Guidelines for the diagnosis and management of multiple myeloma 2011
Jennifer Bird, c/o BCSH Secretary, British Society for Haematology, 100, White Lion Street, London, N1 9PF, UK.
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:
- 1 Methodology, epidemiology and clinical presentation
- 2 Diagnosis, prognostic factors and disease monitoring
- 3 Imaging techniques
- 4 Management of common medical emergencies in myeloma patients
- 5 Myeloma bone disease
- 6 Renal impairment
- 7 Induction therapy including management of major toxicities and stem cell harvesting
- 8 Management of refractory disease
- 9 High dose therapy and autologous stem cell transplantation
- 10 Allogeneic stem cell transplantation
- 11 Maintenance therapy
- 12 Management of relapsed myeloma including drugs in development
- 13 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
1. Methodology, epidemiology and clinical presentation
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.
1.2 Incidence, prevalence and epidemiology
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).
1.3 Clinical presentation
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.
2. Diagnosis, prognostic factors and disease monitoring
2.1 Investigation and diagnosis
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).
Table I. Initial investigations in patients with myeloma.
|FBC, ESR or plasma viscosity||Bone marrow aspirate + trephine biopsy with plasma cell phenotyping||FISH analysis||FBC|| |
|Urea, creatinine, calcium, albumin|
Electrophoresis of serum and concentrated urine
Quantification of non-isotypic immunoglobulins
|Immunofixation of serum and urine||Quantification of Monoclonal protein in serum and urine|
|Serum urea and creatinine|
Creatinine clearance (measured or calculated)
Tissue biopsy (or fat pad aspirate) for amyloid (if suspected)
Quantification of non-isotypic immunoglobulins
|SFLC assay in oligo-secretory, light chain only and non-secretory disease|
|X-ray of symptomatic areas||Skeletal survey||Skeletal survey||Skeletal survey||MRI/CT scan|
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.
2.2 Diagnostic criteria and differential diagnosis
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.
Table II. Diagnostic criteria for MGUS, asymptomatic myeloma and symptomatic myeloma (adapted from International Myeloma Working Group, 2003).
|M-protein in serum <30 g/l||M-protein in serum ≥30 g/l|
Bone marrow clonal plasma cells ≥10%
|M-protein in serum and/or urine*|
|Bone marrow clonal plasma cells <10% and low level of plasma cell infiltration in a trephine biopsy (if done)||Bone marrow (clonal) plasma cells† or biopsy proven plasmacytoma|
|No related organ or tissue impairment (no end organ damage including bone lesions)||No related organ or tissue impairment (no end organ damage including bone lesions) or symptoms||Myeloma-related organ or tissue impairment (including bone lesions)|
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).
Table III. Myeloma-related organ or tissue impairment (ROTI) adapted from International Myeloma Working Group, 2003.
|*Increased calcium levels||Corrected serum calcium >0·25 mmol/l above the upper limit of normal or >2·75 mmol/l|
|*Renal insufficiency||Creatinine >173 μmol/l|
|*Anaemia||Haemoglobin 2 g/dl below the lower limit of normal or haemoglobin <10 g/dl|
|*Bone lesions||Lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify)|
|Other||Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months)|
Recommendations (all Grade C recommendation; level IV evidence)
- • 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
2.3 Monitoring and indications for starting therapy
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)
2.4 Prognostic factors and staging in 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. 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.
Table IV. International Staging System (ISS) for multiple myeloma. Adapted from: Greipp et al, 2005. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
|I||Serum ß2 microglobulin <3·5 mg/l (296 nmol/l) and serum albumin ≥3·5 g/dl (35 g/l or 532 μmol/l)||62|
|II||Neither I or III*||45|
|III||Serum ß2 microglobulin ≥5·5 mg/l (465 nmol/l)||29|
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.
Recommendations (all Grade C recommendation; level IV evidence)
- • 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
2.5 Measuring response to therapy
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.
Table V. International Myeloma Working Group uniform response criteria (Adapted with permission from Durie et al (2006). The latest available modifications (Rajkumar et al, 2011) are also included.
|Stringent complete response (sCR)||CR as defined below plus|
• Normal SFLC ratio
• Absence of phenotypically aberrant plasma cells by multiparameter flow cytometry
|Complete response (CR)*|| • Negative immunofixation on the serum and urine and |
• Disappearance of any soft tissue plasmacytomas and
• <5% bone marrow plasma cells
|Very good partial response (VGPR)*||• Serum and urine M-protein detectable by immunofixation but not on electrophoresis|
• ≥90% reduction in serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to <100 mg/24 h
|Partial response (PR)*||• ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg/24 h|
|Stable disease (SD)||• Not meeting criteria for CR, VGPR, PR or progressive disease|
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.
Table VI. International Myeloma Working Group uniform response criteria: disease progression and relapse adapted with permission from Durie et al (2006). The latest available modifications (Rajkumar et al, 2011) are also included.
|Progressive disease (PD)||Requires at least one of the following: • ≥25% increase in serum M-protein(absolute increase must be ≥5 g/l)|
• ≥25% increase in urine M-protein (absolute increase must be ≥200 mg/24 h)
• ≥25% increase in the difference between involved and uninvolved SFLC levels (used in patients with light-chain, non-secretory and oligo-secretory disease) (absolute increase must be >100 mg/l)
• ≥25% increase in bone marrow plasma cell percentage (absolute percentage must be ≥10%)
• Development of new bone lesions or soft tissue plasmacytoma
• Development of hypercalcaemia
|Clinical relapse||Requires at least one of the following:|
• Development of new bone lesions or soft tissue plasmacytoma
• Increase in size of existing plasmacytomas or bone lesions
• Any of the following attributable to myeloma:
Development of hypercalcaemia
Development of anaemia (drop in Hb ≥2 g/dl)
Rise in serum creatinine
|Relapse from CR||Requires at least one of the following:|
• Reappearance of serum or urine M-protein by immunofixation or electrophoresis
• Development of >5% plasma cells in the bone marrow
• Appearance of any other sign of progression (e.g. new plasmacytoma, new lytic bone lesion)
Recommendations (all Grade C recommendation; level IV evidence)
- • 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
2.6 Rare myelomas
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).
3. Imaging techniques
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.
Recommendations (all Grade C recommendation; level IV evidence except where shown)
- • 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
4. Management of common medical emergencies in 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 treated urgently with plasma exchange; isovolaemic venesection may be useful if plasma exchange facilities are not immediately available. If transfusion is essential, exchange transfusion should be performed. The need for further exchanges over the next few days should be determined by symptoms and requirement for blood transfusion. Rapid reduction of protein levels is mandatory and anti-myeloma treatment should be instituted promptly.
Recommendations (all Grade C recommendation; level IV evidence)
- • Symptomatic hyperviscosity should be treated with therapeutic plasma exchange with saline fluid replacement
- • If plasmapheresis is not immediately available but hyperviscosity symptoms are present, consider isovolaemic venesection with saline replacement as a holding measure
- • Effective treatment of the underlying disease should be started as soon as possible
Up to 30% of myeloma patients present with hypercalcaemia occurring mostly in the context of active disease. Acute hypercalcaemia can present with central nervous system dysfunction (confusion, coma and obtundation), muscle weakness, pancreatitis, constipation, thirst, polyuria, shortening of the Q-T interval on electrocardiogram and acute renal insufficiency. Alternative causes of hypercalcaemia should be considered e.g. hyperparathyroidism. Treatment of the underlying disease should be initiated as soon as possible along with active treatment of hypercalcaemia to minimize long-term renal damage. The mainstays of treatment are hydration and intravenous bisphosphonates.
Mild hypercalcaemia (corrected calcium 2·6–2·9 mmol/l) may be corrected with oral and/or intravenous rehydration. Moderate to severe hypercalcaemia (corrected calcium ≥2·9 mmol/l) requires intravenous rehydration with normal saline. Adequate urine output should be ensured and use of intravenous loop diuretics, such as furosemide, should be considered to avoid volume overload and heart failure and promote urinary calcium excretion.
All patients with moderate to severe hypercalcaemia should receive a bisphosphonate. A randomized controlled trial in patients with hypercalcaemia of malignancy has shown that bisphosphonate is superior to pamidronate (Major et al, 2001). If the calcium remains high after 72 h a further dose of bisphosphonate may be given. Dose modifications are required in renal impairment and reduced dose pamidronate (30 mg) may be more appropriate in patients with severe renal impairment (see Appendix II). Patients with refractory hypercalcaemia may require corticosteroids and calcitonin.
Recommendations (mostly grade C; level III evidence)
- • In mild hypercalcaemia (corrected calcium 2·6–2·9 mmol/ l) re-hydrate with oral and/or iv fluids
- • In moderate to severe hypercalcaemia (corrected calcium > 2·9 mmol/l) re-hydrate with intravenous fluids and give furosemide if required
- • Zoledronic acid is the bisphosphonate of choice in the treatment of hypercalcaemia (grade A evidence; level I recommendation)
4.3 Cord compression
Compression of the spinal cord from extramedullary foci of disease occurs in 5% of patients with myeloma during the course of their disease (Kyle et al, 2003). Clinical features depend on the nature of the cord compression (due to bony/structural lesion or to soft tissue disease), the spinal level, extent of disease and the rate of development of cord compression, but commonly include sensory loss, paraesthesiae, limb weakness, walking difficulty and sphincter disturbance. This is a medical emergency requiring rapid diagnosis and treatment. Upon clinical suspicion of cord compression, dexamethasone 40 mg daily for 4 d should be commenced and MRI spine obtained as soon as possible. Where MRI is unavailable or impossible due to patient intolerance or contraindication, an urgent CT scan should be performed. The differentiation between soft tissue and bone-related cord compression is essential and should be discussed with neurosurgery/orthopaedic teams (depending on local expertise) immediately if there is any question about the need for surgical intervention.
Surgery is usually undertaken for emergency decompression in the setting of structural compression and/or to stabilize the spine and is usually consolidated by post-operative radiotherapy. For soft tissue disease local radiotherapy is the treatment of choice and should be commenced urgently, preferably within 24 h of the diagnosis of cord compression. There are no randomized controlled trials to give guidance on optimal radiotherapy dose and fractionation but a retrospective multi-centre study of 172 myeloma patients has been published and demonstrated a better overall outcome in terms of improvement in motor function for patients treated with at least 30 Gy (Rades et al, 2006).
Recommendations (all Grade C recommendation; level IV evidence unless shown)
- • Urgent MRI should be performed and neurosurgical or spinal surgical/clinical oncology consultation obtained
- • Local radiotherapy is the treatment of choice for non-bony lesions and should be commenced as soon as is possible, preferably within 24 h of diagnosis. A dose of 30 Gy in 10 fractions is recommended (Grade B recommendation; level IIb evidence)
- • Surgery is recommended for emergency decompression in the setting of bony compression and/or to stabilize the spine
- • If cord compression is a presenting symptom, it is important to concurrently pursue a rapid diagnosis and to institute systemic therapy as soon as possible
4.4 Early infection
Myeloma is associated with an increased incidence of early infection. This is related to deficiencies in both humoral and cellular immunity, reduced mobility and poor performance status, which are all associated with both the disease and its treatment. It has been reported that up to 10% of patients die of infective causes within 60 d of diagnosis (Augustson et al, 2005). Neutropenia is not usually a factor in early infection (Augustson et al, 2005).
There is increasing evidence showing that high dose steroids in the elderly or in patients with poor performance may be detrimental, with increased toxicity and a higher mortality rate in the short-term, and consideration should be given to the use of lower doses in this group (Ludwig et al, 2009a; Morgan et al, 2009; Rajkumar et al, 2010). Patient education as well as access to 24-h specialist advice and treatment is crucial in preventing and managing infection in myeloma. Prevention and management of infection in myeloma patients is discussed in more detail in the supportive care guideline (Snowden et al 2011).
Recommendations (all Grade C recommendation; level IV evidence)
- • There must be 24-h access to specialist advice for the patient and/or primary care team
- • Any febrile myeloma patient should be treated promptly with broad-spectrum antibiotics. Intravenous antibiotics are required for severe systemic infection or neutropenic sepsis
- • Aminoglycosides should be avoided, if possible
- • There is insufficient evidence to recommend the routine use of prophylactic antibiotics
5. Myeloma bone disease
5.1 Clinical features of bone disease
Bone disease occurs in 80–90% of myeloma patients. The development of bone disease, either focal or diffuse, can result in pain, pathological fractures, spinal cord compression and hypercalcaemia (Coleman, 1997; Croucher & Apperley, 1998; Terpos & Dimopoulos, 2005) Skeletal events compromise mobility and day-to-day independence, decrease quality of life (Terpos & Rahemtulla, 2004; Vogel et al, 2004; Cocks et al, 2007) and increase overall treatment costs.
5.2 Bone fractures
Long bone fractures require stabilization and subsequent radiotherapy. Radiotherapy is useful to improve pain control and may also promote healing of the fracture site. Where a large lytic lesion may cause skeletal instability, an orthopaedic opinion should be sought and pre-emptive surgery considered in selected patients. Specialized clinical interventions for pain associated with spinal fractures including vertebroplasty and kyphoplasty are discussed in the supportive care guideline (Snowden et al, 2011).
