Guidelines for the diagnosis and management of multiple myeloma 2011

In 2006 guidelines for the diagnosis and management of multiple myeloma were published (Smith et al, 2006). These current guidelines represent a major revision. The guideline has been split into two documents, focussing on the 'Diagnosis and management of multiple myeloma' and 'Supportive care in multiple myeloma 2011' (Snowden et al 2011). They are designed to be used together and to complement each other. The contents of 'Diagnosis and management of multiple myeloma' are listed below: Methodology, epidemiology and clinical presentation Diagnosis, prognostic factors and disease monitoring Imaging techniques Management of common medical emergencies in myeloma patients Myeloma bone disease Renal impairment Induction therapy including management of major toxicities and stem cell harvesting Management of refractory disease High dose therapy and autologous stem cell transplantation Allogeneic stem cell transplantation Maintenance therapy Management of relapsed myeloma including drugs in development Patient Information and Support The key areas that are covered comprehensively in the document entitled 'Guidelines for Supportive Care in Multiple Myeloma 2011' (Snowden et al 2011) are listed below: Anaemia Haemostasis and thrombosis issues Pain management Peripheral neuropathy Other symptom control – gastrointestinal, sedation/fatigue, mucositis Bisphosphonate-induced osteonecrosis of the jaw Complementary therapies End of life care The production of these guidelines involved the following steps: Establishment of working groups in the topic areas detailed above followed by review of key literature to 30th June 2010 including Cochrane database, Medline, internet searches and major conference reports. Development of key recommendations based on randomized, controlled trial evidence. In the absence of randomized data, recommendations were developed on the basis of literature review and a consensus of expert opinion. Involvement of patient advocacy through Myeloma UK. Review by UK Myeloma Forum (UKMF) Executive and British Committee for Standards in Haematology (BCSH) Committees. Review by a British Society for Haematology (BSH) sounding board. Levels of evidence and grades of recommendation are those of the US Agency for Healthcare Research and Quality (see Appendix I, Tables 1 and 2). In preparing these guidelines the authors have considered overall cost-effectiveness of recommended interventions as well as clinical efficacy data but formal health economic assessments have not been carried out. The annual incidence of myeloma in the UK is approximately 60–70 per million (http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma/incidence/index.htm). The overall prevalence is likely to be increasing given the recently published data demonstrating improved survival rates over the last decade (Kumar et al, 2008a; Brenner et al, 2009). The median age at presentation is approximately 70 years. Only 15% of patients are aged <60 years. Myeloma has a higher incidence in Afro-Caribbean ethnic groups than in Caucasians but there are few other distinctive epidemiological features. The majority of cases present de novo but it is now recognized that myeloma is preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in virtually all patients (Landgren et al, 2009). Presenting clinical features include symptoms of: Bone disease Impaired renal function Anaemia Hypercalcaemia Recurrent or persistent bacterial infection Hyperviscosity Other patients are diagnosed following the incidental detection of a raised erythrocyte sedimentation rate (ESR), plasma viscosity, serum protein or globulin. Patients with suspected myeloma require urgent specialist referral. Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate investigation and treatment. Investigation of a patient with suspected myeloma should include the screening tests indicated in Table I, 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 M-protein present. Immunofixation and serum-free light chain (SFLC) assessment are indicated in patients where there is a strong suspicion of myeloma but in whom routine serum protein electrophoresis is negative (Pratt, 2008). 