of the paper and reviews where plasmacytoma was the major focus. The literature was then reviewed by the subgroup of the Guidelines Working Group of the UK Myeloma Forum. Levels of evidence and grades of recommendation are shown in Table I. SBP and SEP are rare diseases and most of the evidence relates to retrospective data from patient series collected over long periods of time. Very few formal clinical trials have been performed. The majority of the recommendations given are therefore based on consensus of expert opinion. Epidemiology and clinical features. Solitary bone plasmacytoma has a male:female ratio of 2:1, with a median age of 55 years and primarily affects the axial skeleton especially the vertebrae (see Table II) (Dimopoulos et al, 2000). Malignant bone tumours of the spine are extremely rare (<0·05% of primary neoplasms). Solitary plasmacytoma is the commonest separate entity within this group, accounting for approximately 30% of the total (McLain & Weinstein, 1989). These tumours occur in the spine twice as often as other bony sites (Chang et al, 1994). The commonest symptom is pain but it can also present with cord or root compression. Involvement of the base of the skull can present with cranial nerve palsies (Vaicys et al, 1999; Vijaya-Sekaran et al, 1999). Localized amyloidosis can be a feature of both SBP and SEP (Pambuccian et al, 1997; Nagasaka et al, 2001). As well as the appropriate blood and urine tests (see below), specific imaging of the spine is required and best achieved by MRI ± computed tomography (CT). Bone scans are unreliable. Biopsy is usually possible percutaneously, guided either by fluoroscopy or CT. The presence of a monoclonal paraprotein (M protein) has been reported in 24–72% of patients in different series (Dimopoulos et al, 2000). The frequency probably depends on the level of sensitivity of the tests used. In a recently reported series of 60 patients from the MD Anderson Hospital presenting between 1995 and 2000 (Wilder et al, 2002), a serum or urinary paraprotein was detectable in 43 patients (62%) by routine electrophoresis or immunofixation/immuno-electrophoresis. However, the levels of paraprotein were generally low. Of the 37 patients who had a serum paraprotein, only 11 had levels over 10 g/l and the highest level was 22 g/l. In the six patients who only had Bence Jones protein in the urine, total daily excretion of urinary-free light chain was below 100 mg/d in all patients. Natural history and prognosis. The majority of patients with apparent SBP develop myeloma, with a median time to progression of 2–4 years (Table II). The median overall survival in different series varies from 7·5 to 12 years (Dimopoulos et al, 2000). Most reported series extend over a long time period and the majority of included patients have not had MRI scans. These patients will therefore include a proportion of patients with asymptomatic myeloma. The progression-free and overall survival in patients with SBP may improve as MRI examination becomes an established part of the staging criteria for the diagnosis and patients with early MM are excluded. Quoted adverse prognostic features for progression to MM include low levels of uninvolved immunoglobulins, axial disease, older age, lesion size >5 cm and persistence of the M protein after treatment (Bataille & Sany, 1981; Holland et al, 1992; Tsang et al, 2001). However, these adverse prognostic features have not been consistent between series (Chak et al, 1987; Frassica et al, 1989; Bolek et al, 1996; Liebross et al, 1998). A recent multivariate analysis of prognostic factors in a series of 60 patients from the MD Anderson Hospital (most of whom were not staged by MRI) concluded that persistence of M protein for more than 1 year after radiotherapy was the only independent adverse prognostic factor (Wilder et al, 2002). The paraprotein disappeared in 13 patients and persisted in 32, while 15 patients had non-secretory disease. At a median follow-up of 7·8 years, only one of 13 patients with resolution of the paraprotein progressed to MM while over 90% of patients with persistent paraprotein had progressed. Most patients with persistent M protein progressed to MM within 2 years of treatment. Age, tumour size and level of paraprotein at diagnosis had no independent prognostic value. In this series, patients with non-secretory disease appeared to do less well than those with a paraprotein that disappeared after radiotherapy. As already indicated, it is likely that many of the patients with apparent SBP who progress actually have disseminated disease at presentation. MRI examination of the spine can detect occult disease in approximately 26% of patients with apparent SBP (Moulopoulos et al, 1993; Wilder et al, 2002). Conversely, a negative MRI of the spine is a good prognostic feature. Liebross et al (1998) showed that in a series of 15 patients with a spinal plasmacytoma who did not have a positive MRI examination, progression to MM occurred in seven of eight patients where MRI had not been performed as opposed to one of seven with a negative MRI of spine (patients with other lesions on MRI were considered to have MM). Positron emission tomography (PET scanning) has recently been evaluated in the staging of patients with myeloma and plasmacytoma (Orchard et al, 2002; Schirrmeister et al, 2002). PET scanning, like MRI, appears to be useful in detecting occult disease in patients with apparent solitary SBP. Those patients with SBP who do subsequently develop MM have a relatively good prognosis. Liebross et al (1998) reported that their patients with SBP who progressed to MM were characterized by low tumour mass, 77% response rate to chemotherapy and a median survival from progression of over 5 years. Patients progressing to MM should be treated according to the British Committee for Standards in Haematology (BCSH) guideline on the management of MM (UK Myeloma Forum, 2001). In addition, patients presenting as SBP but found upon MRI scan to have more extensive disease should be considered as having MM and treated accordingly (see below). Diagnostic criteria. Recommended diagnostic