Recommendations (all grade C; level III evidence)
- • Local radiotherapy is helpful for pain control; a dose of 8 Gy single fraction is recommended
- • Long bone fractures require stabilization and subsequent radiotherapy; a dose of 8 Gy single fraction is recommended
A Cochrane Review of the use of bisphosphonates in myeloma (Djulbegovic et al, 2002) included data from 10 placebo-controlled trials of clodronate, pamidronate, or etidronate and from a preliminary report of a trial of ibandronate. Based on a meta-analysis of trial data at that time, the conclusion was that adding bisphosphonates to the treatment of myeloma reduces vertebral fractures and pain but does not improve survival. The evidence also suggested a benefit in both patients with and without bone disease at presentation. Randomized trials with etidronate, clodronate, pamidronate, zoledronic acid and ibandronate in myeloma patients have now been published (reviewed in Terpos et al, 2009). Oral etidronate has been shown to be ineffective in myeloma and may cause demineralization (Belch et al, 1991). There are as yet no published randomized studies of risedronate or alendronate, while ibandronate failed to show any effect on fracture rates or survival (Menssen et al, 2002).
The trials of sodium clodronate (Lahtinen et al, 1992; McCloskey et al, 1998, 2001) demonstrated benefit for up to four years in patients starting chemotherapy for the first time, including patients with no lytic lesions. Studies using the nitrogen-containing bisphosphonates have been primarily in patients with more extensive bony disease. Both pamidronate and zoledronic acid have demonstrated their effectiveness in the reduction of skeletal related events (SREs) in this setting (Berenson et al, 2001; Rosen et al, 2001, 2003). Zoledronic acid and pamidronate appear equally efficacious with regards to SRE prevention although there has been no randomized comparison and no long-term analysis of treatment benefit. Zoledronic acid is however associated with greater improvements in skeletal morbidity and normalization of N-telopeptide of collagen type 1 (NTX) in some studies (Rosen et al, 2001). The Medical Research Council (MRC) Myeloma IX trial has recently reported with a median follow up of 3·7 years and demonstrated significant benefits of zoledronic acid over sodium clodronate in reduction of SREs (27% vs. 35·3% p = 0·0004), and crucially in overall survival (OS; 50 months vs. 44·5 months, p = 0·0118) and progression free survival (PFS; 19·5 months vs. 17·5 months, p = 0·0179) respectively (Morgan et al, 2010). There was however a higher incidence of bisphosphonate-associated osteonecrosis of the jaw (BONJ) in the zoledronic acid group (3·5% vs. 0·3%). There has also been a suggestion of a survival benefit in the pamidronate trials but this was only demonstrated following subgroup analysis.
Adverse effects on renal function have been reported particularly with the nitrogen-containing bisphosphonates (pamidronate and zoledronic acid) and are most likely if the recommended dose or rate of infusion is exceeded (Berenson et al, 1998; Rosen et al, 2001; Chang et al, 2003; Barri et al, 2004). Specific protocols are provided by the manufacturers with regards to administration in patients with renal impairment (see Appendix II).
Oral calcium and vitamin D supplementation is advised with zoledronic acid. There is no recommendation with pamidronate and it should probably be avoided with sodium clodronate as it may impair absorption of the oral bisphosphonate. All bisphosphonates are associated with a risk of BONJ, but particularly the nitrogen-containing intravenous preparations. This is discussed in detail in the supportive care guideline (Snowden et al, 2011).
Treatment in asymptomatic patients. There is little published evidence to guide the optimal time point to initiate bisphosphonate treatment. A trial of monthly intravenous pamidronate versus placebo in newly diagnosed patients not requiring chemotherapy suggested a bone protective effect, although other manifestations of progression were not influenced (Musto et al, 2003). Similar results have been suggested with zoledronic acid monthly for one year although one patient did develop BONJ (Musto et al, 2008).
Recommendations for bisphosphonate therapy (all grade C recommendation; level IV evidence unless shown)
- • Bisphosphonate therapy is recommended for all patients with symptomatic multiple myeloma, whether or not bone lesions are evident (grade A recommendation; level 1b evidence)
- • Zoledronic acid and pamidronate both show efficacy with respect to SRE prevention (grade A recommendation; level 1b evidence) but early data regarding prolongation of event-free survival (EFS) and OS in a large randomized trial suggest that zoledronic acid should be the bisphosphonate of choice
- • Sodium clodronate is less effective than zoledronic acid but has a significantly lower incidence of BONJ (grade A recommendation; level 1b evidence)
- • There is no consensus regarding the duration of bisphosphonate therapy. The standard of care to date has been indefinite bisphosphonate therapy. However, given the risk of BONJ, it is reasonable to consider stopping therapy under certain circumstances, such as in those patients who have achieved a CR or VGPR with transplantation and/or a novel therapy combination and have no active bone disease; this should be at the discretion of the treating haematologist. In the absence of definitive data the duration of therapy should take into account individual factors such as remission status, extent of skeletal disease, renal function and patient preference. In patients who do stop bisphosphonate therapy, therapy should be reinstituted at the time of relapse
- • Renal function should be carefully monitored and doses reduced in line with the manufacturers’ guidance. For guidance on the use of bisphosphonates in renal impairment, see Appendix II
- • At present there is insufficient evidence to make a recommendation for the use of bisphosphonates in patients with asymptomatic myeloma
- • Dental evaluation should be carried out before starting IV bisphosphonate therapy
6. Renal Impairment
6.1 Incidence and pathophysiology
Renal impairment is a common and potentially serious complication of myeloma occurring at presentation in 20–25% of patients (Knudsen et al, 1994) and in up to 50% of patients at some time during their disease (Kyle, 1975; Eleutherakis-Papaiakovou et al, 2007). It is possible to reverse renal insufficiency in approximately half of patients but the remainder will have some degree of persistent renal impairment and of these, 2–12% will require renal replacement therapy (Clark et al, 1999). Renal failure occurs as a result of damage caused to renal tubules by free light chains (cast nephropathy, or ‘myeloma kidney’). A variety of other nephrotoxic processes may also contribute to this damage including dehydration, hypercalcaemia, nephrotoxic drugs and infection (Clark et al, 1999; Haubitz & Peest, 2006; Penfield, 2006). The risk of renal damage is directly proportionate to the level of urinary free light chain excretion and not attributable to the light chain class or the presence or absence of whole M-proteins. Only 2% of patients without urinary free light chain excretion have renal impairment. This percentage increases to 50% with higher levels of urinary free light chain excretion (Drayson et al, 2006).
Patients presenting with renal failure have a high early death rate; of 367 newly diagnosed myeloma patients with serum creatinine >199 mmol/l, 29·4% died within 60 d of diagnosis (Augustson et al, 2005). In this study 43 of 299 deaths within 60 d were attributed wholly to renal failure. It is therefore critically important to prevent renal failure, or if established, to reverse it as this will significantly improve survival (Knudsen et al, 2000).
6.2 Prevention of renal failure
Early diagnosis of both new and relapsed myeloma enables early intervention and thus prevention of renal damage (Augustson et al, 2005; Drayson et al, 2006). A diagnosis of light chain only myeloma and of light chain escape may be missed if urine is not sent to the laboratory and SFLC levels are not measured (Pratt, 2008). Relapse with rising levels of free light chain and no change in whole paraprotein (light chain escape) occurs in 5% of IgG and 15% of IgA myeloma patients (Mead & Drayson, 2009). Renal function is optimized by maintenance of a high fluid intake, at least 3 l/d (MRC Working Party on Leukaemia in Adults, 1984) and all patients should be instructed as to the importance of this throughout the course of the disease. Potentially nephrotoxic drugs, including aminoglycosides and non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided.
6.3 Early management of renal failure
The goal of initial treatment is to remove precipitating causes and to rapidly reduce the light chain load delivered to the kidney tubule. Hypercalcaemia must be corrected with bisphosphonates, used with modified doses because the kidney is their only route of excretion (see Appendix II). Infection must be treated vigorously, nephrotoxic drugs stopped and patients rehydrated. Dehydration from any cause will increase the concentration of light chains delivered to the renal tubule. Renal recovery can be achieved with intravenous fluid to achieve a urine flow of over 3 l/d (MRC Working Party on Leukaemia in Adults, 1984). Volume replacement should be guided by monitoring of central venous pressure when renal output is reduced. There is little evidence to support urinary alkalinization (Iggo et al, 1997).The advice of a nephrologist should be sought if renal function does not improve within 48 h of initial interventions and there must be clear communication between haematologists and the specialist renal team to optimize outcome. Renal biopsy is desirable to help guide management but is not essential.
Physical removal of light chains by plasma exchange (PE) is theoretically beneficial in cast nephropathy. Data from two early small randomized trials was conflicting (Zucchelli et al, 1988; Johnson et al, 1990) and the results of a further randomized, controlled trial (Clark et al, 2005) were inconclusive. Results of further UK studies of PE and of large pore haemodialysis are awaited.
Reducing light chain production from the plasma cell clone is the most effective mechanism of reducing the light chain load to the kidney. High dose dexamethasone alone is effective as a single agent in this setting (Alexanian et al, 1992) and can lead to 100-fold falls in SFLC within 2 weeks in sensitive disease. Lower levels are associated with renal recovery (Hutchison et al, 2008; Drayson et al, 2009).
Oral high dose dexamethasone should be started without delay whilst decisions about definitive chemotherapy are being made. SFLC measurements in the first 2 weeks may identify patients who are not responding to their anti-myeloma therapy. Further work is needed to evaluate how this finding may influence treatment decisions in the future. The high early death rate in patients with myeloma and renal failure is mainly due to infection, which is a major preventable cause of death in these patients. Close observation and early and intensive treatment of infective episodes is essential if this early loss is to be improved.
Recommendations for initial management of renal failure (all grade C recommendation; level IV evidence)
- • Vigorously rehydrate with at least 3 l of normal saline daily
- • Treat precipitating events e.g. hypercalcaemia, sepsis and hyperuricaemia and discontinue nephrotoxic drugs, particularly NSAIDs
- • Consider physical methods of removing free light chains from the blood (plasma exchange, large pore haemofiltration) within the context of a clinical trial
- • Administer high dose dexamethasone unless otherwise contraindicated pending initiation of definitive treatment which should be started without delay
- • Monitor SFLC levels
- • Identify and treat infection vigorously
- • Patients with renal failure require dose modification of bisphosphonates and the risk of renal adverse events may be greater in patients with impaired renal function. For guidance on use of bisphosphonates in patients with renal impairment, see Appendix II
7. Induction therapy including management of major toxicities and stem cell harvesting
The broad aims of treatment in myeloma are to control disease, maximize quality of life and prolong survival and can be achieved by a combination of specific disease-directed therapy and supportive care. Although high-dose therapy is recommended where possible, many patients will be unable to receive such therapy because of advanced age, co-morbidities or poor performance status. Treatment decisions should be reviewed in an MDT and should take into account individual patient factors and patient choice.
The introduction of novel agents, such as thalidomide, lenalidomide and bortezomib (usually in combination with dexamethasone) has led to a clear improvement in survival of patients with myeloma (Kumar et al, 2008a). However, much work is needed to determine the best sequence and combinations of therapies. It is therefore essential that, wherever possible, patients are entered into clinical trials. As many patients are living longer with myeloma, the impact of therapy on quality of life is particularly important.
Many studies both in the transplant and non-transplant settings have suggested a link between the maximal response attained and long-term outcome after initial therapy and that increasing the complete remission rate after transplant results in prolonged progression-free survival (PFS) and OS (van de Velde et al, 2007; Lahuerta et al, 2008). Improving depth of response is therefore becoming an increasingly important goal.
7.1 Induction therapy prior to high dose therapy (HDT), including management of common side-effects
For patients where HDT is planned, or is a possible future option, the aim of induction treatment is to induce high remission rates rapidly and with minimal toxicity and to preserve haemopoietic stem cell function to ensure successful mobilization of peripheral blood stem cells (PBSC).
Prior to the introduction of novel therapies, the standard of care for patients in whom HDT and autologous stem cell transplantation (ASCT) was planned was the use of induction therapy based on high dose dexamethasone, such as VAD (vincristine, doxorubicin and dexamethasone), or related infusional regimens. These combinations were associated with response rates of 55–84% and CR rates of 8–28% (Gore et al, 1989; Samson et al, 1989; Alexanian et al, 1990) although it should be noted that the current definition of CR is more rigorous. However, there was significant haematological toxicity and the need for central venous access led to an appreciable incidence of line-related infections and thrombosis.
Table VII shows a summary of evidence and toxicity profiles for the novel agents. Strategies for preventing and managing known side effects are included in the relevant sections and in Section 7.3.
Table VII. Comparison of side effects related to myeloma treatment with novel agents.
|Constipation||Yes||Low risk||Low risk|
|Route of administration||Oral||Intravenous||Oral|
General prescribing points
- • Guidance regarding dose-reduction of cytotoxic agents, such as melphalan and cyclophosphamide, in the setting of low blood counts is well established in local clinical practice guidelines and Summary of Product Characteristics (SPC) documents. As a guide, the neutrophil count is recommended to be >1·0 × 109/l and the platelet count >50–75 × 109/l before commencing treatment. Treatment should be delayed until these levels are achieved, unless cytopenias are considered to be due to marrow infiltration.