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 total protein and light chain excretion can be performed directly on a 24 hour (h) urine collection or calculated on a random urine sample in relation to the urine creatinine. Quantification of SFLC levels and κ/λ ratio is an additional tool for the assessment of light chain production. The serum tests are particularly useful for diagnosis and monitoring of light chain only myeloma (Bradwell et al, 2003) and patients with oligosecretory/non-secretory disease (Drayson et al, 2001) and in requests for which urine has not been sent to the laboratory. In renal impairment the half-life, and thus serum concentration of SFLC, can increase ten-fold and there is often an increased κ/λ ratio (Hutchison et al, 2008). A diagnosis of myeloma should be confirmed by bone marrow (BM) assessment. It is recommended that an adequate trephine biopsy of at least 20 mm in length be obtained in all patients as it provides a better assessment of the extent of marrow infiltration than aspirate smears (Ng et al, 2006; Al-Quran et al, 2007). It is recommended that a diagnosis of myeloma be confirmed by the demonstration of an aberrant plasma cell phenotype and/or monoclonality. Plasma cell phenotyping may be performed by flow cytometry and/or immunohistochemistry on trephine sections. The European Myeloma Network have provided practical guidance on the optimal methods for flow cytometry (Rawstron et al, 2008) and rapid and cost effective single-tube assays have been developed (Rawstron et al, 2008). CD138 immunostaining of trephine sections can be useful to determine the extent of infiltration in selected cases (Ng et al, 2006; Al-Quran et al, 2007). All diagnoses should be made or reviewed by an appropriately constituted Multidisciplinary Team (MDT) (National Institute for Health and Clinical Excellence (NICE), 2003). Cytogenetic and radiological investigations are discussed in Sections 2.4 and 3, respectively. A diagnosis of myeloma should be made using the criteria proposed in 2003 by the International Myeloma Working Group (IMWG), which are detailed in Table II. These criteria distinguish between myeloma and MGUS principally on the basis of M-protein concentration, percentage of BM plasma cells and presence or absence of myeloma-related organ and tissue impairment (ROTI) (Table III). Other differential diagnoses in patients with M-proteins include solitary plasmacytoma and other B-cell lymphoproliferative disorders. Detailed guidance on the diagnosis and management of MGUS and solitary plasmacytoma are provided in recently published UKMF/BCSH guidelines (Bird et al, 2009; Hughes et al, 2009). IMWG diagnostic criteria should be used Investigation should be based on the tests shown in Table I including an assessment of possible myeloma-related organ and tissue impairment All diagnoses should be made or reviewed by an appropriately constituted MDT Plasma cell phenotyping by flow cytometry and/or immunohistochemistry on trephine biopsy sections is recommended in all cases Chemotherapy is indicated for the management of symptomatic myeloma defined by the presence of ROTI. Early intervention in patients with asymptomatic myeloma is not required (Hjorth et al, 1993; Riccardi et al, 2000) although chemotherapy may be considered in patients with a rising M-protein concentration in the absence of ROTI. Patients with asymptomatic myeloma require close monitoring under the supervision of a Consultant Haematologist. The overall risk of progression is 10% per year for the first 5 years but, interestingly, declines in subsequent years (Kyle et al, 2007). The SFLC ratio (≤0·125 or ≥8) appears to be predictive of outcome and a risk score incorporating BM plasma cell percentage, M-protein concentration and SFLC ratio has been proposed (Dispenzieri et al, 2008). Flow cytometry is also predictive of outcome as the risk of progression is significantly greater when aberrant phenotype plasma cells determined by flow cytometry comprise ≥95% of total BM plasma cells (Perez-Persona et al, 2007). Chemotherapy is only indicated in patients with symptomatic myeloma based on the presence of ROTI (Grade A recommendation; level of evidence Ib) Patients with asymptomatic myeloma should be monitored under the supervision of a Consultant Haematologist. These patients should be offered entry into clinical trials if available. (Grade C recommendation; level of evidence IV) Monitoring of patients with asymptomatic myeloma should include regular (typically 3-monthly) clinical assessment for the emergence of ROTI and measurement of serum and urinary M-protein (and SFLC when indicated). Repeat BM examination and skeletal imaging should be considered prior to the start of treatment (Grade C recommendation; level of evidence IV) 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. The Durie/Salmon staging system was published in 1975 (Durie & Salmon, 1975) but has been superseded by the International Staging System (ISS) reproduced in Table IV (Greipp et al, 2005). This defines three risk categories determined by the serum concentration of β2-microglobulin and albumin. The use of staging systems to determine choice of therapy for individual patients remains unproven. Certain cytogenetic and molecular genetic abnormalities have been shown