Diagnosis and management of multiple myeloma
These guidelines have been compiled by the Guidelines Working Group of the UK Myeloma Forum on behalf of the British Committee for Standards in Haematology (BCSH). Their production involved the following steps:
• Review of key literature including Cochrane Database, Medline and Internet searches
• Recommendations made based on literature review and consensus of expert opinion
• Consultation with representatives of other specialties
• Involvement of patient advocate groups
• Presented at the British Society of Haematology (BSH) Annual meeting, Bournemouth, March 2000, and UKMF Annual Clinical Meeting, 8th June 2000; revised as necessary following feedback from these presentations
• Reviewed by the UKMF Executive and BCSH Committees
• Liturature review updated to 30 June 2001
• Completion date 24 July 2001
• For annual review by UK Myeloma Forum; updates will be published on the UKMF and BSH/BCSH web-sites
• Planned full revision date July 2004
• A synopsis of these guidelines is being developed for patients with myeloma and will be available on the web-sites of the IMF(UK) and the UK Myeloma Forum (anticipated early 2002)
• Further guidelines will include the management of solitary plasmacytoma, AL amyloidosis, and standards for the use of imaging techniques in myeloma.
These guidelines are intended to set out the key areas of strategy in the effective clinical management of myeloma. Levels of evidence and grades of recommendation are set out in Table I. Detailed chemotherapy protocols and dosages are not included; they are beyond the scope of this document. It is a function of each cancer centre/network to provide the detailed information and local protocols needed for the safe organization, delivery and management of chemotherapy and related clinical care.
Table I. Levels of evidence and grades of recommendation.
|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 |
| 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 |
|Grades of recommendation|
| Grade A|
Evidence level Ia, Ib
|Recommendation based on at least one randomized controlled trial of good quality and consistency |
addressing specific recommendation
| Grade B|
Evidence level IIa, IIb, III
|Recommendation based on well conducted studies but no randomized controlled trials on the topic of |
| Grade C|
Evidence level IV
|Evidence from expert committee reports and/or clinical experiences of respected authorities|
Statements appearing on drug dosage in the text mainly concern dosages used in specific trials or in the context of adjustment for renal impairment. The authors of these guidelines have made extensive efforts to ensure that treatments, drugs and dosage regimens are accurate. However, changes in information resulting from continuing research and clinical experience, reasonable differences in opinions among authorities, and the possibility of human error in preparation of the text require the clinician to exercise individual judgement when making a clinical decision. He/she must check product information and drug dosages before prescribing or administration.
Myeloma – the context
Epidemiology and incidence
Myeloma is a plasma cell tumour with an annual United Kingdom incidence of c. 40 per million (about 2500 new cases) per annum; at any one time there will be 10–15 000 patients with the condition. The median age at diagnosis is 60–65 years; fewer than 2% of myeloma patients are under 40 years of age at diagnosis. It has a higher incidence in Afro-Caribbean ethnic groups than in Caucasians; little else is known specifically about its epidemiology. Most cases present de novo; a minority evolve from monoclonal gammopathy of undetermined significance (MGUS).
Clinical presentation is varied. Common presentations of myeloma include bone pain, recurrent or persistent infection, anaemia, renal impairment, or a combination of these. Some patients are asymptomatic, abnormalities being identified on blood tests being carried out for other clinical reasons.
Presenting features, which require urgent specialist referral, include:
• Bone destruction symptoms:
persistent, unexplained backache associated with loss of height and osteoporosis (especially in men and premenopausal women)
symptoms suggestive of spinal cord/nerve root compression
• Compromised immunity and/or bone marrow function:
recurrent or persistent bacterial infection
anaemia, typically normochromic
leucopenia and/or thrombocytopenia
• Persistent elevation of erythrocyte sedimentation rate (ESR) or plasma viscosity
• Evidence of impaired renal function
Investigations available in primary care which can identify suspected cases of myeloma include:
• ESR or plasma viscosity
• Full blood count
• Serum urea and electrolytes
• Serum calcium
• Serum protein electrophoresis
• Serum immunoglobulins
• Urine sample to test for free light chains (Bence–Jones protein; BJP)
• Standard X-ray imaging of bones, particularly the axial skeleton (NB radionucleide bone scanning is not usually helpful in the diagnosis of myeloma).