- • Myeloma frequently causes anaemia at diagnosis whereas thrombocytopenia is more common in end-stage disease. BM reserve generally improves with effective myeloma therapy
- • Renal or hepatic impairment may compound drug-induced myelosuppression
- • Granulocyte colony-stimulating factor (G-CSF) can reduce/prevent severe neutropenia and should be considered according to local policies
- • Attention should be paid to the SPC
- • Prescribing should occur in close consultation with specialist pharmacists
7.1.1 Thalidomide-containing regimens
Thalidomide has a number of mechanisms of action in myeloma including anti-angiogenic activity, inhibition of tumour necrosis factor-α, stimulation of the secretion of α-interferon (IFN-α) and interleukin-2, induction of apoptosis and regulation of adhesion molecule expression (Hideshima et al, 2000). It was the first of a number of novel agents responsible for improvements in survival in myeloma and has become widely used as part of induction therapy.
Evidence for use of thalidomide-containing regimens as induction prior to SCT:
A retrospective matched case control analysis compared patients treated with VAD as induction therapy with patients treated with thalidomide/dexamethasone. This showed a significantly higher response rate in the thalidomide arm versus the VAD arm (p < 0·001; Cavo et al, 2005). Since then, several randomized phase III trials have evaluated thalidomide-containing combinations as induction therapy although not all of these trials used these regimens specifically as induction prior to high dose therapy. Results of trials comparing thalidomide with conventional induction therapy are summarized in Appendix III, Table 1.
In general, the use of thalidomide and dexamethasone as induction does not produce superior response rates post-ASCT. The phase III HOVON (Stichting Hemato-Oncologie voor Volwassenen Nederland) study comparing TAD (thalidomide, doxorubicin and dexamethasone) to VAD showed improved overall response rate, including major response, and improved PFS following ASCT (Lokhorst et al, 2010). There was no survival benefit for the thalidomide arm, however, because these patients had a shorter post-relapse survival. The MRC Myeloma IX trial compared CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) with CTD (cyclophosphamide, thalidomide and dexamethasone). Preliminary results have shown higher response rates in the CTD arm but information on the benefit for PFS and OS is awaited. This is the now the most widely used combination in the UK following the demonstration that it can be safely and effectively delivered in a large, multi-centre clinical trial setting. Stem cell mobilization and harvesting are not adversely affected by the use of thalidomide-containing regimens.
Toxicity of thalidomide:
The principal non-haematological toxicities of thalidomide and their management are described in Table VIII.
Table VIII. Important thalidomide toxicities.
|Venous thromboembolism: highest risk is at diagnosis and when combined with conventional chemotherapy and/or high dose dexamethasone. All patients require a risk assessment to guide thromboprophylaxis (see section 7.3.2)|
|Sensory peripheral neuropathy: this is common and usually cumulative. It may not resolve for many months following discontinuation of thalidomide. A summary of key recommendations from the supportive care guideline regarding treatment emergent peripheral neuropathy is given in section 7.3.1. Directed questioning, close clinical monitoring and prompt dose reductions if symptoms develop are needed (see Table XI)|
|Constipation: laxatives are often required pre-emptively|
|Haematological toxicity: rare and dose reduction is rarely required|
|Somnolence: evening dosing minimizes this and the effect reduces with use|
|Rashes: these are varied and may respond to dose reduction. Rarely, Stevens-Johnson syndrome.|
|Arrhythmias: known cardiac arrhythmias are a relative contra-indication. Consider cardiology review early in symptomatic patients|
|Thyroid dysfunction: check baseline thyroid function at start of therapy and re-check every 6 months. Patients on thyroxine supplements should have their thyroid function monitored carefully as dosage may change on thalidomide therapy|
|Congenital malformations due to fetal exposure: there have been no reported cases of birth defects in myeloma patients on thalidomide. Risk management protocols to minimize risks should be followed in all patients including strict contraceptive precautions in both sexes|
7.1.2 Bortezomib-based regimens
Evidence for use of bortezomib-containing regimens as induction prior to SCT:
The proteasome inhibitor bortezomib (Velcade, previously PS-341) is active as a single agent in patients with untreated myeloma (Anderson, 2006). A phase II study in 60 patients showed a response rate (RR) of 28% with 10% CR but several phase II trials have confirmed higher response rates when bortezomib is combined with dexamethasone and/or chemotherapy in previously untreated patients who are considered eligible for ASCT. These have shown response rates ranging from 66 to 95% with CR rates (where reported) of 6–24% and details of these studies are shown in Appendix III, Table 2.
Two large phase III trials have been reported and provide substantial evidence that bortezomib-based therapy is a successful pre-ASCT induction regimen. The IFM (Intergroupe Francophone du Myélome) group has completed a randomized phase III trial comparing four courses of VAD with bortezomib/dexamethasone in 482 patients up to the age of 65 years (Harousseau et al, 2010). In this and the HOVON trial, which compared PAD (bortezomib, doxorubicin and dexamethasone) and VAD (Sonneveld et al, 2008), the CR or CR/near CR (nCR) rate increased significantly post-ASCT in the bortezomib-containing arm. In the IFM trial, significant prolongation of PFS was seen but this did not result in longer OS.
Toxicity of bortezomib:
Bortezomib requires intravenous administration. The most frequently reported toxicities are shown in Table IX. All are predictable but require active management and specific guidelines have been developed for their prevention and treatment. A proforma for the early detection of side-effects for use in patients on bortezomib therapy has been developed and is shown in Appendix IV. The key to effective use of bortezomib is the optimal management of treatment emergent toxicities allowing the maximum duration of therapy. Recent data from front line protocols incorporating bortezomib suggest that a weekly regimen is as effective and associated with less neuropathy than twice weekly regimens (Gay et al, 2009; Mateos et al, 2010). In all the trials described above, stem cell mobilization was unaffected by bortezomib therapy and haematological recovery was adequate following stem cell reinfusion after high dose therapy.
Table IX. Important bortezomib toxicities.
|Peripheral neuropathy: predominantly sensory and painful, usually progressive and variably reversible. The incidence, clinical features and risk factors for the development of bortezomib-induced peripheral neuropathy (BIPN) are described in detail in a review by Mohty et al (2010). A summary of key recommendations from the supportive care guideline regarding treatment emergent peripheral neuropathy is given in section 7.3.1. It is managed by early detection, dose-reduction (see Table XI) and analgesia|
|Gastrointestinal toxicity: constipation, diarrhoea, abdominal bloating or pain. Patients should be warned of possible symptoms, Severe diarrhoea is relatively rare but occasional patients with severe diarrhoea, unresponsive to loperamide may require admission for hydration as these patients are at risk of developing pre-renal acute renal failure|
|Postural hypotension and pre-syncope secondary to autonomic neuropathy: pre-hydration with saline infusion prior to each dose of bortezomib is a useful prophylactic measure. Screen for pre-syncope and syncope and assess for a postural drop at the start of each treatment cycle. The administration of 500 ml of normal saline prior to each dose of bortezomib may improve tolerance of the drug. Many patients require dose adjustment of their usual anti-hypertensives for the duration of bortezomib therapy|
|Thrombocytopaenia: usually progressive over 21-d cycle with recovery prior to next cycle. Check full blood count on days 1 and 8; consider dose reduction if platelets <30 × 109/l on day 1 and transfuse platelets if <30 × 109/l on any other treatment day|
Neutropenia secondary to bortezomib is unusual, but thrombocytopenia is a frequent cyclical effect with nadirs around day 11, which usually recover towards baseline by the start of the next cycle. The platelet count should be >30 × 109/l to treat and patients may receive platelet transfusions to allow this. If the platelet count is <30 × 109/l on day 1, dose reduction should be considered e.g. to 1 mg/m2. Thrombocytopenia tends to become less severe with time on treatment. There are no recommended dose reductions for patients with renal or hepatic impairment. Aciclovir prophylaxis is recommended due to increased incidence of varicella zoster infection. Venous thromboembolic events are not a feature with bortezomib either alone or in combination and hence prophylaxis is not required.
7.1.3 Lenalidomide-based regimens
Lenalidomide (Revlimid) is an orally administered thalidomide analogue with a different side-effect profile. It has more potent in-vitro activity, including the inhibition of angiogenesis, cytokine modulation and T-cell co-stimulation than thalidomide (Corral & Kaplan, 1999; Hideshima et al, 2000; Haslett et al, 2003).
Evidence for use of lenalidomide-containing regimens as induction prior to SCT
Several phase II studies of lenalidomide with dexamethasone +/− chemotherapy have demonstrated high response rates of between 76 and 91% and are summarized in Appendix III (Table 3). In a study of 34 patients treated with a combination of lenalidomide 25 mg daily on days 1–21 of a 28-day cycle and high dose dexamethasone, all patients who underwent stem cell mobilization collected sufficient stem cells. (Rajkumar et al, 2005). Despite this, concerns have been raised about failure to harvest adequate stem cells after prolonged lenalidomide treatment and, as a result, it is now recommended that stem cells should be collected within 6 months of initiation of lenalidomide therapy (Kumar et al, 2007).
Toxicity of lenalidomide: Lenalidomide is considered to be better tolerated than thalidomide. In particular, it does not cause significant somnolence, neuropathy or constipation. Key lenalidomide toxicities are shown in Table X. The most frequently seen toxicities occurring grade >3 are myelosuppression (which can usually be managed with dose reduction and growth factor support if necessary) and thrombosis. Recommendations regarding thromboprophylaxis are described in Section 7.3.2. Neutropenia and thrombocytopenia are the commonest Grade 3/4 toxicities. In relapsed patients the reported incidence was 35·4 and 13% respectively, in two large randomized trials (MM-009 and MM-010; Dimopoulos et al, 2009a). The risk of myelosuppression may be higher in patients who have recently (£1 year) had high dose therapy and ASCT. A full blood count should be performed at baseline, weekly for the first 2 months of treatment and at least monthly thereafter. Dose adjustments are recommended to manage grade 3 or 4 neutropenia or thrombocytopenia. The incidence is higher in patients with impaired renal function (Weber et al, 2006). Dose adjustments are recommended within the SPC to manage grade 3 or 4 thrombocytopenia or neutropenia and renal impairment (see Appendix II, Tables 1, 2, and 3).
Table X. Important lenalidomide toxicities.
|Cytopenias: regular blood count monitoring is required (weekly for first two courses); patients may need G-CSF|
|Venous thromboembolism: thromboprophylaxis is recommended (see section 7.3.2 for recommendations)|
|Neuropathy: less frequent than with thalidomide or bortezomib. Lenalidomide may be appropriate for patients with either disease or treatment-related neuropathy but those with pre-existing neuropathy may develop worsening symptoms|
|Diarrhoea, particularly with long-term usage|
Importantly, the incidence of neuropathy is low, grade 3+ neuropathy occurring in <5% of patients with relapsed myeloma (Richardson et al, 2006).
7.1.4 Combinations involving two or more novel agents as induction therapy prior to SCT
There is evidence for high response rates and high CR rates with combinations involving more than one novel agent (reviewed in Lonial & Cavenagh, 2009) but further data are required regarding the toxicity profiles of these combinations and whether these higher response rates translate into longer PFS and OS after ASCT.
Combinations, such as bortezomib, thalidomide, dexamethasone (VTD), have given response rates of 82–92% with CR rates of 18–29% (Cavo et al, 2009; Rosiñol et al, 2009) without an increase in serious adverse events in 3-drug combinations (Cavo et al, 2009). Several other combinations have been explored in phase II trials (see Appendix III, Table 4).
7.2 Initial treatment when HDT is not planned
The aim of therapy in older and less fit patients is to achieve the maximum durable response with minimal treatment-related toxicity. These patients form a heterogeneous group and have a variable tolerance of therapy. Treatment may need to be modified in patients with poor performance status.
A large meta-analysis showed the combination of oral melphalan and prednisolone (MP) to be as effective as combination regimens including intravenous drugs (Myeloma Trialists’ Collaborative Group, 1998). Melphalan and cyclophosphamide were shown in early randomized studies to be equally effective (MRC Working Party for Therapeutic Trials in Leukaemia, 1971). Thus, in the past these drugs, usually with prednisolone (P), have formed the mainstay of first line therapy in this patient group.
7.2.1 Thalidomide based regimens
Use of thalidomide has also been extensively explored in this setting. A phase III study comparing thalidomide and dexamethasone (TD) with dexamethasone in patients with a median age of 65 years showed a significant benefit with regard to response and time to progression (TTP) in the TD group after four cycles, albeit with grade 3 or higher non-haematological toxicity being seen in 67% of patients who received TD (Rajkumar et al, 2006). Only one study has directly compared TD with MP (Ludwig et al, 2009a). This phase III study in 298 elderly patients showed superior responses in the TD arm but similar PFS and TTP in both groups. However, OS was significantly lower in the TD group, and it was thought that this very elderly population (60% of patients between 70 and 79 years) were unable to tolerate the high doses of thalidomide and dexamethasone used.
Five randomized trials have compared oral MP with MPT (melphalan, prednisolone and thalidomide) as first line treatment in elderly patients and the results of these studies are summarized in of Appendix III, Table 5. Despite variation in the doses of all three agents between the five studies, all have shown superior response rates and PFS in the MPT arms and two have shown significant prolongation of OS (Facon et al, 2007; Hulin et al, 2009). The failure of other studies to produce this benefit was probably due to effective salvage therapy incorporating novel agents at relapse (Gulbrandsen et al, 2008; Palumbo et al, 2008a; Wijermans et al, 2008).