criteria are summarized in Table III. Based on the data discussed above, the following criteria are recommended: single area of bone destruction due to clonal plasma cells; histologically normal marrow aspirate and trephine (<5% plasma cells); normal results on skeletal survey, including radiology of longbones; no anaemia, hypercalcaemia or renal impairment due to plasma cell dyscrasia; absent or low serum or urinary level of monoclonal immunoglobulin (level of >20 g/l suspicious of MM, see above); no additional lesions on MRI scan of the spine (see below for criteria of involvement). Pathology review. Solitary bone plasmacytoma is generally diagnosed by biopsy or fine needle aspiration. Percutaneously guided biopsy of the spine is usually possible either by fluoroscopy or CT. As these tumours are rare, pathology review by a histopathologist with a special interest in either bone tumours or lymphoproliferative disorders is strongly recommended. Further investigations. The following investigations should be performed in all patients: full blood count; biochemical screen including electrolytes and corrected calcium; serum immunoglobulin levels; serum and urine protein electrophoresis and immunofixation; full skeletal survey, including standard X-rays of the skeleton including lateral and anteroposterior cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri and femora (UK Myeloma Forum, 2001); MRI of thoracic and lumbar spine; bone marrow aspirate and trephine. Additional investigations may be useful in selected patients, including MRI of pelvis, proximal femora and humeri; immunophenotyping and molecular assessment of bone marrow plasma cells; PET scanning. The role of β2 microglobulin in the diagnosis and management of SBP has not been established. There are, at present, no data on the use of the serum-free light chain assay in SBP. MRI examination. There are no reported guidelines to define involvement on an MRI scan in the context of apparent SBP. However, the MRI appearances in MM have been well described (Baur et al, 2002). The presence of one or more foci of abnormal signal intensity [low on T1 weighted imaging and high on T2 weighted or STIR (Short TI Inversion Recovery) images], which enhance after the administration of paramagnetic contrast in the absence of known recent compression fractures, other primary malignancy or typical characteristics of benign or malignant primary bone tumours, is considered evidence of distant involvement in patients with apparent SBP (M. Dimopoulos, personal communication). Radiotherapy. This subject has recently been reviewed (Hu & Yahalom, 2000). Radical radiotherapy is the treatment of choice for SBP. In common with other rare tumours, the evidence base for treatment is largely composed of retrospective studies of small numbers of patients. Progression to MM is common, despite high local control rates of 83–96% achieved with moderate doses of radiotherapy (Mayr et al, 1990; Holland et al, 1992; Bolek et al, 1996; Liebross et al, 1998; Tsang et al, 2001). Data on dose–response relationships are weak in most series, due to relatively low patient numbers and narrow range of doses used. Mendenhall et al (1980) recommended a minimum dose of 40 Gy following a dose response analysis based on a review of the literature including 81 patients. They reported a 6% local failure rate in patients with SBP treated with doses of 40 Gy or above, in contrast to 31% for doses below 40 Gy. Some centres prefer to use higher doses of 45–50 Gy (Mayr et al, 1990; Liebross et al, 1998), but is evidence for a dose response 40 Gy and local have been reported after doses of Gy (Mayr et al, 1990; Liebross et al, 1998). Tsang et al reported the Hospital of patients with SBP treated between and and concluded that was no dose–response Gy. They reported that tumour was the most factor local control with local control for SBP of 5 cm or less and only for SBP >5 data that SBP of >5 cm requires a higher dose treatment for local This is by other (Mayr et al, 1990; Holland et al, Based on the evidence above, a dose of 40 Gy in is recommended for SBP of 5 cm or SBP >5 a higher dose of to Gy in should be for tumours >5 cm is chemotherapy by radiotherapy. This is but is evidence to The choice of clinical for radiotherapy is also Some that the bone should be treated (Mayr et al, The for this is largely based on in retrospective series treated MRI bone marrow and soft tissue of SBP for radiotherapy recent series local control rates following of the tumour on MRI scan with a than the bone et al, 1997; Liebross et al, 1998; Tsang et al, 2001). The clinical should include tumour that is on MRI with a of at least 2 small as this will include the bone with one uninvolved and the clinical will not include the as this of normal of response following radiotherapy depends upon in levels of monoclonal resolution or progression of and evidence of disease on Patients monoclonal protein with treatment a with a high of cure (see while many of those with persistent paraprotein after 1 year will develop In contrast, on imaging are to and do not with et al, 1998). In of patients the monoclonal protein with radiotherapy. The monoclonal protein usually but the can be years. persistence and level are not an for treatment but these patients should be for of disease Some patients to an monoclonal of Patients not to radiotherapy do not have They may have persistent as a of bone while paraprotein may disease at other In these a biopsy is to the is recommended that SBP is treated with radiotherapy, the tumour shown on MRI with a of at least 2 cm and to a dose of 40 Gy in based on level SBP >5 a higher dose of to Gy in should be considered based on level Patients with SBP to detect progression to MM, for with of of and should be in with laboratory investigations serum and urine paraprotein based on level Patients not to radiotherapy (see should be treated with A is to guidelines for the treatment of MM (UK Myeloma Forum, 2001). In patients, this include high dose and cell based on level Patients presenting as SBP but found on MRI to have disease at other sites should be