Appropriate setting for the management of myeloma
A consultant haematologist or oncologist, who is part of an approved Cancer Network in accordance with UK National Health Service (NHS) strategy, should lead the care of patients with multiple myeloma. Effective and high-quality care in myeloma requires a multispecialty and multidisciplinary team familiar with the range of clinical problems likely to be encountered. There are currently a number of government initiatives focused on improving standards of care, including the NHS Cancer Plan. Clinicians managing patients must be aware of these initiatives and develop strategies to achieve these standards locally. The centre should be capable of achieving the 2-week government standards for referral. It needs to maintain a database of cases for registration and clinical audit. A minimum data set for myeloma registration and audit is included as Appendix 1. Improved registration and systems to facilitate this are part of the NHS Cancer strategy.
| date of birth, postcode, sex (male/female), NHS number (if known), GP name|
| origin of referral (GP/hospital specialist/other), date of referral, date first seen, date of diagnosis, (MGUS/multiple|
| myeloma/solitary plasmacytoma)|
| paraprotein type (IgG/IgA/light chain/IgD/non secretory/other), pretreatment quantification, bone marrow percentage|
| plasmacytosis, bone marrow cytogenetics/FISH (normal; abnormal; not done), skeletal survey (normal/osteoporosis/lytic|
| World Health Organization (WHO) Performance status, serum/plasma creatinine and Hb after hydration, β2-microglobulin,|
| cytogenetic results (if available)|
| treatment intent (observation only/chemotherapy/radiotherapy/surgery/palliative or supportive treatment only), clinical trial|
| offered (yes/no), type of trial if entered (MRC/local/UK multicentre/international multicentre), date started therapy|
| date of birth, postcode, sex (male/female), NHS number (if known), GP name|
|Transplantation/Stem cell procedure:|
| ‘rainy day’ harvest (yes/no; date collected), autograft (yes/no/date), allograft (yes/no/date)|
|Outcome at 12 months and annual follow up:|
| current survival status (alive/dead/unknown), current disease status (refractory/response/progression), further treatment|
| since initial treatment programme (Yes/No)|
| date of death, cause of death|
The following represent the core range of essential accessible expertise and services, which may be available locally or in a neighbouring hospital. There should be clear policies and protocols for access to these services.
• Haematology/Oncology nurse specialists
• Clinical pathology
• Diagnostic radiology
• Pharmacy facilities and expertise for dispensing cytotoxic drugs
• Renal services, including rapid access to haemodialysis
• Clinical oncology
• Orthopaedic surgery
• Accredited bone marrow/stem cell transplant centre
• Primary care liaison
• Palliative care physicians/nurses
• Administrative support for case registration, audit and clinical trials
• Social services and financial advice
• Patient support group
• Written information as well as guidance on access to electronic information
• Treating centres must meet standards required for level 1 care (British Committee for Standards in Haematology Clinical Haematology Task Force, 1995)
• When therapy involves autologous stem cell transplantation this must be done in a European Group for Blood and Marrow Transplantation (EBMT) accredited centre, equipped to provide Level 3 care for haematological malignancies, as defined by the British Committee for Standards in Haematology Clinical Haematology Task Force (1995).
Diagnosis, investigation and indications for treatment
Diagnosis and investigation
Patients typically present with bone pain, renal impairment, anaemia, or a combination of these. Myeloma should also be considered in patients with unexplained backache, loss of height or radiological evidence of osteoporosis, or recurrent bacterial infection. Asymptomatic patients may be diagnosed on routine testing.
Investigation of a patient with suspected myeloma should include the following [N.B. it is a government recommendation that clinical pathology investigations are undertaken in laboratories accredited under the Clinical Pathology Accreditation (CPA) scheme]:
• Full blood count
• Serum urea, electrolytes and creatinine
• Serum calcium
• Serum albumin
• Serum uric acid
• Electrophoresis of serum and concentrated urine followed by immunofixation to confirm and type any paraprotein present. Immunofixation is also indicated in patients in whom there is a strong suspicion of myeloma but routine electrophoresis is negative
• Quantification of serum paraprotein
• Quantification of urinary light chain excretion; either calculated on a random urine sample in relation to the urine creatinine or measured directly on a 24-h urine collection
• Quantification of non-isotypic serum immunoglobulins
• Creatinine clearance, measured or calculated
• Plasma viscosity
• Standard X-rays of the skeleton including lateral and antero-posterior (AP) cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri and femora (radionucleide bone scanning is not usually helpful)
• Magnetic Resonance Imaging (MRI) is an essential investigation for patients with suspected spinal cord compression
• Computerized tomography (CT) scanning is not routinely indicated in assessment but is helpful for imaging extramedullary disease
• Bone marrow aspirate
• Trephine biopsy and clonality studies (e.g. light chain restriction) are helpful in selected patients
• β2-microglobulin (in the presence of normal renal function), lactate dehydrogenase (LDH) and C-reactive protein are prognostic markers
• A marrow sample should be sent for cytogenetic studies whenever possible.