Most randomized studies have shown that thalidomide doses above 200 mg/d are poorly tolerated by elderly patients. In general patients receiving MPT in the above trials did experience an increased incidence of side effects, notably cytopenias, thrombosis, fatigue and peripheral neuropathy.
Given the historical equivalence of cyclophosphamide to melphalan, UK investigators have developed an alternative regimen to MPT comprising cyclophosphamide, thalidomide and dexamethasone (CTD). In older less fit patients attenuated doses (CTDa) are given. CTDa was used in the non-intensive arm of the Myeloma IX trial. Early results from this study demonstrate superior response rates for CTDa over MP and suggest similar efficacy to MPT although PFS and OS data are not yet available (Morgan et al, 2009).
7.2.2 Bortezomib- and lenalidomide-based regimens
The newer agents, bortezomib (Velcade, V) and lenalidomide (Revlimid, R) are also effective when used in combination with steroid +/− alkylator. A phase III study comparing M, P and bortezomib (VMP) with MP showed superior response rates, PFS and OS in the VMP group (San Miguel et al, 2008b). This included a 30% CR rate vs. 4% with MP (p < 0·001) and median PFS 24 month vs. 16·6 months with MP. The VMP regimen was generally well tolerated, although peripheral neuropathy (grade 3 or above) affected 13% of patients. This resolved or improved in 75% of cases in a median of approximately 60 d. Patients receiving VMP also had a higher incidence of gastro-intestinal complications and fatigue. More recent trials have investigated once weekly bortezomib in a modified VMP which results in similar response rates but reduced toxicity, especially neurotoxicity (Mateos et al, 2010). A combination of M, P and lenalidomide (MPR) is also being explored. A phase I/II study produced comparable response rates to MPT with a low incidence of non-haematological adverse events (Palumbo et al, 2007). The relative efficacy of lenalidomide with low dose dexamethasone (Rd) when compared with melphalan-based regimens is now being tested in a phase III trial (Palumbo et al, 2009).
A randomized trial of 445 patients comparing lenalidomide with either high dose or low dose dexamethasone in newly diagnosed myeloma showed significant benefits for low dose dexamethasone in terms of OS at 1 year (96% vs. 86%, p = 0·0002; Rajkumar et al, 2010). For this reason, the trial was stopped early and patients on high-dose dexamethasone therapy were crossed over to low-dose therapy. The decision regarding dexamethasone dose should be made on an individual patient basis based upon assessment of co-morbidities, tolerance and performance status.
Plasma cell leukaemia
The outcome with conventional chemotherapy is poor, as the reported median survival is 8–12 months (Dimopoulos et al, 1994; Garcia-Sanz et al, 1999) although an improvement in outcome has been reported with autologous transplantation (Drake et al, 2010) and bortezomib treatment (Finnegan et al, 2006).
Summary of treatment recommendations
General (all Grade C recommendations; level IV evidence)
- • Chemotherapy prescribing should be undertaken by an experienced clinician with input from a specialist chemotherapy-trained pharmacist
- • SPC recommendations for dose adjustments of chemo-therapy drugs and use of G-CSF support should be followed wherever possible
- • Patients should be appropriately dosed, to allow for renal and liver function
- • Patients with cytopenias at baseline due to limited marrow reserve require more frequent monitoring and dose adjustment
- • All patients should be considered for entry into a clinical trial
- • The choice of therapy should take into account patient preference, co-morbidities and toxicity profile
Specific treatment recommendations for induction therapy prior to high dose therapy (HDT)
- • VAD or single agent dexamethasone should no longer be routinely used as induction therapy
- • Induction regimens should contain at least one novel agent
- • Examples of induction regimens that are superior to VAD in terms of response rates include CTD, TAD, bortezomib/dexamethasone and PAD
- • Decisions regarding the most appropriate induction for individual patients will require the assessment of a number of factors, such as renal function, thrombotic risk and pre-existing neuropathy although it is appreciated that some agents are not routinely funded as initial therapy in the UK. CTD is the combination of which there is the most clinical experience in the UK
Specific treatment recommendations for older and/or less fit patients in whom HDT is not planned initial therapy
Specific treatment recommendations for patients with plasma cell leukaemia and rarer myeloma subtypes Recommendations (all are Grade C based on level IV evidence)
- • The use of initial treatment with bortezomib and autologous stem cell transplantation should be considered in responding patients with plasma cell leukaemia
- • IgD, IgE and IgM myeloma are associated with a poor outcome but there is insufficient data to support specific alternative treatment strategies at this time
7.3 Prevention and management of treatment related complications of therapy
7.3.1 Peripheral neuropathy
The investigation and management of peripheral neuropathy is described in detail in the supportive care guideline (Snowden et al, 2011). Key recommendations for the management of peripheral neuropathy are listed below (all are Grade C recommendations; level IV evidence):
- • Peripheral neuropathy is common at diagnosis and as a result of many myeloma therapies
- • Peripheral neuropathy and autonomic neuropathy symptoms and signs should be actively sought and sequentially graded during the course of therapy using a scale, such as the National Cancer Institute Common Toxicity Criteria (http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf) to provide an objective assessment and allow identification of trends
- • Any patient who develops a significant (e.g. >NCI grade 2) or progressive peripheral or autonomic neuropathy following treatment should be managed with graded dose reduction or drug withdrawal. Guidelines for dose reductions of thalidomide and bortezomib are shown in Table XI. Continuation of dose intense treatment in the face of neuropathy may cause permanent neurological damage
- • The management of peripheral neuropathy should include symptom control along with treatment of any potentially reversible causes. Optimal management of co-morbid causes such as diabetes mellitus may also improve tolerance of neurotoxic drugs
- • Neuropathic pain is poorly responsive to simple analgesics, NSAIDs and opioid drugs. Neuromodulatory agents are increasingly recommended to treat neuropathic pain. Patients with progressive neuropathic pain despite appropriate analgesia should be referred promptly for specialist advice regarding pain management
Table XI. Guidelines for the management of bortezomib and thalidomide-induced PN evaluated according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Reproduced from Mohty et al (2010). Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.
|Grade 1 (paraesthesiae, weakness and/or loss of reflexes without pain or loss of function)||No action||No action|
|Grade 1 with pain or Grade 2 (interfering with function but not with daily activities)||Reduce bortezomib to 1·0 mg/m2||Reduce thalidomide dose to 50% or suspend thalidomide until disappearance of toxicity, then re-initiate at 50% dose|
|Grade 2 with pain or Grade 3 (interfering with daily activities)||Suspend bortezomib until disappearance of toxicity then re-initiate at 0·7 mg/m2 and administer once weekly||Suspend thalidomide until disappearance of toxicity, then re-initiate at low dose if PN grade 1|
|Grade 4 (permanent sensory loss interfering with function)||Discontinue bortezomib||Discontinue thalidomide|
Myeloma and other plasma cell disorders have a well-established association with venous thromboembolism (VTE; Srkalovic et al, 2004). Active disease, cancer therapies, infection, previous VTE, immobility and paraplegia are all well-recognized additional risk factors for VTE in hospitalized patients. Thalidomide and lenalidomide have been demonstrated to further increase this risk. Use of thromboprophylaxis and treatment of both thrombosis and bleeding problems in myeloma patients are discussed in detail in the Guidelines for Supportive Care in multiple myeloma (Snowden et al, 2011). Key recommendations from that document are listed below.
Recommendations (all are Grade C recommendations; level IV evidence)
- • Cancer, cancer therapies, infection, previous VTE, immobility, obesity, paraplegia, erythropoietin treatment, dehydration and renal failure are all well-recognized risk factors for VTE, particularly in hospitalized patients. As with other areas of thromboprophylaxis, a risk stratified approach is appropriate in patients with myeloma
- • A risk assessment model for the prevention of venous thromboembolism in multiple myeloma patients treated with thalidomide or lenalidomide is contained within the Guidelines for Supportive Care in multiple myeloma (Snowden et al, 2011; adapted from Palumbo et al, 2008b)
- • All patients who are due to start thalidomide or lenalidomide-containing therapy should undergo a risk assessment for VTE and prospectively receive appropriate thromboprophylactic measures
- • In patients receiving thalidomide or lenalidomide, aspirin (75325 mg) may be considered as VTE prophylaxis in low risk patients only (i.e. without risk factor present), unless contraindicated
- • Patients receiving thalidomide or lenalidomide in addition to combination chemotherapy/anthracyclines/high dose steroids, or those with two or more myeloma/individual risk factors should be offered prophylaxis with LMWH (high risk prophylactic dose) or dose-adjusted therapeutic warfarin, unless contraindicated. There is no role for fixed, low dose warfarin
- • The duration of thromboprophylaxis remains unclear but should be guided by risk factors such as active disease (e.g. for the first 4–6 months of treatment until disease control achieved) and de-escalated or discontinued unless there are ongoing significant risk factors
- • Treatment of confirmed VTE should follow current practice guidelines using adjusted dose warfarin or LMWH and appropriate monitoring
7.4 Can novel agents overcome the poor prognosis associated with adverse cytogenetic abnormalities?
This group comprises some 15–20% of newly diagnosed patients, and includes those with the following cytogenetic abnormalities: t(4;14), t(14;16), t(14;20), del(17q) or non-hyperdiploid disease (Stewart et al, 2007). Although del(13q) by metaphase cytogenetic analysis is an adverse prognostic marker, these patients invariably have a t(4;14) translocation. Gain of chromosome (1q21) has also recently been described as conferring a poor outcome, however, this occurs in association with t(4;14) and del(13q), and may not be an independent prognostic marker (Fonseca et al, 2006).
An important unanswered question is whether the use of novel agents may overcome cytogenetically-defined poor prognosis disease. In the VISTA (Velcade® as Initial Standard Therapy in Multiple Myeloma) study (Mateos et al, 2008) in the non-transplant setting, patients with high risk disease who received bortezomib had equivalent response rates, PFS and OS to standard risk patients but the number of patients in this group was small. In the IFM study, pre-ASCT induction with bortezomib partially overcame the poor prognosis of t(4;14) disease (67 patients), but had no impact on 17p disease (51 patients) (Avet-Loiseau et al, 2009). In 16 patients with high risk disease treated with lenalidomide and dexamethasone, response rates and survival were similar to standard risk patients, albeit with shorter duration of response (Kapoor et al, 2009). All these data are derived from retrospective sub-analyses of trials, and prospective data on larger patient numbers with longer follow up are needed to establish the role of novel agents in the setting of high risk disease. Available information to date, however, suggest that bortezomib may be able to overcome the poor prognostic impact of some genetic subtypes, such as t(4;14) disease.
- • Novel agents have increased the overall and complete remission rates if used pre-ASCT.
- • Confirmation is needed that these higher response rates translate into longer PFS and OS after ASCT.
- • Further data regarding a number of combinations are required, particularly those containing more than one novel agent.
7.5 Stem cell harvesting after induction therapy including novel agents
Duration of induction treatment prior to SCT
The majority of patients achieve maximum response to induction therapy after four to six cycles. Response should be assessed after each cycle. Although CR prior to HDT is a good prognostic factor, there is currently no evidence that prolongation of induction treatment to achieve a CR improves outcome. It is currently therefore recommended to treat to at least PR, which usually occurs within four to six cycles and to switch to an alternative regimen if there is evidence of progressive disease after two cycles or less than PR after 4. The treatment of refractory disease is discussed in more detail in Section 8. Alternatively, in responses <PR it is also reasonable to proceed directly to HDT after completion of four cycles of induction therapy if stem cells can be successfully harvested.
Stem cell mobilization
Mobilization with cyclophosphamide and G-CSF may overcome the effects of lenalidomide (Mark et al, 2008) and is recommended if induction therapy with a lenalidomide-containing regimen has continued for >4 cycles.
Recommendations (all are Grade C recommendations; level IV evidence)
- • Peripheral blood stem cell harvesting (PBSCH) should be carried out within four to six cycles for all induction regimens that incorporate a novel agent
- • If induction therapy with a lenalidomide-containing regimen has continued for >4 cycles, mobilization with cyclophosphamide and G-CSF is recommended
- • Ideally patients should undergo stem cell mobilization within 6–8 weeks of completion of induction therapy
7.6 Chemotherapy in patients with renal failure
In addition to the steps described in Section 6, effective treatment of myeloma is the most successful way of ensuring renal recovery. Regimens that can be used without dose reduction in renal impairment and that produce the highest response rate and most rapid responses should theoretically produce the highest rates of renal recovery. It is essential to understand how agents should be used in the presence of renal impairment to ensure maximal safety and efficacy (see Table XII).
Table XII. The key features with regard to renal excretion and recommended dose adjustment in renal impairment for drugs commonly used in the treatment of myeloma.
|Melphalan||Yes||Yes||Dose titration with bone marrow toxicity|
|Thalidomide||Unchanged thalidomide was <3% of the dose in urine but pharmacologically active metabolites are excreted in the urine||No||The manufacturer recommends that patients with severe renal impairment should be carefully monitored for adverse reactions|
Melphalan is hydrolysed and excreted via the kidneys and there is concern that BM suppression may develop if full doses are used in patients with renal impairment. The manufacturer recommends that initial doses of melphalan should be reduced by 50% if the glomerular filtration rate (GFR) is <40–50 ml/min, and that it should not be used in patients in whom the GFR is below 30 ml/min. However this is at variance with data which shows that the extent of drug accumulation is variable in each individual and cannot be predicted from the degree of renal impairment (Osterborg et al, 1989) and also that, even with doses of melphalan 25 mg/m2 intravenously, patients with severe renal impairment, including dialysis dependency, did not have longer periods of leucopenia nor adverse OS (Vigneau et al, 2002). A retrospective analysis of data from patients with renal impairment treated in clinical trials led Carlson et al (2005) to propose a 25% initial dose reduction with titration according to BM toxicity for subsequent courses.