to predict outcome in myeloma. It is generally accepted that the t(4;14), t(14;16) and deletion 17p, demonstrated by fluorescence in situ hybridization (FISH), confer an adverse outcome in myeloma. It has therefore been proposed that these abnormalities define 'high-risk' myeloma and should be specifically sought at diagnosis in all patients (Fonseca et al, 2009; Munshi et al, 2011). The prognostic significance of chromosome 13 deletions has been difficult to clarify as some studies have suggested that it is only of prognostic significance when demonstrated by conventional karyotyping, which significantly underestimates the overall incidence of the abnormality. Emerging data however suggests that the adverse effect of chromosome 13 deletion relates to its close association with high-risk abnormalities, particularly the t(4;14) and there is now consensus that conventional karyotyping has little or no added value in the routine setting (Fonseca et al, 2009). Although there are preliminary data to suggest that the adverse effect of these factors may be abrogated by newer agents (San Miguel et al, 2008a), the current international consensus is that further prospective evaluation is required before clinical decisions can be guided by genetic factors (Munshi et al, 2011). A number of groups have used gene expression profiling to define risk in both newly diagnosed and relapsed patients (Mulligan et al, 2007; Shaughnessy et al, 2007) but its role in determining treatment decisions is yet to be defined. Baseline SFLC concentration may also provide useful prognostic information (Dispenzieri et al, 2008). It is essential that new prognostic indicators continue to be evaluated in prospective clinical trials. The International Staging System based on serum albumin and β2-microglobulin should be used FISH studies are encouraged for all patients at diagnosis as they provide important prognostic information but their role in directing therapy needs further evaluation in prospective clinical trials The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) criteria (Blade et al, 1998) were updated by the IMWG in 2006 (Durie et al, 2006) and further modifications were subsequently proposed (Rajkumar et al, 2011). The uniform response criteria are detailed in Table V. There are two new response categories, stringent complete response (sCR) and very good partial response (VGPR). The criteria now incorporate changes in the SFLC assay to support the uniform reporting of clinical trials. In routine clinical practice there is a clear rationale for utilising the SFLC assay to assess response in light chain only disease, irrespective of the extent of light chain excretion in the urine (Pratt, 2008). The response category 'sCR' (for use in the reporting of clinical trials) has been refined recently to incorporate the use of flow cytometry to detect minimal residual disease on the basis of the presence of an aberrant immunophenotype (Rajkumar et al, 2011). Low levels of residual disease may also be demonstrated using allele-specific polymerase chain reaction (PCR) and a further new category of molecular CR is proposed, which is defined as the absence of disease by sequence specific PCR methods with a sensitivity of 10−5. Delayed achievement of complete remission (CR) is seen in a significant proportion of patients following high-dose therapy (Davies et al, 2001). The majority of such patients will have IgG M-proteins which have a half-life of approximately 23 d, significantly longer than that of IgA (6 d) and free light chains (4 h) (Mead et al, 2004). Repeat BM aspirate assessment is required to confirm CR (repeat trephine biopsy is not required under the response criteria but may be needed for accurate assessment; Durie et al, 2006) and should be performed in all patients at Day 100 following high-dose therapy in accordance with EBMT standards. Flow cytometric assessment of minimal residual disease at this time point also provides prognostic information (Paiva et al, 2008) and may in the future be used to guide maintenance/consolidation therapies. The definitions of progressive disease and relapse have also been revised by the IMWG (Table VI) and include a new category of clinical relapse, which reflects the fact that progressive disease (PD) as defined does not necessarily indicate a need for further therapy. Response to therapy should be defined using the IMWG uniform response criteria The response category sCR is recommended only for use in the clinical trial setting The SFLC assay should be used to assess response in all patients with light chain only, non secretory and oligo-secretory disease The rare myelomas comprise up to 7% of all myelomas and consist of plasma cell leukaemia, IgD, IgE, IgM and non-secretory