considered as having MM and treated accordingly based on level the treatment of choice of the primary pathology and surgery is in the absence of or However, early diagnosis and for a is in most with spinal to the of spinal over the treatment is a and for patients who develop pain by within the or a of A of have been recently this et al, 1997; et al, 1998; et al, 2001). of requires of and this is most performed by In of is also surgery usually best to the a to the which can occur in i.e. et al, 2000). to the high of survival in these patients (McLain & Weinstein, of the of the spine may be and have been used. As are no data to the of from the of the to be more The relatively of et al, 2002), which has been with in MM, has not been reported in solitary is in of of in solitary plasmacytoma with is likely to be of given in most the of destruction the The choice of surgery and to be to the specific of on as and of and of the and the and of the in of and pain have been reported in small series in the using this et al, 1998; et al, 1998). is often recommended that surgery is required or in the it should be radiotherapy is is more in patients who have radiotherapy. However, it is to that surgery may radiotherapy, by the of which may of disease from liaison between haematologist, radiotherapist and surgeon is therefore crucial in planning optimum treatment for patients. the treatment of choice for SBP and surgery is in the absence of or based on level surgery is required radiotherapy should also be given and the of surgery to radiotherapy should be for patient based on level In of spinal plasmacytoma, for an from an surgeon or in spinal surgery is based on level of the may be based on level The role of chemotherapy is at present not & & Yahalom, 2000). The of chemotherapy to radiotherapy in the treatment of SBP be in local control and or progression to Some that chemotherapy may progression to MM (Mayr et al, 1990; Holland et al, However, no et al, Tsang et al, 2001). one randomized-controlled has been This from and given for years after radiotherapy et al, a median follow-up of years, 15 of patients in the radiotherapy progressed to myeloma with only of patients in the treatment between the of patients showed a survival for this was a randomized-controlled the of patients was The results therefore to be by studies that chemotherapy is in of of and There are data to chemotherapy in SBP. may be appropriate to chemotherapy in patients at higher risk of treatment those with disease based on level The literature search no with the role of in the management of There are, as no reported data on the role of in progression of asymptomatic myeloma or SBP. is an Group to the of in these et al, at the present time an recommendation be is interest in the role of in plasma cell has been in the treatment of soft tissue plasmacytoma in the context of MM et al, and is in the of asymptomatic myeloma but are no data on in SBP. Patients that present as SBP but are found upon MRI scan to have more extensive disease marrow should be considered as having However, the plasmacytoma is the only of clinical and is no other involvement it be appropriate to the plasmacytoma according to the guidelines and to chemotherapy are of as the UK Myeloma Committee for Standards in Haematology guidelines for myeloma (UK Myeloma Forum, 2001). Solitary extramedullary are less common than SBP but a as the majority can be by local radiotherapy (Dimopoulos et al, 1999). SEP can the 90% in the and especially in the including the and et al, 1990; et al, 1993; et al, 1997; Liebross et al, 1999; et al, 2000). The most is the A of other sites can be including and et al, 1990; et al, 1990; et al, 1992; et al, 1992; et al, et al, 1996; et al, 1996; & 1996; et al, 1999; et al, et al, 2001). A monoclonal paraprotein is in the serum urine in than 25% of patients (Table II). rates of have been after radiotherapy et al, 1999). The risk of distant appears to be i.e. less than with SBP (Mayr et al, disease may present as MM, SBP or soft tissue involvement of or distant this to be within years of At least of patients for years et al, 1990; et al, 2000). Diagnostic criteria. or MRI is required to the of the lesion but the role of MRI of other in the staging of SEP has not been As is a low risk of progression to MM in these patients and the role of MRI in the staging of SEP has not been do not MRI of the spine to be for the diagnosis of Recommended diagnostic criteria are shown in Table III. Pathology review. most patients the diagnosis can be established by fine needle or biopsy et al, As these tumours are rare, and can be with pathology review by a histopathologist with a special interest in lymphoproliferative disorders is strongly recommended. As above, or MRI is required to the of the lesion but do not MRI of other (see to be investigations should be as for SBP (see Radiotherapy. Solitary extramedullary plasmacytoma are control rates of are reported with moderate doses of radiotherapy (Mayr et al, 1990; Bolek et al, 1996; et al, 1997; Liebross et al, 1998). dose and should be to early and and local There is no established dose–response of small patient series and low local failure Tsang et al achieved local control in 13 of of patients with Gy. The only failure was in a patient with a primary tumour >5 et al achieved local control in six of seven patients with Gy dose 40 Gy in The only failure was in a patient with an extensive dose–response was Holland et al also reported local control in tumours >5 cm and no evidence of a dose–response over a dose range of Gy dose series local control Bolek et al reported local control in 10 patients with doses from to Gy dose and concluded by a dose of 40 Gy in et al reported on 10 patients with seven of whom were treated by radiotherapy, using doses of Gy. control was achieved in all the patients, the that local control have been achieved with The dose therefore appears to be in the range of Gy. SEP cm have an of local control with doses in the of 40 Gy in is a higher risk of local failure in tumours >5 which a higher dose in the of Gy in The radiotherapy is SEP in the or