Cyclophosphamide metabolites are excreted in the urine. Manufacturers recommend a dose reduction of 25% if the GFR is 10–50 ml/min, and of 50% if GFR is <10 ml/min. Clinical experience suggests it is safe to titrate the dose in subsequent courses according to response.
Anthracyclines and high dose dexamethasone
Doxorubicin and dexamethasone are commonly used agents, particularly in combination with novel agents (e.g. PAD) and do not require dosage adjustment in the presence of renal impairment even if it is severe (Aitchison et al, 1990).
The pharmacokinetics of thalidomide seems to be unaltered in patients with renal dysfunction (Eriksson et al, 2003). Less than 3% of thalidomide is excreted unchanged in the urine and it is not hepatically or renally metabolized to any large extent, appearing to undergo non-enzymatic hydrolysis in plasma to form multiple degradation products. However metabolically active hydrolytic products formed via non-enzymatic processes are also present in plasma and urine and their major route of excretion is the urine (>90%). Although the clearance of thalidomide is increased during dialysis it appears unnecessary to give a supplementary dose. A report of thalidomide use in 20 patients with renal impairment did not show any increase in toxicity (Tosi et al, 2004) although there have been case reports of hyperkalaemia and tumour lysis syndrome. The manufacturers recommend that patients with severe renal impairment should be carefully monitored for adverse reactions but do not recommend dose reduction in renal impairment.
In vitro studies indicate that bortezomib is metabolized primarily through oxidative deboronation by the liver cytochrome P450 system and that early disposition kinetics of bortezomib are not affected by creatinine clearance (range <30–>80 ml/min) in patients (Bortezomib SPC). Bortezomib can therefore be used in renal impairment without dose reduction. There have been no large prospective randomized studies of the use of bortezomib in patients with myeloma and renal impairment. However, a number of studies have shown that bortezomib either alone, or in combination with other agents, produces similar response rates in these patients to those seen in patients with normal renal function and that there is no excess toxicity. These include sub-analyses of patients with renal impairment in a number of large studies (Jagannath et al, 2005a; San Miguel et al, 2008c; Dimopoulos et al, 2009b). Median time to first response in the VISTA trial was 1·4 months with VMP compared to 3·5 months with MP (Dimopoulos et al, 2009b). Whilst there are a number of studies showing high levels of renal recovery using bortezomib containing regimens (Chanan-Khan et al, 2007; Kastritis et al, 2007; Roussou et al, 2008; Ludwig et al, 2009b) there is no randomized clinical trial evidence to justify recommendation of its routine use in this setting.
There are limited data on the clinical use of lenalidomide in renal failure but a pharmacokinetic study in patients with varying degrees of renal impairment following a single dose of lenalidomide 25 mg orally showed that lenalidomide is substantially excreted by the kidneys (Chen et al, 2007) with a mean urinary recovery of unchanged lenalidomide of 84% of the dose in subjects with normal renal function. Recovery declined to 43% in subjects with severe renal impairment (creatinine clearance <30 ml/min), and still further in end stage renal impairment. This study also showed that a 4-h haemodialysis removed 31% of lenalidomide. Lenalidomide should be used with caution and appropriate dose reductions used in patients with renal impairment because of the increased risk of cytopenias. Recommended dose reductions for patients with renal impairment are shown in Appendix II, Table 4.
Recommendations (all Grade C recommendation; level IV evidence)
- • Dexamethasone alone can be given as initial treatment pending decisions on subsequent chemotherapy and the outcome of full supportive measures
- • Melphalan can be considered for patients with renal impairment in whom other regimens may be relatively contraindicated. The dose should be reduced by 25% in the first course if GFR <30 ml/min and titrated against marrow toxicity in subsequent courses
- • Cyclophosphamide can be used with a dose reduction of 25% if the GFR is 10–50 ml/min, and of 50% if GFR is <10 ml/min and titrated in subsequent courses according to response
- • Thalidomide can be used without dose modification in patients with renal failure
- • Bortezomib can be safely used in myeloma patients with renal failure including those on dialysis at the standard starting dose of 1·3 mg/m2. However, because of limited data on toxicity, patients with renal impairment (creatinine clearance ≤30 ml/min) and patients on haemodialysis should be closely monitored for toxicity. Although there is mounting evidence that bortezomib appears effective in this setting, further studies are needed to confirm results derived from subgroup analyses of large randomized trials and data from other non randomized studies
- • Lenalidomide can be given in patients with renal impairment but dose adjustments as recommended by the manufacturer should be implemented
8. Myeloma refractory to induction therapy
Primary refractory myeloma is defined as disease that is non-responsive in patients who have never achieved a minimal response or better with any therapy. It includes patients who never achieve MR or better in whom there is no significant change in M-protein and no evidence of clinical progression and also patients with progressive disease (Rajkumar et al, 2011). The principles of managing primary refractory disease differ depending on whether the patient is still considered a candidate for high dose therapy.
Patients for whom high dose therapy remains an option
It is important to distinguish patients who have refractory but non-progressive disease, i.e. are clinically stable, from those who have evidence of disease progression on induction therapy. There is evidence that the former group still stand to benefit from consolidation with high dose therapy (Alexanian et al, 1994a,b; Kumar et al, 2004). The decision whether to proceed straight to PBSCH and HDT may depend on co-morbidities, toxicity from previous treatment and degree of BM infiltration. Such decisions should ideally be undertaken in an MDT meeting.
In cases where the BM is heavily infiltrated, two options are available.
- 1 Use a non-cross-reactive mobilization regimen such as ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) (D’Sa et al, 2004) in patients with normal renal function to achieve further cytoreduction prior to HDT
- 2 For patients who are fit enough (sufficient BM reserve, no prohibitive toxicity), use of a salvage regimen prior to stem cell harvesting and HDT is recommended to achieve a greater depth of response as this correlates with improved outcome (Morris et al, 2004)
Patients with progressive disease on first-line therapy should receive salvage treatment. These patients have a bleak outlook and often have poor genetic markers. It is important that such patients are identified early so that salvage therapy can be instituted before further organ damage occurs. Careful monitoring of urinary Bence-Jones protein (BJP) is important to avoid renal damage, and salvage regimens that include platinum agents should be avoided in patients with significant BJ proteinuria (>1 g/24 h).
Where possible, patients should be entered into clinical trials. Outside trials, a bortezomib-based regimen should be used, if the patient received thalidomide as part of their induction therapy. If they did not, a thalidomide-containing regimen is an option e.g. CTD or DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) (Lee et al, 2003a). Other alternative regimens include platinum-based regimens (see above), which can also be used as mobilizing chemotherapy together with growth factors, or lenalidomide–containing regimens for patients with ≥ grade 2 peripheral neuropathy.
Patients for whom SCT is (no longer) an option
Disease that is non-responsive to initial treatment may remain clinically stable with no evidence of either clinical or laboratory progression for prolonged periods and therefore these patients may not require immediate further treatment but should be closely monitored (MRC, unpublished data). Second-line treatment for those requiring therapy should be a combination including an alternative novel agent e.g. VMP in patients who have received upfront CTDa.
Recommendations (all grade C recommendation; level IV evidence)
- • All patients should be considered for entry into a clinical trial
- • For patients intolerant of thalidomide, or refractory to first-line therapy, a bortezomib-based salvage regimen is recommended
- • Patients with ≥ grade 2 peripheral neuropathy should receive a lenalidomide-based regimen
9. High dose therapy and autologous stem cell transplantation (ASCT)
There is more than 20 years experience of HDT and ASCT in the management of myeloma since the efficacy of high dose melphalan in the treatment of high-risk myeloma and plasma cell leukaemia was first reported (McElwain & Powles, 1983). ASCT has become the first line standard of care in those deemed biologically fit enough for this option mainly because of the low transplant-related mortality (TRM) and prolongation of EFS resulting in improved quality of life. Four pivotal randomized studies have been published comparing combination chemotherapy with a high dose approach as first-line therapy for newly diagnosed myeloma patients aged up to 65 years. In most of these studies, maintenance IFN was given in both arms. The results of these studies are summarized in Appendix III, Table 6.
Stem cells are now almost exclusively derived from peripheral blood following stimulation with growth factors with or without chemotherapy. The optimal regimen for mobilizing PBSC is unclear but cyclophosphamide (1·5–4 g/m2) with G-CSF is widely used. Purging harvested stem cells with monoclonal antibodies and/or CD34+ stem cell selection does reduce contamination with tumour cells but does not influence the relapse risk (Stewart et al, 2001; De Rosa et al, 2004).
High dose melphalan (200 mg/m2) remains the standard conditioning prior to ASCT. Recent studies have shown that the dose of melphalan can be increased to 220 mg/m2 (Garban et al, 2006), with improved PFS compared with historical controls, or to 240–300 mg/m2, in combination with amifostine, (Reece et al, 2006) but at the cost of increased toxicity. The addition of total body irradiation (TBI) results in increased toxicity (Moreau et al, 2002) with no improvement in response rate or PFS, whilst combination chemotherapy increases the toxicity (Capria et al, 2006; Benson et al, 2007; Vela-Ojeda et al, 2007). Bortezomib has shown synergistic effects with melphalan without prolonged haematological toxicity. The recently reported IFM phase II study enrolled 54 untreated patients to receive bortezomib (1 mg/m2 × 4) and melphalan (200 mg/m2) as conditioning regimen (Roussel et al, 2010). The authors reported a response ≥VGPR in 70% of patients and 32% CR. No toxic deaths were observed with minimal peripheral neuropathy. Due to limited follow-up, response durability data are not yet available (Roussel et al, 2010).
Though to date randomized controlled data (RCT) data on the use of ASCT have related mostly to patients ≤65 years, results have indicated that, in selected patients aged >65 years, outcomes are similar to those in younger patients (Siegel et al, 1999; Reece et al, 2003; Jantunen, 2006). Data from the ABMTR (Reece et al, 2003) comparing the outcome of 110 patients aged >60 years with 382 patients aged <60 years showed no difference in TRM, EFS or OS. Over 70 years, the toxicity of melphalan 200 mg/m2 is increased, with a TRM of 16% reported in one series (Badros et al, 2001a). An alternative HDT is modified/intermediate dose melphalan, as reported by (Palumbo et al, 2004), where two cycles of intermediate dose melphalan (100 mg/m2; IDM) with PBSC support was compared with six cycles of MP in patients aged 65–70 years in a RCT, demonstrating a median OS of 58 months with IDM compared to 37·2 months for MP. Kumar et al (2008b) compared a group of 33 patients ≥70 years at the time of HDT with a group of 60 patients <65 years. Despite the fact that more of the elderly patients received a reduced dose of melphalan, the overall response rate and TTP was similar between the two groups. These results indicate that ASCT can be safely performed in patients aged >65 years if care is taken with patient selection, taking into account pre-existing co-morbidities and performance status. Limited data exist to demonstrate that stem cell yields in mobilized blood of patients >60 years are lower and that this can affect platelet recovery (Morris et al, 2003; Fietz et al, 2004).
9.3 Timing of ASCT
The encouraging results reported with novel agents have challenged the role of ASCT as part of upfront therapy. Several groups have reported early results of prospective studies evaluating the use of ASCT at the time of disease progression after initial induction and consolidation using novel agent combinations. It is, however, likely that ASCT will further increase the rate and depth of responses achieved with induction therapy with a consequent improvement in PFS. There is therefore currently no evidence to support deferral of the first ASCT until the time of first relapse, though prospective studies are underway to explore this possibility further.
9.4 Single versus tandem autologous stem cell transplant
Barlogie et al (1997) pioneered the use of tandem ASCT in the early management of myeloma in the Total Therapy I program, producing a CR rate of 41% and median OS of 79 months. The IFM94 trial was the first randomized study comparing single and tandem transplants, reporting improved EFS (30 months vs. 25 months) and OS (58 months vs. 48 months; Attal et al, 2003). However, the recently published systematic review of 6 RCTs including more than 1800 patients failed to demonstrate an improvement in OS or PFS with the use of tandem ASCT in previously untreated patients (Kumar et al, 2009a). Two studies suggest that the second procedure is most beneficial in those individuals that have not achieved at least a VGPR (>90% reduction in serum monoclonal protein) with the first transplant (Attal et al, 2003; Cavo et al, 2007).
An alternative strategy is to collect sufficient stem cells to support two ASCT but to defer the second ASCT until the time of relapse and this approach is increasingly employed. Individuals with the best outcome following a ‘deferred’ second ASCT are those achieving a first progression-free interval of at least 2 years following their first transplant (Mikhael et al, 2004). Definitive recommendations regarding the use of a second ASCT at the time of relapse cannot be made, especially in light of emerging new biological agents. It is recommended that the use of ASCT in the relapse disease setting should, where possible, be performed as part of a clinical study protocol, such as the current joint UKMF/British Society of Bone Marrow Transplantation (BSBMT) study, Myeloma X.