myeloma. Plasma cell leukaemia. Plasma cell leukaemia (PCL) may be primary or secondary to multiple myeloma and is characterized by the presence of ≥20% circulating plasma cells and/or an absolute level of >2·0 × 109/l (Kyle et al, 1974). IgD, E and M Myelomas. IgD myeloma may comprise up to 1·8% of all myelomas (Blade & Kyle, 1994; Wechalekar et al, 2005). Diagnosis may be difficult because some patients may present with a very small or no visible monoclonal spike on serum electrophoresis. Care must be exercised to avoid a false diagnosis of non-secretory or light chain only myeloma (Sinclair, 2002). The clinical features are similar to that of other myelomas but Bence-Jones proteinuria, extramedullary involvement, lytic lesions and amyloidosis seem to be more frequent (Jancelewicz et al, 1975). Relatively few cases of IgE myeloma have been reported in the literature (Endo et al, 1981; Kairemo et al, 1999Morris et al, 2010). There may be clinical similarities with IgD myeloma and in both conditions the prognosis appears to be poor (Morris et al, 2010). With the increased use of BM trephine biopsies and improved immunohistomorphology (Konduri et al, 2005; Feyler et al, 2008), IgM myelomas are being recognized more frequently and may comprise up to 0·3% of all myelomas (Morris et al, 2010). It is important that such cases are distinguished from other IgM secreting disorders, particularly Waldenstrom macroglobulinaemia (Avet-Loiseau et al, 2003a). There is a high incidence of the t(11;14) and prognosis appears to be poor (Avet-Loiseau et al, 2003b; Feyler et al, 2008; Morris et al, 2010). Non-secretory myeloma. Non-secretory myeloma poses particular diagnostic difficulties as there is no serum M-protein and no urinary Bence-Jones protein excretion. The SFLC assay is informative in approximately two thirds of patients (Drayson et al, 2001). While the clinical presentation is essentially similar to standard myeloma, anaemia and lytic lesions may be seen more frequently while renal failure is uncommon (Morris et al, 2010). Significant advances in available imaging technologies have paralleled developments in therapy for myeloma and may play a more prominent role in determining prognosis in the future (Durie, 2006). A detailed guideline for the use of imaging in myeloma has been published (D'Sa et al, 2007). Key recommendations are summarized below. The skeletal survey remains the screening technique of choice at diagnosis The skeletal survey should include a postero-anterior (PA) view of the chest, antero-posterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic areas should be specifically visualized with appropriate views Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) 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 visualize on plain radiographs, such as ribs, sternum and scapulae Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse (Grade B recommendation; level IIB evidence). Urgent CT scanning is an alternative, when MRI is unavailable, intolerable or contraindicated (Grade B recommendation; level III evidence) CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy may be guided by CT scanning (Grade B recommendation; level IIB evidence) There is insufficient evidence to recommend the routine use of positron-emission tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial Bone scintigraphy has no place in the routine staging of myeloma Routine assessment of bone mineral density cannot be recommended, owing to the methodological difficulties of the technique and the universal use of bisphosphonates in symptomatic myeloma patients Hyperviscosity syndrome may develop in patients with high serum paraprotein levels, particularly those of IgA and IgG3 type. Symptoms include blurred vision, headaches, mucosal bleeding and dyspnoea due to heart failure. All patients with high protein levels should undergo fundoscopy, which may demonstrate retinal vein distension, haemorrhages and papilloedema. Patients usually have raised plasma viscosity and symptoms commonly appear when it exceeds 4 or 5 mPa. This usually corresponds to a serum IgM level of at least 30 g/l, an IgA level of 40 g/l and an IgG level of 60 g/l (Mehta & Singhal, 2003). Plasma viscosity results should not be used to determine the need for plasma exchange as this may result in delay but testing should be carried out both before and after the procedure. Symptomatic patients should be with plasma may be useful if plasma exchange are not available. is exchange should be The need for further over the few should be determined by symptoms and for of protein levels is and treatment should be Symptomatic should be with plasma exchange with is not available but symptoms are with as a treatment of the disease should be as as possible to