Finn Wislöff

Summary. We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S‐Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony‐stimulating factor (G‐CSF) + Epo. S‐Epo ≤ 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S‐Epo > 500 U/l and ≥ 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G‐CSF + Epo. The overall response rate was 42% with 28·3% achieving a complete and 13·2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample ( P < 0·001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment ( P = 0·01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48–74%) to treatment with G‐CSF + Epo. The majority of these patients have shown complete and durable responses.

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.

High-dose therapy has become a common treatment for myeloma. The objectives of this study were to estimate in a prospective, population-based setting the impact on survival of high-dose therapy in newly diagnosed, symptomatic patients less than 60 years old and to compare the results with those of conventionally treated historic controls. The prospective population comprised 348 patients. Of these, 274 were treated according to a specified intensive-therapy protocol (Nordic Myeloma Study Group [NMSG] #5/94) and constituted the intensive-therapy group. The historic population consisted of 313 patients identified from 5 previous population-based Nordic studies. Of these, 274 fulfilled the eligibility criteria for high-dose therapy stated in NMSG #5/94 and constituted the control group. The expected numbers of patients in the prospective population and the historic population were 450 and 410, respectively, estimated from previously established data on the incidence in this population and the population base for each study. Survival was prolonged in the intensive-therapy group compared with the control group (risk ratio for the control group 1.62; 95% confidence interval 1.22-2.15; P =.001). These groups represented more than 60% of the expected number of patients. When survival for all the registered patients in the 2 populations was compared, representing more than 75% of the expected number of patients, the advantage for the prospective population persisted (risk ratio for the historic population 1.46; 95% confidence interval 1.14-1.86; P =. 002). These results indicate that the introduction of high-dose therapy for newly diagnosed myeloma has resulted in prolonged survival for the total patient population aged less than 60 years. (Blood. 2000; 95:7-11)