Guidelines on the diagnosis and management of multiple myeloma 2005
2005; Wiley; Volume: 132; Issue: 4 Linguagem: Inglês
10.1111/j.1365-2141.2005.05867.x
ISSN1365-2141
AutoresAlastair G. Smith, Finn Wislöff, Diana Samson,
Tópico(s)Hematological disorders and diagnostics
ResumoIn 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 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 improve on the Durie/Salmon system as it does not include either albumin or serum β2-microglobulin concentrations. A working group has recently proposed an International Prognostic Index based on serum levels of β2-microglobulin and albumin that separates patients into three prognostic groups irrespective of type of therapy; see Table VII (Greipp et al, 2003). Incorporation of cytogenetic data into this model may further improve staging. The following recommendations are grade C based on level IV evidence. The International Prognostic Index based on serum albumin and β2-microglobulin is recommended in preference to the Durie/Salmon staging system. Prognosis should be evaluated before starting treatment, requiring, as a minimum, serum levels of β2-microglobulin and albumin. Cytogenetic and/or FISH analysis may be helpful if available. These, however, should be interpreted with caution in individual patients. At present there is no evidence to support using prognostic factors to choose therapy in individual patients. Evaluation of tumour response is based on changes in serum levels of M-protein and/or urinary light chain excretion. In addition, a clinical response requires that no new myeloma-related organ or tissue damage occurs. The criteria in Table VIII are summarised from those of an International Working Group (see Blade et al, 1998 for full details). Confirmation of complete remission requires that there is no detectable paraprotein by immunofixation (IF). It has been shown that patients who have no paraprotein detectable by routine electrophoresis but have paraprotein still detectable by IF have a similar prognosis to other patients in partial response (PR), while those with a negative IF have a significantly better outlook (Lahuerta et al, 2000; Davies et al, 2001). IF should, therefore, be performed if there is no detectable paraprotein by electrophoresis. Bone marrow assessment is only essential to confirm complete response (CR) and to define response in non-secretory myeloma. These criteria also include definitions of relapse and progression. Relapse is defined as reappearance of disease in patients previously in CR, while progression applies to patients not previously in CR. It is not yet clearly established that the object of treatment should be to achieve CR although achieving CR after HDT appears to be a good prognostic factor for remission duration and overall survival (OS) (Lahuerta et al, 2000; Davies et al, 2001), Plateau phase is reached by a quarter of patients with <50% reduction in M-protein levels using conventional therapy and in a 10th with <25% decrease in M-protein levels – these patients have as good a prognosis as patients achieving better responses in terms of paraprotein levels (Olojohungbe et al, 1996; Durie et al, 2004a). Serum FLC assays are useful for monitoring FLC only and non-secretory myeloma (Drayson et al, 2001; Bradwell et al, 2003). FLC assay has also recently been shown to be helpful in monitoring response in the majority of patients with an intact immunoglobulin paraprotein; because of the short half-life of FLC this may provide an earlier indication of response to therapy than changes in intact paraprotein concentration (Mead et al, 2004). The role of imaging in the management of myeloma includes the assessment of the extent and severity of the disease at presentation, the identification and characterisation of complications, and subsequent assessment of disease status. Plain radiography, CT, and MRI are established examination techniques in myeloma. Positron emission tomography (PET) imaging with 18Fluorine-fluoro-deoxyglucose (FDG) and 99Technetium sestamibi (MIBI) imaging are promising newer scanning techniques under current evaluation. The use of dual energy X-ray absorptiometry (DEXA) scanning has not been thoroughly evaluated in myeloma. With the increasing availability of more sophisticated imaging techniques, it is important to consider carefully which investigations are most appropriate. At all times during the investigation and follow up of a patient, the potential usefulness of a proposed imaging investigation (i.e. the likelihood that it will alter management) should be assessed. Provision of accurate clinical information to the Radiology Department when the imaging request is made will ensure that the right imaging technique is performed at the right time. The skeletal survey remains the standard method for radiological screening at diagnosis, with clear association between the extent of disease and tumour load at diagnosis (Durie & Salmon, 1975). Plain radiography is universally available, allows large areas of the skeleton to be visualised and may identify long bones at risk of impending fracture. A scoring system based on clinical and radiological findings may be employed to predict the likelihood of fracture in long bones and identify patients who may benefit from internal fixation (Mirels, 1989). However, plain radiography has low sensitivity, only demonstrating lytic disease when at least 30% of trabecular bone substance has been lost (Snapper & Khan, 1971), provides an inadequate assessment of generalised osteopenia (Scane et al, 1994) and has low specificity. Computed tomography has higher sensitivity than plain radiographs at detecting small lytic lesions and can accurately depict the presence and extent of associated soft tissue disease and aid in directing