of to in of et al, 1997; & Yahalom, 2000). The of in the to and especially which may not local control rates are reported the are included et al, However, good results are also reported from series in which the are only included Tsang et al the primary in patients primary was in the tissue of the were There were no in patients. et al the primary only in seven patients and reported no et al treated the primary only in patients and only included the in patients with clinical no In contrast, et al reported in of 11 patients treated to the primary only and recommended In of the of and the high local control rates reported the of evidence a of the primary with a and including the only or as at high as in primary sites involving Solitary extramedullary plasmacytoma should be treated by radiotherapy the primary tumour with a of at least 2 cm based on level The should be included The should be included in SEP of based on level SEP to 5 cm a radiotherapy dose of 40 Gy in is recommended. SEP of >5 a higher dose of to Gy in is recommended based on level The majority of SEP occur in the and is generally not required for Radical surgery with is a generally that is not as the tumours are generally and the majority of patients are with radiotherapy. patients with SEP in other should be A review of the literature by et al the of patients treated with surgery radiotherapy or surgery and radiotherapy. They found of involving the and in other Most of the patients were treated with surgery or treatment and only were treated with radiotherapy The risk of was the same for the treatment is not the patients that a did of the most of the patients with SEP in the were treated with radiotherapy or radiotherapy and surgery surgery was in and survival were in those treated with They concluded that patients with plasmacytoma from a However, this review is to as it a to and radiotherapy was not in for at least of this are likely to have been between the patients treated by the different There is therefore no good evidence that surgery additional over radiotherapy in patients with SEP of the and is in the majority of patients. However, patients have been treated by primary radiotherapy only be required in patients with In contrast to radiotherapy can be following surgery as are not in this is the treatment of choice for and SEP based on level Radical surgery should be in and SEP based on level SEP at other sites should be considered based on level Patients with should radiotherapy based on level recommendation for radiotherapy can be made for patients who have with negative There is no evidence on the role of chemotherapy in the treatment of may have a role in selected patients. et al a higher failure rate in tumours using the MM criteria of et al Tsang et al and Holland et al that tumours >5 cm are at higher risk of chemotherapy should be considered in patients with tumours >5 cm and those with high tumours based on level is for patients with disease. as for MM is based on level treatment There is no and no data the use of in has been to extramedullary plasmacytoma in the context of MM with results et al, et al, et al, but is no data on use in of appropriate patient and an part of the of patients with SBP and are the same as those for patients with myeloma (UK Myeloma Forum, 2001). The Myeloma a for patients with solitary The and in these guidelines is to be and at the time of to However, the the British for Haematology and the do not or for or that may have been are to for with the literature with the of an from the Myeloma

BACKGROUND AND METHODS: In contrast to autologous bone marrow transplants for hematologic cancers, allogeneic transplants contain no tumor cells that might cause a relapse. We report the results of such allogeneic bone marrow transplantation using HLA-compatible sibling donors in 90 patients with multiple myeloma performed in 26 European centers between 1983 and 1989. RESULTS: At the time of the most recent follow-up, 79 months after the start of the study, 47 patients were alive and 43 were dead. The rate of complete remission after bone marrow transplantation was 43 percent for all patients and 58 percent for the patients who had engraftment. The actuarial survival at 76 months was 40 percent. The median duration of relapse-free survival among patients who were in complete remission after bone marrow transplantation was 48 months. The stage of the disease at diagnosis and the number of treatment regimens tried before bone marrow transplantation were predictive of the likelihood of complete remission after engraftment. There were trends toward longer survival among patients who were responsive to treatment before bone marrow transplantation, patients with Stage I disease at diagnosis, and patients who had received only first-line treatment before transplantation, as compared with those who were not responsive, those with Stage II or III disease at diagnosis, and those who had received three or more lines of treatment, but the differences in these factors were not statistically significant. Two post-transplantation factors predicted better long-term survival: complete remission after engraftment and grade I graft-versus-host disease, rather than grade II, III, or IV. CONCLUSIONS: Allogeneic bone marrow transplantation with the use of HLA-matched sibling donors appears to be a promising method of treatment for some patients with multiple myeloma.