Although routine cytogenetic studies rarely provide helpful diagnostic or prognostic information, interphase cytogenetics using fluorescence in situ hybridization (FISH) analysis will identify abnormalities in most patients, the most frequent being translocations involving 14q and deletions of chromosome 13. Complete or partial deletion of chromosome 13 is a powerful adverse prognostic factor (Desikan et al, 2000; Konigsberg et al, 2000; Zojer et al, 2000; Facon et al, 2001). Cytogenetic information may therefore be useful in guiding decisions about treatment.
The diagnosis is usually confirmed by demonstration of a paraprotein in serum or urine and/or lytic lesions on X-ray, together with over 10% plasma cells in bone marrow (Greipp, 1992). Other conditions in which a paraprotein may be present include monoclonal gammopathy of undetermined significance (MGUS), AL amyloidosis, B-cell non-Hodgkin's lymphoma (including Waldenstrom's macroglobulinaemia), chronic lymphocytic leukaemia and connective tissue disorders.
Currently accepted criteria for distinguishing myeloma from MGUS are shown in Table II. Clear distinction may require careful observation over time (3–6 months). In patients in whom the investigations fulfil the diagnostic criteria of myeloma rather than MGUS, but in whom the disease is asymptomatic and stable over the period of observation, the disease has variously been termed equivocal, indolent or smouldering myeloma (Greipp, 1992; Malpas, 1998). Distinguishing between each of these terms is of no practical value as the main issue is whether or not treatment is required. A new staging system and clinical classification of MGUS and myeloma is currently in preparation by an international working group. It is anticipated that the recommendations will be available by 2002 and will be incorporated in the first revision of these guidelines.
Table II. Differential diagnosis of myeloma and monoclonal gammopathy of undetermined significance (MGUS).
|Bone marrow plasma cells||> 10% on aspirate||< 10% on aspirate|
|Serum paraprotein||Variable concentration in serum; |
no specific diagnostic levels
|IgG usually < 20 g/l |
IgA usually < 10 g/l
|Bence–Jones proteinuria||> 50% cases||Rare|
|Immune paresis||> 95% cases||Rare|
|Lytic bone lesions||Often present||Absent|
|Hypercalcaemia||May be present||Absent|
|Abnormal renal function||May be present||Absent|
Indications for starting therapy
Chemotherapy is indicated for management of symptomatic myeloma. Chemotherapy is not indicated for patients with MGUS or those with equivocal/indolent/smouldering myeloma. Patients with no symptoms, normal haemoglobin (Hb), calcium and renal function, and no bone lesions may remain stable for a long period without treatment. Early intervention has shown no benefit in two randomized controlled trials (Hjorth et al, 1993; Riccardi et al, 2000)
An observational study of factors influencing disease progression showed that patients who are asymptomatic but have radiological evidence of bone disease (at least one lytic lesion) are at high risk of progression, with a median time to progression of 8 months (Dimopoulos et al, 1993). Two studies have shown that patients with no evidence of bone disease but with abnormal marrow appearances on MRI examination are also at higher risk of disease progression (Weber et al, 1997; Mariette et al, 1999). The prognostic effect of an abnormal MRI is much less marked than that of lytic bone disease. In the study reported by Mariette et al (1999), median time to progression had not been reached by 25 months even in patients with an abnormal MRI, while in the study of Weber et al (1997), MRI was only discriminatory in patients with other adverse features (high levels of paraprotein or BJP excretion or IgA isotype).
• Treatment should be delayed until there are signs of progression in patients with equivocal/indolent/smouldering myeloma and no bone lesions (Grade A recommendation; level Ib evidence). Such patients must, however, be carefully monitored by 3 monthly physical examination, and measurement of both serum and urinary paraprotein. Repeat bone marrow examinations and skeletal X-rays will be required less often or when new symptoms or signs develop (Grade C recommendation; level IV evidence)
• Patients with radiological evidence of bone disease should commence treatment immediately (Grade B recommendation; level IIb evidence)
• MRI examination may be helpful in selected patients.