9.5 High Dose Therapy in Renal Failure
High dose therapy with ASCT has been reported by several centres as a feasible treatment modality in patients with renal failure including those patients requiring dialysis. The use of melphalan at 200 mg/m2 is associated with a high TRM (16–29%) in patients on dialysis (San Miguel et al, 2000; Knudsen et al, 2005). This compares with a TRM of only 5% in a series of 38 patients with renal failure not on dialysis receiving melphalan 200 mg/m2 reported by Sirohi et al (2001) and one out of 17 patients died who received melphalan at 100 mg/m2 whilst on dialysis (Raab et al, 2006). A retrospective BSBMT study looking at high-dose melphalan in 31 patients (27 with myeloma), of whom 23 were on dialysis, conditioned with doses of melphalan 60–200 mg/m2 recorded a TRM of 19% (Bird et al, 2006). All studies describe up to 24% of patients coming off dialysis post-transplant (Lee et al, 2004; Bird et al, 2006).
The largest series of reported patients is from the Little Rock team. In an initial report (Badros et al, 2001b), severe toxicities, were observed in 60 patients receiving melphalan 200 mg/m2, leading them to reduce the dose in subsequent patients to 140 mg/m2. The threshold for melphalan dose reduction was a creatinine of over 179 mmol/l, equivalent to a GFR of <30 ml/min. These data were extended in a subsequent report, showing a TRM of 19% in 59 patients on dialysis at the time of transplant, 27 of whom had received melphalan 200 mg/m2 (Lee et al, 2004). Even at reduced doses of melphalan, toxicity can be significant with prolonged mucositis and hospitalization (Raab et al, 2006). The response rates in patients are similar to matched controls.
- • HDT with ASCT should be part of primary treatment in newly diagnosed patients up to the age of 65 years with adequate performance status and organ function (Grade A recommendation; level Ib evidence)
- • HDT with ASCT should be considered in patients aged >65 years with good performance status (Grade B recommendation; level IIa evidence)
- • Conditioning with melphalan alone, without TBI, is recommended (Grade B recommendation; level IIa evidence). The usual dose is 200 mg/m2 but this should be reduced in older patients (over 65–70 years) and those with renal failure (see below)
- • Planned double (‘tandem’) ASCT cannot be recommended on the current evidence. However, it is recommended that enough stem cells are collected to support two high dose procedures in patients with good performance status (Grade C recommendation; level IV evidence)
- • Purging is not of clinical benefit and is not therefore recommended (Grade A recommendation; level Ib evidence)
- • HDT and ASCT may be considered for patients with severe renal impairment (creatinine clearance/GFR <30 ml/min) but the dose of melphalan should be reduced to a maximum of 140 mg/m2 (Grade B recommendation; level IIb evidence) and the procedure should only be carried out in a centre with special expertise and specialist nephrology support (Grade C recommendation; level IV evidence)
10. Allogeneic Stem Cell Transplantation (AlloSCT)
10.1 Myeloablative (full intensity, FI) allogeneic matched family donor (MFD) stem cell transplantation
AlloSCT can result in long-term disease-free survival but its role in the management of patients with myeloma has been controversial because of the high TRM and morbidity, primarily related to co-morbidities and advanced age (Gahrton et al, 1991). However, outcomes have improved significantly over time. In cohorts transplanted from 1983–1993 and 1994–1998, TRM decreased from 46% to 30% (Gahrton et al, 2001). Three key studies in the area of FI AlloSCT have reported results: the US intergroup (Barlogie et al, 2006a), the Hovon group (Lokhorst et al, 2003) and BSBMT (Hunter et al, 2005). These results are summarized in Appendix III, Table 8. The reported TRM of 34–54% demonstrated the limitations of this type of conditioning despite the long-term EFS of 22–36% and OS 28–44% with follow-up between 5 and 7 years. Although these studies examined variations in the conditioning used, including T-cell depletion, no significant impact on TRM was noted with the exception of the superiority of melphalan over cyclophosphamide (Hunter et al, 2005).
Patient selection through careful pre-transplant assessment is important. Co-morbidity scores may be of value, and may be of greater significance than biological age. Outcome after FI AlloSCT is inferior in patients transplanted beyond first remission or in patients with refractory disease (Maloney et al, 2003; Crawley et al, 2005). The remission status post-transplant is also important, with the achievement of a molecular CR being associated with a very low risk of relapse (Corradini et al, 2003). Prior ASCT is associated with poorer outcomes with myeloablative conditioning (Hunter et al, 2005; Crawley et al, 2007). A negative impact on outcome is also seen with a prolonged time to transplant and with donor/recipient sex-mismatching.
The purest ‘proof of principle’ of the activity of a graft-versus-myeloma (GvM) effect is the efficacy of donor lymphocyte infusions (DLI) at the time of relapse of disease. The largest series reported (Lokhorst et al, 2004), demonstrated that there is clearly a DLI-mediated GvM. Importantly, tumour response was strongly associated with the presence of graft-versus-host disease (GvHD). These data indicate that GvM and GvHD are closely related and largely overlapping phenomena. There are emerging data that concurrent treatment with DLI and novel therapies can increase response rates (Kröger et al, 2004). DLI should be considered for patients with relapsed or persistent disease.
10.2 Reduced intensity conditioned (RIC) AlloSCT
To reduce TRM and to permit the application of AlloSCT to older, less fit patients, reduced intensity conditioned AlloSCT (RIC AlloSCT) has been explored. Several studies have shown that this approach is feasible with a significant reduction in TRM. As the conditioning is less cytoreductive, RIC transplants are dependent to a large extent on GvM. One strategy is to perform sequential ASCT/RIC AlloSCT such that minimal disease burden is present at the time of AlloSCT, allowing time for the GvM to be effective. The results of a number of these studies are summarized in Appendix III, Table 8. The Seattle group has studied this approach using sequential ASCT followed by a T-replete, low-dose TBI-based RIC AlloSCT (Maloney et al, 2003). A day 100 TRM of 0% and 48 month OS and PFS values of 69% and 45% respectively have been reported, with a low incidence of acute but a high incidence of chronic GvHD.
A number of Phase II studies have reported similar findings (Le Blanc et al, 2001; Perez-Simon et al, 2003; Mohty et al, 2004; Gerull et al, 2005; Rotta et al, 2009). In these studies, the presence of chronic GvHD was associated with the achievement of CR and OS/PFS. In a retrospective EBMT study, Crawley et al (2005) showed that the best outcomes were associated with the development of limited chronic GvHD, with T cell depletion being associated with significantly higher relapse rates. Taken together, these data suggest that clinically effective GvM is intimately associated with GvHD and that, by implication, strategies designed to abrogate GvHD could have deleterious effects on disease control. Severe GvHD is tolerated poorly by older patients and impacts significantly on quality of life and is an important cause of late mortality after AlloSCT.
Several ‘biological’ (donor versus no donor) studies have been reported (Garban et al, 2006; Bruno et al, 2007; Rosiñol et al, 2008), summarized in Appendix III, Table 7. TRM rates of <20% are reported with 29–80% EFS and 41–80% OS resulting from short and variable reported follow-up. In these studies, differences in patient selection/characteristics (e.g. del l3q, high β2-microglobulin patients versus unselected), conditioning and GvHD incidence are likely to have resulted in the observed differences in outcomes. In at least one of the studies, there were no event-free survivors at 5 years (Garban et al, 2006). Recently, longer term results (median follow up 6·3 years) of 102 patients from the Italian group have been published (Rotta et al, 2009). Forty-two per cent of patients developed grade 2–4 acute GvHD and 74% extensive chronic GvHD. Five-year OS and PFS were 64% and 36% respectively but the median time to relapse was 5 years. These data indicate a continuing problem with relapse, including late events and extramedullary relapse and the high rate of chronic GvHD is likely to result in further TRM. No prospective trials have compared ablative with RIC AlloSCT in this setting. However, an EBMT analysis (Crawley et al, 2007) has shown similar OS with both approaches. RIC AlloSCT patients had a lower TRM but a higher relapse rate and lower PFS.
10.3 Matched unrelated donor (MUD) AlloSCT
In many diseases, outcomes with MUD AlloSCT have improved with time and, in many settings, have become equivalent to matched sibling transplantation. However, retrospective studies in myeloma have shown a significantly higher TRM than with sibling AlloSCT (Shaw et al, 2003) and as a result, myeloablative MUD AlloSCT is not currently recommended and should only be carried out in the context of prospective clinical trials.
The role of RIC MUD AlloSCT remains to be defined although encouraging results have been reported, with short-term TRM of approximately 20% (Kröger et al, 2002; Shaw et al, 2003). Further prospective trials are warranted in order to better define the role of RIC MUD AlloSCT for patients with myeloma.
- • Treatment decisions that involve AlloSCT are some of the most difficult for patients. Patients need to be fully informed and involved in the decision making process. Young patients with matched sibling donors who are interested in pursuing curative therapy should be referred to a haematologist with an interest in allografting myeloma patients so that they gain an understanding of the risks and benefits of this procedure (Grade C recommendation, level IV evidence)
- • Allogeneic SCT should be carried out in EBMT accredited centres where data are collected prospectively as part of international transplant registries and, where possible, should be carried out in the context of a clinical trial (Grade C recommendation, level IV evidence)
- • Allogeneic transplant procedures for patients with myeloma in first response should only be considered for selected groups because of the risk of significant transplant-related morbidity and mortality (Grade C recommendation, level IV evidence)
- • A myeloablative MFD AlloSCT should only be considered in selected patients up to the age of 40 years who have achieved at least a partial response to initial therapy (Grade B recommendation; level IIb evidence)
- • A myeloablative MUD AlloSCT is not recommended except in the context of a clinical trial (Grade C recommendation, level IV evidence)
- • A RIC MFD or MUD AlloSCT is a clinical option for selected patients preferably in the context of a clinical trial. If carried out, RIC AlloSCT should generally be performed following an autograft, early in the disease course in patients with responsive disease (Grade B recommendation, level IIb evidence)
- • DLI should be considered for patients with persistent or progressive disease following transplantation or for mixed chimerism. If given for disease progression, cytoreduction should probably be carried out first (Grade B recommendation, level IIa evidence). Effective doses of DLI are associated with a significant risk of GVHD
11. Maintenance therapy
With the introduction of new agents, there is increasing interest in the role of maintenance therapy. No benefit has been demonstrated for the role of maintenance with chemotherapy (Belch et al, 1988; Drayson et al, 1998).
11.1 α-Interferon (IFN-α)
Many studies of IFN-α as maintenance have been carried out and have given conflicting results, but a meta-analysis of randomized trials (Fritz & Ludwig, 2000) showed that although IFN-α results in moderate prolongation of PFS, the benefit in terms of OS is only minimal. In addition, IFN-α is associated with significant toxicity – in one trial more than one third of patients had to discontinue treatment due to side-effects (Schaar et al, 2005). This toxicity, the marginal benefits and the associated cost of long-term treatment have meant that IFN-α maintenance is no longer considered standard therapy.
Corticosteroid maintenance was evaluated in 125 patients who were treated with either 50 or 10 mg of prednisolone on alternate days after induction therapy with VAD (Berenson et al, 2002). Therapy was continued until disease progression. EFS was significantly longer in the 50 mg group (14 months vs. 5 months, P = 0·003) as well as OS (37 months vs. 26 months, P = 0·05). This effect was not confirmed, however, in a multi-centre Canadian study, which randomized 292 patients to dexamethasone maintenance after induction treatment with either MP or M-Dex (Shustik et al, 2007). PFS was improved in the dexamethasone arm (2·8 years vs. 2·1 years, P = 0·0002) but no difference in OS was observed. In addition, there were significantly more non-haematological toxicities reported in the dexamethasone arm including hyperglycaemia (44% vs. 27%) and infections (40% vs. 27%). Currently, steroid maintenance is not recommended but trials of its use in combination with novel agents are ongoing.
Several randomized prospective studies have investigated thalidomide as potential maintenance therapy post-ASCT and are summarized in Appendix III, Table 9. A recent meta-analysis assessed four randomized controlled trials investigating thalidomide maintenance (Hicks et al, 2008). An OS benefit in favour of thalidomide became apparent when the Barlogie trial (Barlogie et al, 2006b) was excluded.
In the IFM-99 02 study, patients with deletion of chromosome 13 and patients who achieved at least a VGPR did not benefit from thalidomide maintenance (Attal et al, 2006). A dose finding study of thalidomide maintenance post-autograft showed significantly higher discontinuation rates due to toxicity at doses above 150 mg but no difference in EFS suggesting that lower doses are better tolerated but equally effective (Feyler et al, 2007). VTE was not significantly increased. In combination with prednisolone, lower doses of thalidomide (200 plus 50 mg prednisolone) are better tolerated than higher doses (400 plus 50 mg prednisolone; Stewart et al, 2004). Long term treatment with thalidomide (>12 months) is associated with a very high incidence of peripheral neuropathy of approximately 75% (Tosi et al, 2005).