In 2001, guidelines for the diagnosis and management of myeloma were published by the Guidelines Working Group of the UK Myeloma Forum (UKMF) on behalf of the British Committee for Standards in Haematology (BCSH) (UK Myeloma Forum; British Committee for Standards in Haematology, 2001). That same year, the second edition of guidelines prepared by the Nordic Myeloma Study Group (NMSG) in 1995 was issued (in the Scandinavian languages; http://www.myeloma-nordic.org). As both sets of guidelines were intended to be evidence based, it was reassuring to note that the recommendations were similar. Subsequently, informal contact between members of the two groups led to the decision to prepare these common, updated guidelines. These revised and updated guidelines include new sections on imaging and the management of skeletal disease, cover new developments in disease classification and staging and the use of new therapeutic approaches, such as thalidomide, bortezomib and reduced-intensity allogeneic transplantation. The guidelines are presented in specific sections as follows: The production of these guidelines involved the following steps: Establishment of working groups on the various topics, with representatives from both organisations. Reappraisal of existing UK and Nordic guidelines from 2001. Review of key literature to 30 November 2004 including Cochrane database, Medline and Internet searches; key references subsequent to this date incorporated in final drafting where relevant. Review of major conference reports. Recommendations based on literature review and consensus of expert opinion. Consultation with representatives of other specialties. Involvement of patient advocacy through the International Myeloma Foundation (UK). Review by UKMF Executive, BCSH Committee and regional coordinators of the NMSG. Review by a sounding board group of 100 members of the British Society for Haematology (BSH). These guidelines set out the key areas of strategy for the effective clinical management of myeloma. Levels of evidence and grades of recommendation are summarised in Tables I and II. Detailed chemotherapy protocols and dosages are not included; they are beyond the scope of this document. Provision of the detailed information and local protocols needed for the safe organisation, delivery and management of chemotherapy and related clinical care are the responsibility of each cancer centre/network (or equivalent in other countries). Statements appearing on drug dosage in the text mainly concern dosages used in specific trials or in the context of adjustment for renal impairment. The authors of these guidelines have made extensive efforts to ensure that treatments, drugs and dosage regimens are accurate. However, changes in information resulting from continuing research and clinical experience, reasonable differences in opinions among authorities, and the possibility of human error in preparation of the text require the clinician to exercise individual judgement when making a clinical decision. He/she must check product information and drug dosages before prescribing or administration. Contributory authors are listed in Appendix 1. Updates of these guidelines will be available on the BSH, BCSH, UKMF and NMSG web sites. A full revision is planned for 2008/09. Myeloma is a plasma cell tumour with an annual incidence in the UK and Scandinavian countries of approximately 50 per million and a median age at presentation of about 70 years (Turesson et al, 1984; Hjorth et al, 1992; Office of National Statistics, 2001; Phekoo et al, 2004). Myeloma has a higher incidence in Afro-Caribbean ethnic groups compared with Caucasians; little else is known specifically about its epidemiology. Most cases present de novo; a minority evolve from Monoclonal Gammopathy of Undetermined Significance (MGUS). Approximately 15% of patients are aged <60 years and a further 15% are aged between 60 and 65 years. Fewer than 2% of myeloma patients are under 40 years old at diagnosis. This age distribution has implications for the population eligible for specific types of treatment, such as high-dose therapy (HDT) and stem cell transplantation. Although there has been a rise in the upper age limit for intensive therapy, the majority of myeloma patients are still treated with oral chemotherapy. Clinical presentation is varied. Presenting features include: Symptoms of bone disease: typically persistent, unexplained backache. Impaired renal function. Anaemia: typically normochromic, normocytic, and less frequently leucopenia and/or thrombocytopenia. Hypercalcaemia. Recurrent or persistent bacterial infection. Hyperviscosity. Symptoms suggestive of spinal cord/nerve root compression. Features suggestive of amyloidosis, such as nephrotic syndrome and cardiac failure. Persistently raised erythrocyte sedimentation rate (ESR) or plasma viscosity as an incidental finding. Symptomatic patients with suspected myeloma require urgent specialist referral. Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate admission to hospital. Patients with a paraprotein found on routine testing and who have no clinical symptoms and no anaemia, hypercalcaemia or renal impairment do not necessarily require urgent referral, but specialist advice should be sought. A consultant haematologist or oncologist should lead the care of patients with myeloma, but there needs to be input from other professionals familiar with the range of problems that are likely to be encountered. In the UK, this will be delivered as part of the multidisciplinary team, within an approved Cancer Network (see Appendix 2). In Denmark, Norway and Sweden, corresponding recommendations will be worked out in association with the appropriate national haematology societies. Effective and high-quality care in myeloma requires the availability of other specialist expertise and services (see Table III), which may be available locally or in a neighbouring hospital. There should be clear policies and protocols for access to these services. Where therapy involves autologous or allogeneic stem cell transplantation, this must be carried out in an European Group for Blood and Marrow Transplantation (EBMT) accredited centre, equipped to provide level 3 care for haematological malignancies (British Committee for Standards in Haematology Clinical Haematology Task Force, 1995). Optimal supportive care is a fundamental part of overall management throughout the course of the disease. Patients should be informed and instructed appropriately about the importance of supportive measures. Despite its importance there is a little published research. The majority of recommendations on supportive care in these guidelines are thus grade C based on level IV evidence. Throughout the course of the patient's illness, it is essential that good communication be maintained between the haematology