of myeloma patients present with hypercalcaemia in the context of hypercalcaemia can present with system and of the on and renal of hypercalcaemia should be considered of the disease should be as as possible with treatment of hypercalcaemia to renal The of treatment are and hypercalcaemia may be with and/or to hypercalcaemia with urine should be and use of such as should be considered to avoid and heart failure and urinary excretion. All patients with to hypercalcaemia should a A randomized controlled trial in patients with hypercalcaemia of has shown that is to et al, 2001). the remains high after a further dose of may be modifications are required in renal impairment and dose may be more appropriate in patients with renal impairment (see Appendix Patients with refractory hypercalcaemia may require and In hypercalcaemia with and/or In to hypercalcaemia with and if required is the of choice in the treatment of hypercalcaemia A level I of the cord from extramedullary of disease in of patients with myeloma the of their disease (Kyle et al, 2003). Clinical features on the nature of the cord compression to or to soft tissue the extent of disease and the rate of development of cord compression, but commonly include and This is a medical requiring rapid diagnosis and treatment. clinical suspicion of cord compression, 40 for 4 should be and MRI obtained as as MRI is or due to patient or an urgent CT should be The between soft tissue and cord compression is essential and should be discussed with on if there is any the need for is usually for in the setting of compression and/or to the and is usually by soft tissue disease is the treatment of choice and should be preferably within 24 of the diagnosis of cord There are no randomized controlled trials to guidance on optimal dose and but a of myeloma patients has been published and demonstrated a better overall outcome in of in function for patients with at least 30 et al, 2006). Urgent MRI should be performed and or obtained is the treatment of choice for lesions and should be as as is preferably within 24 of diagnosis. A dose of 30 in is recommended (Grade B recommendation; level evidence) is recommended for in the setting of compression and/or to the cord compression is a it is important to a rapid diagnosis and to therapy as as possible Myeloma is with an increased incidence of This is to in both and and poor which are all with both the disease and its treatment. It has been reported that up to 10% of patients of within 60 of diagnosis et al, 2005). is not usually a in infection et al, 2005). There is increasing evidence that high dose in the or in patients with poor may be with increased and a higher rate in the and should be given to the use of in this et al, et al, 2009; et al, 2010). Patient as well as to specialist and treatment is in and infection in myeloma. and management of infection in myeloma patients is discussed in more in the care guideline (Snowden et al 2011). There must be to specialist for the patient and/or primary care myeloma patient should be with are required for infection or should be if possible There is insufficient evidence to recommend the routine use of Bone disease in of myeloma The development of bone disease, or can result in cord compression and hypercalcaemia & & and of life & et al, et al, 2007) and increase overall treatment bone require and subsequent is useful to control and may also of the a lytic may skeletal an should be sought and considered in selected clinical interventions for with including and are discussed in the care guideline (Snowden et al, 2011). is for a dose of is recommended bone require and subsequent a dose of is recommended A Cochrane Review of the use of bisphosphonates in myeloma et al, data from trials of or and from a preliminary of a trial of on a of trial data at that the was that bisphosphonates to the treatment of myeloma vertebral and but does not The evidence also suggested a in both patients with and without bone disease at trials with and in myeloma patients have now been published in et al, 2009). has been shown to be in myeloma and may et al, There are as yet no published randomized studies of or while to any effect on rates or survival et al, 2002). The trials of et al, et al, 2001) demonstrated for up to years in patients chemotherapy for the first including patients with no lytic using the bisphosphonates have been in patients with more and have demonstrated their in the of skeletal in this setting et al, et al, 2003). and appear with to although there has been no randomized and no of treatment is however with greater in skeletal and of of type 1 in some studies et al, 2001). The Research Myeloma trial has recently reported with a median up of years and demonstrated significant of