Bortezomib in the maintenance setting has been shown to be beneficial following stem cell transplantation in a large phase III randomized study. Superior response and PFS rates were reported in the PAD arm compared to thalidomide in the VAD arm (Sonneveld et al, 2008). In elderly patients, bortezomib (in combination with either thalidomide or prednisolone) maintenance has been studied following induction therapy with either bortezomib, melphalan and prednisolone (VMP) or bortezomib, thalidomide and prednisolone (VTP) (Mateos et al, 2010). 178 patients were randomly assigned into either maintenance arm for up to 3 years. A complete remission rate of 42% was achieved after maintenance therapy (44% bortezomib plus thalidomide, 39% bortezomib plus prednisolone). This was an improvement of response rates after induction of 28% in the VTP group and 20% in the VMP group. After maintenance, no grade 3 haematological toxicities and low level peripheral neuropathy (2% bortezomib plus prednisolone, 7% bortezomib plus thalidomide) was detected. In another study of newly diagnosed elderly patients, maintenance with bortezomib plus thalidomide did not increase the response to induction with the 4-drug combination of VMP plus thalidomide (VMPT) (Boccadoro et al, 2010).
Given the toxicity of thalidomide, in particular peripheral neuropathy, lenalidomide would be an attractive alternative in the maintenance setting. In a phase III study, 614 patients age ≤65 years were randomized after ASCT to lenalidomide consolidation (25 mg on 21 d per month for 2 months) followed by lenalidomide maintenance (10–15 mg daily until relapse) or placebo (Attal et al, 2010). Maintenance with lenalidomide improved the 3-year PFS significantly, at 68% vs. 35% with placebo with similar 2-year OS. Another phase III randomized study investigated maintenance lenalidomide 10 mg/d escalated to 15 mg/d after 3 months until disease progression in 418 patients age ≤70 years after ASCT (McCarthy et al, 2010) with significantly improved TTP (25·5 months in placebo arm versus not reached in lenalidomide arm) after 12 months follow up. OS and adverse events were similar in both arms. Lenalidomide maintenance in elderly patients (age 65–75 years) after reduced dose ASCT (tandem 100 mg/m2 melphalan) also resulted in improved CR rates (66% vs. 38% after ASCT) with acceptable toxicity in a phase II study of 102 patients (Palumbo et al, 2010).
Recommendations (Grade C recommendation, level IV evidence unless stated)
- • IFN-α or single-agent corticosteroids cannot be routinely recommended as maintenance therapy (grade A, level Ib recommendation). In the allograft setting, IFN-α may be useful for patients who have not achieved a CR (grade B, level IIa)
- • Maintenance with single agent thalidomide therapy may improve EFS and OS in patients who did not achieve VGPR post high-dose therapy and in this setting maintenance therapy could be considered (grade A, level Ia). Patients with deletion 13q may not benefit
- • The dose of thalidomide should not exceed 150 mg (grade B, level IIa recommendation) and no recommendation can be made with regards to the duration of thalidomide maintenance
- • In the maintenance setting, routine anticoagulant prophylaxis is not required
- • At present, there is no evidence of benefit for the use of thalidomide maintenance in elderly patients who did not undergo autologous transplantation
- • The combination of steroids and thalidomide is not recommended in the maintenance setting due to increase toxicity and unclear benefit over thalidomide alone
- • Although promising data are emerging for the use of bortezomib or lenalidomide in the maintenance setting, long term published data are still awaited to be able to recommend their use outside clinical trials
12. Management of relapsed myeloma including drugs in development
The introduction of a number of active anti-myeloma agents with mechanisms of action different from chemotherapy has increased the options available for patients in the relapse setting. Despite this, resistance usually develops over time. For most patients, the aims of treatment are similar to those at diagnosis – to achieve disease control, ameliorate symptoms, improve quality of life and prolong survival. However, for significant numbers of patients, the side-effects of treatment limit the choices available. Previously it was thought that early relapse carried a poor prognosis and that patients were likely to respond poorly to conventional chemotherapy but the introduction of thalidomide, bortezomib and lenalidomide has changed this.
Large data sets from randomized studies of traditional chemotherapy in relapsed patients do not exist. The largest randomized studies in this setting have employed the newer agents, and include the comparisons of bortezomib against dexamethasone (Richardson et al, 2005), and lenalidomide and dexamethasone against dexamethasone alone (Dimopoulos et al, 2007; Weber et al, 2007). Despite this lack of randomized data, some principles can be identified, based on published studies and UK experience, which may influence the choice of treatment at relapse. These include:
- 1 Re-exposure to the same treatment used at presentation is associated with increased rates of treatment resistance. Short remission duration with a given treatment is a strong indicator to employ an alternative regimen
- 2 Single agent activity of the novel agents is limited and these agents should normally be given in combination to maximize benefit
Because of disease heterogeneity and variability in patient-specific factors including co-morbidities and the persistence of toxicities related to previous therapy, there can be no standard approach recommended for the treatment at relapse. However, some of the evidence informing recommendations for the treatment of relapsed myeloma in the UK is summarized below.
12.1 Use of novel agents at relapse
The three agents most often used in treating relapsed patients are thalidomide, bortezomib and lenalidomide. They are generally used in combination with corticosteroids (pulsed or weekly dexamethasone), and sometimes an alkylating agent, most commonly cyclophosphamide. The evidence for efficacy and issues relating to toxicity for each are summarized below.
Numerous studies have confirmed the efficacy of thalidomide in the relapsed and refractory setting with a response rate of 30–40% when used alone (Barlogie et al, 2001) and 60% when used in combination with dexamethasone (Dimopoulos et al, 2001; Palumbo et al, 2001). Synergy has been further demonstrated by the observation that when thalidomide is combined with dexamethasone in patients documented to be refractory to both drugs given separately (not necessarily sequentially) up to 25% of patients will respond to the combination (Weber et al, 1999). The response rate is increased further by the addition of chemotherapy. Numerous combinations of thalidomide with cytotoxic chemotherapy in addition to dexamethasone have also been explored resulting in improved response rates compared with the single agent. The most frequently used combination in the UK is CTD with reported response rates of up to 80% (Kropff et al, 2003; Dimopoulos et al, 2004; Garcia-Sanz et al, 2004; Kyriakou et al, 2005; Sidra et al, 2006).
Response to therapy is rapid with responding patients showing a decline in their M-protein in the first 28 d, although the maximal response occurs considerably later than this (Waage et al, 2004). The optimal dose remains unclear. Although in the original studies the target dose was 800 mg/d this is rarely achievable and in a meta-analysis the median tolerated dose was 400 mg/d (Glasmacher et al, 2006). The optimal duration of therapy has also not been defined. To date most studies have dosed until progression or adverse events required discontinuation; in the CTD regimen a maximum of six courses is usually given although in the relapse setting it is common for thalidomide alone to be continued after completion.
Bortezomib has US Food and Drug Administration (FDA) and European Union (EU) licensing for patients with relapsed myeloma and NICE approval as monotherapy for patients at first relapse. In a phase III study, 669 patients with relapsed myeloma were randomized to either bortezomib or high dose dexamethasone (Richardson et al, 2005), bortezomib demonstrated superiority with an updated response rate of 42% compared to 18% in the dexamethasone group (p < 0·001) and an advantage in both TTP (median 6·22 months vs. 3·49 months, p < 0·001) and OS (p < 0·001; Richardson et al, 2007) despite more than 60% cross-over to bortezomib from the dexamethasone arm. In addition, 56% of patients improved their initial response with continued therapy, suggesting a potential role for extended therapy.
Phase II data indicate improvement in response when dexamethasone is added in patients with a sub-optimal response to bortezomib alone (Richardson et al, 2003). This is consistent with in vitro data of additive cytotoxicity (Hideshima et al, 2001) and provides the rationale for the use of bortezomib with dexamethasone at the commencement of therapy. In these studies, bortezomib was administered twice a week by intravenous bolus for two weeks of a 21-d cycle up to a maximum of eight cycles, although the majority of responses occurred within three cycles. Dexamethasone was given at 20 mg on the day of and the day after each bortezomib dose.
Many studies combining bortezomib with chemotherapeutic or other novel agents have also been performed in the relapsed setting. A large phase III study comparing bortezomib and liposomal doxorubicin to bortezomib alone demonstrated superior response rates and response duration for the combination (Orlowski et al, 2007). Data from numerous phase II trials demonstrate other combination approaches to be safe with higher response rates than with single agents. However, longer follow up and data from randomized phase III studies are awaited.
In the EU, lenalidomide is licensed in combination with dexamethasone for the treatment of myeloma patients who have received at least one prior therapy and, in the UK, recent National Institute of Clinical Excellence (NICE) guidance has approved the drug also in combination with dexamethasone for the treatment of patients at second or greater relapse.
Lenalidomide is given at a dose of 25 mg/d orally for 21 d of a 28-d cycle (Richardson et al, 2002) with dexamethasone initially with three 40 mg/d for 4 d pulses per cycle, reducing to a single pulse in subsequent cycles. Two phase III randomized, multi-centre, double-blind, placebo-controlled studies using identical protocols have been carried out comparing its use to dexamethasone alone (results summarized in Dimopoulos et al, 2009a). Results of the studies were similar, showing significantly higher overall response rates in the lenalidomide/dexamethasone group compared to the control group (60·6% vs. 21·9%, p < 0·001). At a median follow up of 48 months, a pooled analysis of the two trials showed TTP and OS were also significantly longer in the lenalidomide/dexamethasone group despite the fact that patients in the dexamethasone only arm were allowed to receive lenalidomide treatment at relapse, and following the early unblinding of these two studies, patients randomized to dexamethasone alone were offered lenalidomide (Dimopoulos et al, 2009a).
Further analysis of these phase III trial results suggests that higher response rates and improved TTP is achieved in patients treated at first relapse, compared to those treated at subsequent relapse (65% vs. 58% and 71 weeks vs. 41 weeks respectively), although the outcomes for patients treated later in their disease course were still significantly higher in the lenalidomide/dexamethasone arms (Stadtmauer et al, 2009). Patients who had been exposed to thalidomide also benefited from lenalidomide (54% response rate vs. 15% in the dexamethasone arm) although response rates were slightly lower compared to patients who had not been previously exposed to thalidomide (63% and 27% for lenalidomide/dexamethasone and dexamethasone respectively) (Wang et al, 2006). Grade 3 or 4 neutropenia or thrombocytopenia occurred in 35% and 13% respectively, in patients receiving lenalidomide and dexamethasone for relapsed myeloma (Dimopoulos et al, 2009a).
12.2 Transplantation at relapse
High dose therapy and stem cell transplantation may be considered in patients who have not had a prior stem cell transplant (Fermand et al, 1998). A second transplant can also be an effective strategy in selected patients who relapse more than 18 months after an initial autograft and this is currently under investigation in a randomized trial in the UK. This is discussed in more detail in Section 9.4.
12.3 Combinations of novel agents and newer anti-myeloma therapies
Ongoing phase II and III studies are comparing combinations of the above agents as therapy both at relapse and in the front line setting. Initial results are very promising and suggest that combinations of lenalidomide, bortezomib and dexamethasone and bortezomib, thalidomide and dexamethasone are well tolerated and give high response rates.
12.4 Drugs in development
Many new drugs are in development. Promising results in early trials have been reported with several drugs including second and third generation immunomodulatory drugs, such as pomalidomide (Lacy et al, 2009), proteasome inhibitors including carfilzomib (O’Connor et al, 2009) and alkylating agents such as bendamustine (Pönisch et al, 2008). High response rates have been reported with good side-effect profiles, although the studies are too early to comment on any survival benefits.
In addition, the safety and efficacy of a number of novel anti-myeloma therapies is currently being explored in clinical trials, either as single agents or in combination with more traditional chemotherapeutics. Examples include target-specific compounds such as AKT, fibroblast growth factor receptor 3 and interleukin-6 inhibitors, heat shock protein 90 inhibitors and chromatin structure modifying agents, such as histone deacetylase inhibitors and demethylating agents. Pre-clinical in-vitro and in-vivo studies are encouraging but there is currently not enough clinical evidence to support their use outside of clinical trials.
12.5 Local radiotherapy
Some patients may relapse with local disease, e.g. spinal plasmacytoma, with little evidence of active disease elsewhere. Such patients, especially if they are beyond first relapse, may be treated with local radiotherapy, avoiding the additional toxicity of systemic therapy, which would be an option for subsequent disease re-activation.
12.6 Choice of treatment at relapse
Decisions regarding treatment at relapse should be made according to a number of factors including the timing of relapse, efficacy and toxicity of drugs used in prior therapy (e.g. peripheral neuropathy), age, BM and renal function, co-morbidities (e.g. diabetes) and patient preference. A suggested algorithm (contained in the online version of this guideline) takes these factors into account and provides broad guidance but it should be noted that the evidence for recommending one treatment over another at specific time points does not always exist. Despite this, there are a number of common treatment pathways developed in the UK on the background of trial evidence, experience and NICE approvals. As far as possible, treatment should be individualized and it should be recognized that it is not necessarily best practice to mandate particular therapies at specified time points. In the future, it is likely that therapy will be ‘risk-adapted’ and the presence or absence of specific prognostic factors may determine choice of therapy (reviewed in San Miguel et al, 2008a) both at diagnosis and relapse. Entry into clinical trials should be considered at each relapse.