team, other teams involved in care and the patient's general practitioner. Initial investigation of a patient with suspected myeloma should include the screening tests indicated in Table IV followed by further tests to confirm the diagnosis. Electrophoresis of serum and concentrated urine should be performed, followed by immunofixation to confirm and type any monoclonal protein (M-protein/paraprotein) present. Immunofixation is also indicated in patients where there is a strong suspicion of myeloma but in whom routine electrophoresis is negative. Quantification of serum M-protein should be performed by densitometry of the monoclonal peak on electrophoresis; immunochemical measurement of total immunoglobulin (Ig) isotype level can also be used and is particularly useful for IgA and IgD M-proteins. Quantification of urinary light chain excretion can be performed directly on a 24-h urine collection or calculated on a random urine sample in relation to the urine creatinine. Quantification of serum-free immunoglobulin light chain levels (FLC assay) and κ/λ ratio can be used as an alternative to quantifying urinary light chains. The serum free light chain tests are particularly useful for diagnosis and monitoring light chain only myeloma (Bradwell et al, 2003) and patients in whom the serum and urine is negative on immunofixation (non-secretory myeloma) (Drayson et al, 2001). While bone marrow aspirate alone may be sufficient to confirm the diagnosis (showing over 10% plasma cells), trephine biopsy or clot section can provide a more reliable assessment of plasma cell infiltration (Rajkumar et al, 2001). Bone marrow trephine biopsy should be done, where possible, at diagnosis, even if an apparently adequate aspirate is obtained, as it provides a baseline if post-treatment aspiration yields a poor specimen and trephine biopsy has to be used for assessment of response to treatment. Data from current ongoing clinical trials investigating conventional cytogenetic and fluorescence in situ hybridisation (FISH) analysis may provide important prognostic information and clarify the applicability of these techniques to routine clinical practice. Flow cytometry of a bone marrow aspirate can permit assessment of plasma cell phenotype, confirm clonality and permit determination of the proportion in cell cycle (plasma cell labelling index). It is important to assess abnormal phenotype and clonality when the bone marrow plasma cells are <10%. Identification of an abnormal and unique plasma cell phenotype may be of value for later response evaluation. Clonality can also be assessed by immunohistochemistry on trephine biopsy sections. Standard X-rays of the skeleton should be performed in all patients. Computed tomography (CT) and magnetic resonance imaging (MRI) scanning may be helpful in particular circumstances (see Section 3). The diagnosis of myeloma is usually confirmed by demonstration of a monoclonal protein (M-protein/paraprotein) in the serum or urine and/or lytic lesions on X-ray together with an increased number of plasma cells in the bone marrow (Greipp, 1992). Other conditions in which an M-protein may be present include: MGUS; AL amyloidosis; solitary plasmacytoma (skeletal or extra-medullary); B-cell non-Hodgkin lymphoma (including Waldenstrom macroglobulinaemia); chronic lymphocytic leukaemia. Because of the high prevalence of MGUS (up to 2% in people over 50 years old and 3% in those over 70 years old) and the frequent use of serum protein electrophoresis, most patients presenting with an M-protein in the serum will have MGUS rather than myeloma. Criteria for distinguishing these conditions are, therefore, important. An international working group has recently recommended a new classification of MGUS and myeloma, 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 (Table V). The distinction between symptomatic and asymptomatic myeloma depends on the presence or absence of ROTI (Table VI). Asymptomatic myeloma, in this classification, is largely equivalent to the categories previously termed equivocal, indolent or smouldering myeloma. However, some patients without clinical symptoms may fall into the 'symptomatic' group because of organ impairment and require immediate therapy. Patients with asymptomatic myeloma do not require immediate treatment, but do require careful follow-up. Over-investigation of healthy persons with a small M-protein should be avoided. Although bone marrow plasmacytosis below 10% and a radiologically normal skeletal survey are listed as criteria for the diagnosis of MGUS, it is not reasonable or practical to perform bone marrow examinations and extensive X-rays in asymptomatic elderly patients with a low-level paraprotein and no clinical evidence of ROTI. The additional results are very unlikely to alter management. The extent of diagnostic procedures in asymptomatic patients should take into consideration the age of the patient, the presence of other disease and the levels of M-protein. It should also be noted that low-level Bence Jones proteinuria and a reduced level of polyclonal immunoglobulins may be observed in some patients with MGUS and are not in themselves indications of malignancy (Kyle et al, 2002). The investigation and diagnosis of AL amyloidosis and of solitary plasmacytoma have been reviewed in recent UKMF/BCSH guidelines (Soutar et al, 2004; UK Myeloma Forum; British Commitee for Standards in Haematology, British Society for Haematology, 2004). The following recommendations are grade C based on level III evidence. The diagnostic criteria agreed by the International Myeloma Working Group should be used. Investigation should include the tests shown in Table IV. A careful assessment for myeloma-related organ and tissue impairment should be carried out, in order to identify asymptomatic patients who require treatment. Cytogenetic abnormalities have prognostic significance but should primarily be analysed within the context of clinical trials designed to elucidate their importance for choice of therapy. The extent of diagnostic procedures in asymptomatic patients with an M-protein should take into consideration