needle biopsy for histological diagnosis (Kyle et al, 1985). It frequently clarifies the significance of suspicious areas on plain films, symptomatic areas that do not show abnormalities on plain films or parts of the skeleton that cannot be accurately visualised by plain radiography, e.g. scapulae, ribs and sternum. CT is helpful in the planning of radiotherapy and surgery (Walker et al, 2003). Magnetic resonance imaging is useful for the assessment of the extent and nature of soft tissue disease. It is the technique of choice for investigation of patients with a neurological presentation suggestive of cord compression (Joffe et al, 1988), providing an accurate assessment of the level and extent of cord or nerve root compression, size of the tumour mass and degree to which it has extended into the epidural space (see Section 9). In addition, MRI may yield information about the pattern of bone marrow involvement. Certain patterns of MRI abnormality have prognostic significance, with association between focal and diffuse appearances and higher tumour burden (Moulopoulos et al, 1992; Carlson et al, 1995; Stabler et al, 1996; Lecouvet et al, 1998a). Abnormal MRI of the spine in patients with advanced stage myeloma may predict a higher risk of fracture than patients who have normal appearances (Lecouvet et al, 1997), but does not predict the site of fracture (Lecouvet et al, 1998b). Magnetic resonance imaging is an essential investigation in the differential diagnosis of solitary plasmacytoma and myeloma. In the staging of apparently solitary bone plasmacytoma, magnetic resonance screening of the spine and pelvis reveals lesions that are radiographically occult in up to 80% of patients (Moulopoulos et al, 1993). The diagnosis and management of solitary plasmacytoma have been reviewed in a recent BCSH guideline (Soutar et al, 2004). Standard bone scintigraphy has a low sensitivity in myeloma owing to the lack of osteoblastic activity that characterises the lytic lesions of myeloma (Bataille et al, 1982; Ludwig et al, 1982). Occasionally, it may show foci of disease not revealed by X-ray, e.g. in the scapula or sternum, but CT is more sensitive. A number of preliminary reports indicate that PET scanning can be useful in detecting occult sites of disease in myeloma and solitary plasmacytoma (Kato et al, 2000; Orchard et al, 2002; Schirrmeister et al, 2003). This is the standard procedure for diagnosing osteoporosis (Kanis & Gluer, 2000). In myeloma patients, low-lumbar spine bone mineral density at diagnosis is correlated with an increased risk of early vertebral collapses (Abildgaard et al, 2004). However, the estimated bone mineral density can be influenced by spondylosis and spinal osteophytes (Masud et al, 1993) and the presence of vertebral collapse, giving rise to methodological difficulties in using DEXA scanning in myeloma patients. Skeletal survey should be part of the staging procedure of newly diagnosed myeloma patients and should include a postero-anterior (PA) view of the chest, antero-posterior (AP) and lateral views of the cervical spine (including an open-mouth view), thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis. In addition, any symptomatic areas should be specifically visualised with appropriate views (grade C recommendation; level IV evidence). CT should be used to clarify the significance of ambiguous plain radiographic findings, such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualise on plain radiographs, such as ribs, sternum and scapulae (grade B recommendation; level III evidence). CT should also be used to examine symptomatic areas of the skeleton where no pathological lesion is found on the skeletal survey (grade B recommendation; level III). CT or MRI is indicated to delineate the nature and extent of soft tissue disease and these two imaging techniques can give complementary information (grade B recommendation; level III evidence). Tissue biopsy may be guided where appropriate by CT scanning (grade B recommendation; level III evidence). MRI is the technique of choice for investigation of patients with a neurological presentation suggestive of cord compression (grade B recommendation; level IIB evidence). MRI of the whole spine should be performed in patients with an apparently solitary plasmacytoma of bone irrespective of site of the index lesion (grade C recommendation; level IV evidence). Bone scintigraphy has no place in the routine investigation of myeloma (grade C recommendation; level IV evidence). DEXA scanning has no role in the routine management of myeloma (grade C recommendation; level IV evidence). Lytic bone lesions seldom heal in responsive patients so that plain X-rays are of a little or no value in assessing disease response. On the contrary, development of new lytic lesions or definite increase in size of an existing lesion represent one criterion of disease relapse/progression (Table VIII). Symptomatic areas should specifically be targeted. It is essential that images be compared with relevant previous images. If disease progression occurs within 3 months of the previous skeletal survey, in the absence of new skeletal symptoms, a new skeletal survey is unlikely to provide additional information. Bone pain is initially explored with plain radiographs. CT or MRI may be employed for evaluation of symptomatic areas where no pathological lesion is identified on the plain films. MRI can help to distinguish vertebral collapse due to disease from that due to accompanying osteoporosis (Lecouvet et al, 2001; Uetani et al, 2004). It is not always necessary to repeat a complete skeletal survey at the time of progression, whether or not there is clinical evidence of progression of bone disease. Lytic
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