General measures and supportive care
Optimal general management is fundamental and should be a key part of the overall care plan (Fig 1 and Table III). Patients should be informed appropriately about the condition, its potential complications and the importance of supportive measures. These are summarized in Table III. Despite the importance of supportive care, there is little published research and the majority of the recommendations in Table III are Grade C based on Level IV evidence.
Table III. General aspects of care in myeloma.
|Hydration; renal function||Maintain adequate hydration (fluid intake of at least 3 l/d)in all patients. Avoid potentially |
nephrotoxic drugs when possible.
|Hypercalcaemia||Volume replacement with intravenous saline and an intravenous bisphosphonate. |
(A loop diuretic is not of additional benefit unless there is volume overload).
|Bone disease and pain management: |
There should be an active approach
to pain control; it can be helpful to
enlist the support of palliative care
teams in obtaining pain control for
|Analgesia: a variety of analgesics may be used, including simple analgesics, opiates and fentanyl |
patches. NSAIDs should be avoided in patients with renal impairment and used with caution in
Chemotherapy and radiotherapy: response to chemotherapy is a major factor in reducing progression
of bone disease. Local radiotherapy may be of benefit in patients with localized severe pain. The
long-term use of bisphosponates is recommended.
|Orthopaedic surgery: fixation of long bones may be required to treat or prevent pathological fracture. |
Radiotherapy, if required, is better given post operatively once healing has occurred rather than
|General measures: It is important to maintain mobility as immobility increases bone loss and the risk |
of infection, as well as impairing quality of life. Physiotherapy and aids such as spinal supports may
High levels of paraprotein can
lead to increased plasma viscosity.
|Symptomatic patients should be treated urgently with plasma exchange; isovolaemic venesection |
may be used if plasma exchange facilities are not immediately available. If transfusion is essential,
exchange transfusion should be performed. Chemotherapy should be instituted promptly.
|Spinal cord compression: |
Malignant infiltration of
|Management requires emergency hospital admission and investigation with MRI scanning to |
define the site and extent of tumour. CT scanning is less satisfactory but may be used if MRI
is unavailable or contra-indicated.
|and/or paravertebral tissues |
spinal cord compression.
|Dexamethasone should be commenced immediately. Local radiotherapy is the treatment of |
choice; there is no advantage in outcome for surgical treatment in the absence of spinal instability.
|Spinal surgery in myeloma patients may be difficult because of osteoporosis but may be |
indicated for spinal instability.
Patients with multiple myeloma
are immunosuppressed as a result of
|Arrangements should be in place to ensure 24 h access to specialist team advice for either the |
patient or for the primary care team. Admission for intravenous antibiotic therapy is usually
needed for severe systemic infection.
|both the disease and its treatment.||Influenza vaccination should be given to myeloma patients annually in primary care in line |
with NHS recommendations. Pneumococcal and Haemophilus vaccinations may be given to myeloma
patients although there is no evidence of their efficacy in multiple myeloma patients.
|Prophylactic immunoglobulin infusions have not been shown to improve overall survival but |
offer some protection against serious infections and reduce the risk of recurrent infections (Chapel
et al, 1994).
|Anaemia||Discussed in the text. |
|Psychological problems||Depression and anxiety occur and should be actively managed with appropriate referral to |
Anaemia is present in two-thirds of patients at presentation and becomes more common in patients with recurrent or progressive disease. Mild to moderate anaemia is common during chemotherapy. Contributing factors should be sought if the anaemia is unexpectedly severe. Red cell transfusion must be given with caution in patients with high paraprotein levels because of the risk of exacerbating hyperviscosity. Anaemia usually improves with response to therapy.
Traditionally, symptomatic anaemia has been managed by red cell transfusion. There is now a growing body of evidence for the efficacy of recombinant human erythropoietin (EPO) in the treatment of chemotherapy-related anaemia in a number of cancers, including myeloma. It has been shown to improve Hb and reduce transfusion requirement in patients without renal impairment in randomized controlled trials.