the age of the patient, the presence of other disease and levels of M-protein. Skeletal survey and bone marrow examination are not mandatory to make a diagnosis of MGUS in the absence of relevant clinical symptoms, anaemia, hypercalcaemia or renal impairment, but are recommended in younger patients and may be considered for older patients with M-protein levels above 20 g/l. Clinical review and repeat measurements of paraprotein levels at 3 and 6 months are advised to establish a firm diagnosis of MGUS. Chemotherapy is indicated for the management of symptomatic myeloma and asymptomatic myeloma with myeloma-related organ damage. Early intervention in other asymptomatic myeloma has shown no benefit in two randomised controlled trials (Hjorth et al, 1993; Riccardi et al, 2000). The average risk of progression from MGUS to active disease (myeloma or other B-cell malignancy) is about 1% per year, with the only proven prognostic factor for progression to myeloma being serum M-protein level (Kyle et al, 2002; Kyle & Rajkumar, 2003). The percentage risk of progression in 10 years roughly equates with the M-protein level in g/l (e.g. 20 g/l is associated with a 20% risk). Despite associated low levels of polyclonal immunoglobulins there is only a twofold increase in the risk of bacteraemia for patients with MGUS compared with normal controls (Gregersen et al, 1998). The median time to progression (TTP) from asymptomatic to symptomatic myeloma is 12–32 months (Wisloff et al, 1991; Dimopoulos et al, 1993; Hjorth et al, 1993; Weber et al, 1997). Nine of 71 patients with asymptomatic myeloma died of infection without disease progression (Wisloff et al, 1991). Patients who are clinically asymptomatic but have radiological evidence of bone disease (at least one lytic lesion) are at high risk of progression with a median TTP of 8 months (Wisloff et al, 1991; Dimopoulos et al, 1993). Note that in the new International Classification (The International Myeloma Working Group, 2003), patients with bone disease are classified as 'symptomatic' and requiring treatment even in the absence of clinical symptoms. Two studies have shown that patients with no evidence of bone disease but with abnormal marrow appearances on MRI examination are also at higher risk of disease progression (Weber et al, 1997; Mariette et al, 1999). The prognostic effect of an abnormal MRI is much less marked than that of lytic bone disease detected radiologically. Mariette et al (1999) reported that median TTP had not been reached by 25 months even in patients with an abnormal MRI and Weber et al (1997) found MRI only to be discriminatory in patients with other adverse features (high levels of paraprotein or urinary Bence-Jones protein or IgA isotype). Monitoring of patients with MGUS and asymptomatic myeloma should be indefinite; frequency may vary according to the risk of progression, MGUS with high M-protein levels and asymptomatic myeloma being associated with the highest risk (grade B recommendation; level III evidence). Monitoring of asymptomatic myeloma should include regular (usually three monthly) clinical assessment and measurement of both serum and urinary paraprotein. Repeat bone marrow examinations and skeletal X-rays will be required less often or when new symptoms or signs develop (grade C recommendation; level IV evidence). Monitoring of MGUS similarly should include regular clinical assessment and follow-up measurement of serum paraprotein; six monthly or annual will usually be sufficient in those with low risk of progression (grade C recommendation; level IV evidence). Patients and general practitioners should be provided with information on risk and clinical features of disease progression, particularly those listed in Table VI (grade C recommendation; level IV evidence). Treatment should be deferred until there is evidence of disease progression or organ impairment (grade A recommendation; level Ib evidence). Patients without clinical symptoms but with radiological evidence of bone disease should commence treatment immediately (grade B recommendation; level IIb evidence). These patients are now grouped with symptomatic myeloma. The natural history of myeloma is heterogeneous with survival times ranging from a few weeks to >20 years. Analysis of prognostic factors is essential to compare outcomes within and between clinical trials. For individual patients the best staging systems can predict survival outcome with around 70% sensitivity and specificity. Whether staging systems can beneficially influence choice of therapy is unproven. High serum levels of β2-microglobulin and C-reactive protein and low-serum levels of albumin correlate with worse survival (Bataille et al, 1992; Jacobson et al, 2003). Atypical plasma cell morphology and high proliferative activity also indicate a bad prognosis (Greipp et al, 1993). Cytogenetic abnormalities are strong prognostic factors. Deletions/monosomy of chromosome 13, non-hyperdiploidy and certain balanced translocations, t(4;14), t(14;16), have a strong negative impact on prognosis (Fonseca et al, 2004). Gene profiling with microarray techniques can be expected to expand our knowledge in this field. Many attempts to construct prognostic models have been made since the Durie/Salmon staging system was devised (Durie & Salmon, 1975). In particular, attempts have been made to on the Durie/Salmon system as it not include albumin or serum β2-microglobulin A working group has recently an International based on serum levels of β2-microglobulin and albumin that patients into three prognostic groups of type of Table (Greipp et al, 2003). of cytogenetic into this may further The following recommendations are grade C based on level IV evidence. The International based on serum albumin and β2-microglobulin is recommended in to the Durie/Salmon staging should be before treatment, as a serum levels of β2-microglobulin and Cytogenetic and/or analysis may be helpful if should be with in individual patients. present there is no evidence to prognostic factors to therapy in individual patients. of tumour response is based on changes in serum levels of M-protein