Many patients in the UK will receive a thalidomide-based therapy at induction +/− HDT/ASCT. It is recommended that these patients should be considered for bortezomib +/− steroids and/or chemotherapy at first relapse. For some, this will not be considered the best therapy e.g. patients with pre-existing neuropathy, immobility, lack of venous access, or patient choice. Patients who have enjoyed a long first plateau phase (>18 months) following their initial therapy, and are unsuitable for bortezomib may be treated with the same regimen. Many patients will have responded to thalidomide as their initial therapy, and such patients are likely to respond again at relapse. The use of a second ASCT is discussed below and in Section 9.4.
Patients at second and subsequent relapse, or patients at first relapse intolerant of thalidomide or bortezomib should be considered for lenalidomide. For patients presenting in renal failure strong consideration of treatment with a bortezomib-containing regimen should be given, to achieve rapid reduction in light chain load to the kidneys, and maximize chances of regaining renal function.
Recommendations (all grade C recommendations; level IV evidence)
- • The most appropriate management should be determined on an individual basis depending on the timing of relapse, age, prior therapy, BM function and co-morbidities and patient preference
- • Extensive trial data support the use of thalidomide, bortezomib and lenalidomide-based regimens as treatment modalities at first and subsequent relapse
- • Clinical effectiveness of thalidomide, bortezomib and lenalidomide is not dependent on the number of previous lines of therapy, or type of therapy previously received
- • Unless contraindicated, treatment with thalidomide, bortezomib or lenalidomide treatment should be delivered with dexamethasone +/− chemotherapy to increase the response rate
- • A second ASCT may be considered in patients who had a good response to the initial transplant procedure (≥18 months to disease progression)
- • Where possible, patients should be treated in the context of a clinical trial. Phase I/II trials are appropriate for patients with relapsed/refractory myeloma
- • Good supportive therapy is essential
13. Patient information and support
Provision of information and support for patients and their carers is essential if a patient is to come to terms with their diagnosis and make informed decisions about treatment options. It will also enable them to understand the importance of compliance with treatment regimens that can be demanding. Myeloma is an individual cancer affecting patients and their carers in many physical, emotional and social ways. Therefore, information and support should, if possible, be tailored to individual needs.
As a minimum, it is important for patients and their families to understand the disease and the aims and risks of treatment and that, although treatment is not curative, it will relieve symptoms, prolong survival and improve quality of life; the positive aspects of treatment need to be stressed. They should be aware that their treatment and care will have been discussed and agreed by an MDT and should be given the details of key workers. Patients should be told about appropriate clinical studies and be given a sufficient level of information and time to make an informed decision as to whether to take part or not. Patients with myeloma should be aware of support networks in the community; the specialist team should provide patients and their families with information on local support networks, whether these are specific to myeloma or in relation to cancer generally.
Finally, the symptoms of myeloma and the side-effects of treatment may result in long-term disability and preclude many patients from returning to work. High-dose and conventional chemotherapy regimens also make employment impractical for periods of several months. Patients commonly need advice on socio-economic problems resulting from the condition and its treatment. The specialist team needs to be able to provide information on state benefits, e.g. Disability Living Allowance and other appropriate social services.
- • The diagnosis needs to be communicated honestly to the patient and their family without delay
- • Information should be communicated in a quiet area with privacy, ideally in the company of a close relative and with the presence of a specialist nurse. The information needs of the patient’s family need to be facilitated wherever possible
- • Patients and their partners/carers should be given time to ask appropriate questions once they have been given the diagnosis; this may be best be done after an interval of a few hours or days
- • Patients should be made aware of appropriate clinical studies
- • Treatment plans need to be communicated simply to the patient and his/her carer and should be clearly written in the case record so that the information is readily accessible to other members of the multi-disciplinary specialist team
- • Patients need to be informed of the names of the key members of the specialist team who are in charge of their care and given clear information on access to advice/support from the team
- • At the end of a consultation it is recommended that patients and their family/carers have written information on the condition. It should also guide patients and their family/carers on access to other information services
Useful information sources
Myeloma UK provides information and support to all those affected by myeloma and aims to improve treatment and care through education, research, campaigning and awareness. http://www.myeloma.org.uk.
Leukaemia and lymphoma Research supports research in myeloma and also provides patient information booklets. http://www.llresearch.org.uk.
Macmilllan cancer support provides practical, medical and financial support to patients http://www.macmillan.org.uk.
While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the UK Myeloma Forum, the British Society for Haematology (BSH) nor the publishers accept any legal responsibility for the content of these guidelines.
Annual review of recommendation updates will be undertaken and any altered recommendations posted on the websites of the British Committee for Standards in Haematology (http://www.bcshguidelines.com/) and UKMF (http://www.ukmf.org.uk/).
This guideline document was produced with the help of an educational grant from Myeloma UK.
Appendix I: Levels of evidence and grades of recommendation
Table 1. Levels of Evidence.
|Ia||Evidence obtained from meta-analysis of randomized controlled trials|
|Ib||Evidence obtained from at least one randomized controlled trial|
|IIa||Evidence obtained from at least one well-designed, non-randomized study, including phase II trials and case-control studies|
|IIb||Evidence obtained from at least one other type of well-designed, quasi-experimental study, i.e. studies without planned intervention, including observational studies|
|III||Evidence obtained from well-designed, non-experimental descriptive studies. Evidence obtained from meta-analysis or randomized controlled trials or phase II studies which is published only in abstract form|
|IV||Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities|
Table 2. Grades of Recommendation.
Evidence level Ia, Ib
|Recommendation based on at least one randomized controlled trial of good quality and consistency addressing specific recommendation|
Evidence level IIa, IIb, III
|Recommendation based on well conducted studies but no randomized controlled trials on the topic of recommendation|
Evidence level IV
|Evidence from expert committee reports and/or clinical experiences of respected authorities|
Appendix II: Recommended dose reductions for various toxicities
Bisphosphonates and renal function
Adverse effects on renal function have been reported with the nitrogen-containing bisphosphonates (pamidronate and zoledronic acid) and are most likely if the recommended dose or rate of infusion is exceeded (Berenson et al, 1998; Rosen et al, 2001; Chang et al, 2003; Barri et al, 2004). Although acute renal dysfunction may be reversible, renal impairment due to acute tubular necrosis may result in chronic renal failure. Pamidronate has also been associated with nephrotic syndrome due to a collapsing variant of focal segmental glomerulosclerosis, which can lead to end-stage renal failure. Patients with pre-existing renal impairment are thought to be particularly susceptible to bisphosphonate-induced renal damage. It is essential to check the creatinine before each infusion of pamidronate and zoledronic acid and withhold the next dose until the renal function has returned to within 10% of the baseline value.
The manufacturers’ guidance on dose reduction in renal impairment is currently as follows:
Clodronate: half dose if creatinine clearance 10–30 ml/min; contraindicated if <10 ml/min.
Pamidronate: slower infusion rate (20 mg/h) if mild to moderate renal impairment; not recommended if creatinine clearance <30 ml/min.
Zoledronic acid: Reduced dosing recommended in patients with creatinine clearance 30–60 ml/min; not recommended if serum creatinine >35 μmol/l.
Potentially this would mean that patients with severe renal failure including those on dialysis could not be treated with a bisphosphonate. However the SPC for Pamidronate states that ‘Pamidronate should not be administered to patients with severe renal impairment (creatinine clearance <30 ml/min) unless in case of life-threatening tumour induced hypercalcaemia where the benefit outweighs the potential risk’, although does not make dose recommendations in this circumstance.
In addition there is wide clinical experience of using 30 mg of pamidronate in patients with severe renal impairment and appears safe if administered at a slower rate of 2–4 h. Its use should be in consultation with a renal physician. (Grade C Evidence level IV).
The following table summarizes the recommended dose reductions of bisphosphonates in renal impairment.
|30/35–60 ml/min||No dose modification||No dose modification. The infusion rate should not exceed 90 mg over 4 h||No dose modification|
|10–30 ml/min||Half dose||30 mg to be given over 2–4 h||Not recommended|
|<10 ml/min||Contra indicated||30 mg to be given over 2–4 h||Not recommended|
Lenalidomide and myelosuppression
Table 1. Dose adjustment levels for lenalidomide.
|Starting daily dose||25 mg|
|Daily dose level – 1||15 mg|
|Daily dose level – 2||10 mg|
|Daily dose level – 3||5 mg|
Table 2. Dose adjustment for thrombocytopenia.
|First fall to <30 × 109/l||Pause lenalidomide treatment|
|Return to >30 × 109/l||Resume at dose level – 1|
|For each subsequent drop to <30 × 109/l||Pause lenalidomide treatment|
|Return to >30 × 109/l||Resume at next lower dose level; do not dose below 5 mg daily|
Table 3. Dose adjustment for neutropenia.
|First fall to <0·5 × 109/l||Interrupt lenalidomide treatment|
|Return to ≥0·5 × 109/l when neutropenia is the only observed toxicity||Resume lenalidomide at starting dose once daily|
|Return to ≥0·5 × 109/l when dose-dependent haematological toxicities other than neutropenia are observed||Resume lenalidomide at dose level – 1 once daily|
|For each subsequent drop below <0·5 × 109/l||Interrupt lenalidomide treatment|
|Return to ≥0·5 × 109/l||Resume lenalidomide at next lower dose level (Dose level 2 or 3) once daily. Do not dose below 5 mg once daily.|
Lenalidomide and renal impairment
Given the increased incidence of grades 3 and 4 thrombocytopenia in patients with impaired renal function, careful platelet monitoring is highly recommended in patients with an elevated serum creatinine, and attention is drawn to the importance of dose adjustment due to renal impairment (Table 4). There are currently no recommendations for dose adjustments in patients with hepatic insufficiency.
Table 4. Suggested dose reductions for renal insufficiency.
|Mild renal impairment (creatinine clearance ≥50 ml/min)||25 mg once daily (full dose)|
|Moderate renal impairment (30 ≤creatinine clearance <50 ml/min)||10 mg once daily|
|Severe renal impairment (creatinine clearance <30 ml/min, not requiring dialysis)||15 mg every other day|
|End-stage renal disease (ESRD; creatinine clearance <30 ml/min, requiring dialysis)||5 mg once daily (following dialysis on dialysis days)|
Appendix III: Evidence summaries
Table 1. Results of trials comparing thalidomide-based induction with conventional chemotherapy.
Table 2. Results of phase II/III studies of bortezomib/dexamethasone induction therapy.
Table 3. Results of phase II studies of lenalidomide and dexamethasone +/− as induction therapy.
Table 4. Results of trials investigating combinations involving 2 or more novel agents as induction therapy prior to SCT.
Table 5. Summary of randomized trials comparing MPT with MP as induction therapy in elderly patients.
Table 6. Summary of randomized controlled trials comparing conventional chemotherapy with high dose therapy and ASCT.
Table 7. Results of prospective, ‘biologically randomized’ studies of tandem autografting compared to ASCT/RIC Allo (adapted from San-Miguel and Mateos, 2009, with permission. © the American Society of Hematology).
Table 8. Summary of selected reported series of Allo-SCT in myeloma.
Table 9. Results of randomized prospective studies investigating thalidomide as potential maintenance therapy post autologous transplantation.
|IFM 99-02 (Attal et al, 2006)||597||3-year 52% vs. 37% (p = 0·002)||4-year 87% vs. 77% (p = 0·04)||Median 15 months, 200 mg/d|
|Total therapy (Barlogie et al, 2006b)||668||5-year 56% vs. 41% (p = 0·01)||No benefit||Until relapse or toxicity, 400 mg/d|
|Thalidomide and prednisolone (Spencer et al, 2009)||269||3-year 42% vs. 23% (p < 0·001)||86% vs. 75% (p = 0·004)||12 months, 200 mg/d|
Appendix IV: Suggested proforma for the early detection of bortezomib-associated toxicities.
|Bortezomib Nursing Assessment|
|Temp|| ||Pulse|| ||BP|| ||RR|| ||Sats|| ||AVPU|| |
|None||Mild tingling not interfering with function|
|Numbness, cramps, burning sensation or stabbing pain. Not interfering with activities of daily living (ADL)|
|Numbness, burning or pain, Interfering with ADL Inform DR||Severe pain and permanent loss of function|
|None||Mild pain not interfering with function||Moderate pain; pain or analgesics interfering with function but not with ADL|
|Severe pain; pain or analgesics severely interfering with ADL|
|Life threatening consequences|
|None||1 episode in 24 h||2–5 episodes in 24 h may require IV Fluids|
|>5 episodes in 24 h requiring IV Fluids|
|Life threatening consequences|
|None||1–3 episodes in 24 h, advise to increase fluid intake|
|4–6 episodes in 24 h may require IV fluids: not interfering with ADL|
|>6 episodes in 24 h: requiring IV fluids: interfering with ADL Inform DR||Life threatening consequences|
|None||Occasional or intermittent symptoms; occasional use of laxatives||Persistent symptoms with regular use of laxatives|
|Symptoms interfering with ADL; enema required|
|Life threatening consequences|
|None||Mild fatigue, Over baseline/little tired||Moderate or causing difficulty to ADL|
|Severe fatigue, interfering with ALL ADL’s|
|None||Occasional dizziness on standing|
(<3 times per week)
|Regular dizziness on standing with no postural drop (>3 times per week)|
|Postural drop >20 mmHg +/− regular Dizziness|
|>1 syncopal episode (fainting) associated with fall in BP|
|Day 1 Only||Lying BP|| ||Standing BP|| |
|Cannula gauge:||Vein Used:||By:|
|Dose reduced date:||Neuropathy Questionnaire D1 & 8:|