Patients with myeloma were included in two large placebo-controlled trials of EPO in anaemic patients receiving chemotherapy for non-myeloid malignancies (Glaspy et al, 1997; Demetri et al, 1998), each involving over 2000 patients. Both studies reported significant improvements in Hb level, decreases in transfusion requirements and improvements in patient-assessed quality of life in patients receiving EPO. These benefits were independent of tumour type or response to chemotherapy.
In a study of EPO vs. no EPO in 121 patients with myeloma or non-Hodgkin's lymphoma, Osterborg et al (1996) found an improvement in Hb level and elimination of transfusion requirement in 60% of patients on EPO compared with 24% of the control group. In a double-blind placebo-controlled trial in 145 myeloma patients, Dammacco et al (2001) also observed a rise in Hb and a decrease in transfusion requirements in patients receiving EPO. Hb levels increased by a mean of 1·8 g/dl in patients receiving EPO and 28% required transfusion during the first 3 months of treatment compared with no rise in Hb levels and a 47% incidence of transfusion requirement in patients receiving placebo. As well as improved levels of Hb and haematocrit, significant improvements in patient-assessed quality of life have been demonstrated with EPO therapy (Glaspy et al, 1997; Demetri et al, 1998; Dammacco et al, 2001).
Currently there are no reliable predictors of response to EPO. With appropriate dosage, > 80% of patients show an Hb increment of > 1 g/dl after 4 weeks EPO therapy and improved quality of life is recorded in responding patients (Demetri et al, 1998).
To date there have been no cost–benefit analyses comparing the use of EPO therapy and red cell transfusion in patients with myeloma. However, when considered in comparison with the increasing total costs relating to red cell transfusion, as well as the risks of transfusion, a therapeutic trial of 4–6 weeks of EPO appears justifiable for patients with symptomatic anaemia. The objective of avoidance of unnecessary red cell transfusion is in line with NHS strategy encompassed in the recent NHS Executive circular (Health Service Circular, 1998).
• A therapeutic trial of EPO should be considered in patients with symptomatic anaemia (Grade A recommendation; Level Ib evidence)
• EPO is indicated for the treatment of anaemia in patients with myeloma and chronic renal failure, as per the European best practice guidelines for the management of anaemia in patients with chronic renal failure (Cameron, 1999).
Currently available options include:
• single agent melphalan or cyclophosphamide (with or without prednisolone), or combination chemotherapy regimens (containing alkylating agents) given with the aim of achieving a stable response or ‘plateau’
• VAD (vincristine, adriamycin, dexamethasone) and similar regimens (which include high-dose dexamethasone but do not contain alkylating agents); these are normally followed by high-dose chemotherapy with stem cell rescue.
The choice of initial therapy will depend on factors such as age, performance status, and whether it is planned to proceed to stem cell collection and high-dose therapy (HDT). Whenever possible, patients should be treated in appropriate clinical trials.
Melphalan with or without prednisolone
Melphalan produces an objective response or partial remission (PR), defined as a greater than 50% reduction in paraprotein levels, in approximately 50% patients when administered at a dose of 6–8 mg/m2/d with prednisolone 40–60 mg/d for 4–7 d at 4–6 week intervals (Alexanian et al, 1969; Mellstedt et al, 1977). Response is gradual and maximum response may take several months. Complete remissions are rare. Most patients reach a stable plateau phase, defined as paraprotein level stable for at least 3 months and transfusion independent with minimal symptoms. The plateau phase usually lasts for 18–24 months before relapse. The median duration of survival is between 2 and 4 years from diagnosis in most series (Bergsagel, 1995). Continuing chemotherapy after attainment of plateau phase does not prolong remission (Belch et al, 1988).
The addition of prednisolone increased the response rate in an early randomized study (Alexanian et al, 1969), and it has been widely used in combination with melphalan (M). However, the results of comparative trials of melphalan vs. melphalan/prednisolone (MP) are contradictory. In two Medical Research Council (MRC) trials there was no benefit from the addition of standard doses of corticosteroids to oral melphalan or to the ABCM [adriamycin, carmustine (BCNU), cyclophosphamide] combination chemotherapy regimen (MRC, 1980; Olojohungbe et al, 1996).
Doses of melphalan in different protocols have varied between 7 and 12 mg/m2/d, when given for 4 d every 3–4 weeks (Myeloma Trialists Collaborative Group, 1998). Meta-analysis of trials comparing MP with combination chemotherapy concluded there was no evidence for a difference in outcome depending on melphalan dose intensity in patients receiving MP (Myeloma Trialists Collaborative Group, 1998). Absorption of oral melphalan is variable and it has been suggested that the dose be increased until there is evidence of myelosuppression (Bergsagel, 1995). However, there is no evidence that this produces benefit in practice and in one trial haematological toxicity was similar in responders and non-responders (Fernberg et al, 1990).