and/or urinary light chain In a clinical response requires that no new myeloma-related organ or tissue The criteria in Table are summarised from those of an International Working Group (see et al, for full of requires that there is no paraprotein by immunofixation It has been shown that patients who have no paraprotein by routine electrophoresis but have paraprotein still by have a prognosis to other patients in response those with a negative have a et al, et al, 2001). therefore, be performed if there is no paraprotein by Bone marrow assessment is only essential to confirm response and to response in myeloma. These criteria also include of and is as of disease in patients previously in progression to patients not previously in It is not that the of treatment should be to to be a good prognostic factor for and overall survival et al, et al, is reached by a of patients with in M-protein levels conventional therapy and in a with in M-protein levels these patients have as good a prognosis as patients in of paraprotein levels et al, et al, are useful for monitoring only and myeloma (Drayson et al, 2001; et al, 2003). has also recently been shown to be helpful in monitoring response in the majority of patients with an immunoglobulin paraprotein; because of the of this may provide an of response to therapy than changes in paraprotein et al, 2004). The of imaging in the management of myeloma the assessment of the extent and of the disease at the and of and subsequent assessment of disease and MRI are examination techniques in myeloma. tomography imaging with and imaging are scanning techniques under current evaluation. The use of X-ray scanning has not been in myeloma. the availability of more imaging it is important to which are most all times the investigation and of a patient, the of a imaging investigation the that it will alter should be Provision of clinical information to the when the imaging is made will ensure that the imaging is performed at the The skeletal survey the for radiological screening at diagnosis, with clear association between the extent of disease and tumour at diagnosis (Durie & Salmon, 1975). is areas of the skeleton to be and may identify at risk of A system based on clinical and radiological may be to predict the of in and identify patients who may benefit from However, has low only lytic disease when at least of bone has been & provides an assessment of et al, and has low specificity. Computed tomography has higher sensitivity than at small lytic lesions and can the presence and extent of associated tissue disease and in biopsy for diagnosis (Kyle et al, It frequently the significance of areas on symptomatic areas that do not abnormalities on or of the skeleton that be by and is helpful in the of and et al, 2003). resonance imaging is useful for the assessment of the extent and of tissue disease. It is the of choice for investigation of patients with a presentation suggestive of cord et al, an assessment of the level and extent of cord or root compression, of the tumour and to which it has into the (see Section In MRI may information about the of bone marrow of MRI have prognostic with association between and appearances and higher tumour et al, 1992; et al, et al, et al, MRI of the in patients with myeloma may predict a higher risk of than patients who have normal appearances et al, but not predict the of et al, resonance imaging is an essential investigation in the diagnosis of solitary plasmacytoma and myeloma. In the staging of apparently solitary bone magnetic resonance screening of the and lesions that are in to of patients et al, 1993). The diagnosis and management of solitary plasmacytoma have been reviewed in a recent BCSH (Soutar et al, 2004). Standard bone has a low sensitivity in myeloma to the of activity that the lytic lesions of myeloma (Bataille et al, et al, it may of disease not by in the or but is more A number of indicate that scanning can be useful in of disease in myeloma and solitary plasmacytoma et al, et al, 2002; et al, 2003). This is the for & 2000). In myeloma bone at diagnosis is with an increased risk of et al, 2004). However, the bone can be by and spinal et al, and the presence of rise to in scanning in myeloma patients. Skeletal survey should be part of the staging of myeloma patients and should include a of the and of the (including an and and of the and of the In any symptomatic areas should be specifically with appropriate (grade C recommendation; level IV evidence). should be used to clarify the significance of such as lytic in of the skeleton that are to on such as and (grade B recommendation; level III evidence). should also be used to symptomatic areas of the skeleton where no is found on the skeletal survey (grade B recommendation; level or MRI is indicated to the and extent of tissue disease and these two imaging techniques can information (grade B recommendation; level III evidence). biopsy may be where appropriate by scanning (grade B recommendation; level III evidence). MRI is the of choice for investigation of patients with a presentation suggestive of cord (grade B recommendation; level evidence). MRI of the should be performed in patients with an apparently solitary plasmacytoma of bone of of the (grade C recommendation; level IV evidence). Bone has no in the routine investigation of myeloma (grade C recommendation; level IV evidence). scanning has no in the routine management of myeloma (grade C recommendation; level IV evidence). bone lesions in patients that X-rays are of a little or no value in disease the of new lytic lesions or increase in of an existing one of disease (Table Symptomatic areas should specifically be It is essential that be compared with relevant disease progression within 3 months of the skeletal in the absence of new skeletal symptoms, a new skeletal survey is unlikely to provide additional Bone is with or MRI may be for of symptomatic areas where no is on the MRI can to to disease from that to et al, 2001; et al, 2004). It is not to repeat a skeletal survey at the time of progression, or not there is clinical evidence of progression of bone disease.