Melphalan and MP are generally well tolerated and alopecia is rare. Mild degrees of nausea do occur. Response is gradual, which may be a disadvantage for patients with aggressive disease. A meta-analysis of published trials shows no convincing survival benefit for combination chemotherapy compared with oral melphalan and prednisolone (Myeloma Trialists Collaborative Group, 1998). Melphalan should be avoided in patients in whom it is planned to proceed to HDT. Toxicity to normal marrow stem cells may be cumulative and may compromise their subsequent harvest (Tricot et al, 1995a; Demirer et al, 1996; Clark & Brammer, 1998).
• Melphalan with or without prednisolone is the initial treatment of choice for most patients in whom HDT is not planned (Grade A recommendation; level Ia evidence)
• The neutrophil count should be > 1·0 × 109/l and the platelet count > 75 × 109/l before treatment. The dose should be modified if severe myelotoxicity occurs (Grade B recommendation; level IIb evidence)
• Treatment should be continued to plateau phase (paraprotein level stable for 3 months) and then stopped (Grade A recommendation; level Ib evidence)
• Melphalan should be used with caution in patients with renal impairment
• The evidence of benefit from steroids in standard doses is controversial. It is therefore reasonable not to include prednisolone, particularly in patients at risk of steroid-related side-effects (Grade A recommendation; level Ib evidence).
Cyclophosphamide with or without prednisolone
Randomized trials have shown that cyclophosphamide (C) produces results similar to those of melphalan in terms of response rate and survival (MRC, 1971, 1980). The C-weekly regimen combines weekly intravenous or oral cyclophosphamide with alternate-day prednisolone for the first 6–8 weeks (Brandes & Israels, 1987). C-weekly is less myelotoxic than MP and was used in the Vth MRC trial for patients with cytopenia (MacLennan et al, 1992). There have been no randomized trials comparing C-weekly with MP; cross-trial analysis of C-weekly with melphalan in the MRC Myeloma IV and V trials suggested similar efficacy (MacLennan et al, 1992). There are also no data from randomized controlled trials on the effect of adding prednisolone to cyclophosphamide.
• Cyclophosphamide is suitable for patients who would otherwise be treated with melphalan or MP but in whom the neutrophil and/or platelet counts are below the required level (Grade A recommendation; level Ib evidence)
• The C-weekly regimen is recommended, in line with practice in current UK trials (Grade B recommendation; level IIa evidence)
• Treatment should be continued to plateau phase (paraprotein level stable for 3 months) and then stopped
• Cyclophosphamide should be used with caution in patients with renal impairment.
Alkylator-based combination chemotherapy regimens
Various combination regimens have been used in at attempt to improve the outcome obtained with simple alkylating agents. These regimens generally include cyclophosphamide and melphalan with two or more of the following drugs: vincristine (V), adriamycin (A), prednisolone (P) and BCNU (B). Such combinations require intravenous delivery and more frequent hospital attendance. They are also more toxic (e.g. more myelo-suppression, vomiting, alopecia, cardiotoxicity, infection). As with melphalan alone, complex regimens which include melphalan or nitrosoureas may prejudice subsequent stem cell harvesting (Tricot et al, 1995a; Demirer et al, 1996; Clark & Brammer, 1998).
Over 20 randomized trials have been carried out comparing such regimens with melphalan or MP (Myeloma Trialists' Collaborative Group, 1998). While many of the studies found an increased response rate compared with MP, and a complete remission (CR) rate up to 10%, only two studies have shown a significant survival benefit. The first of these was an early South-west Oncology Group (SWOG) study comparing VMCP/VBAP with MP (Salmon et al, 1983), a benefit not confirmed in other studies (Osterborg et al, 1989a; Boccadoro et al, 1991). The other was the MRC Myeloma V trial, which showed a significant survival benefit for ABCM compared with melphalan alone: median survival 32 vs. 24 months, P < 0·0001 (MacLennan et al, 1992).
A meta-analysis of 6633 patients in 27 randomized trials comparing combination chemotherapy with MP (Myeloma Trialists' Collaborative Group, 1998) concluded that there was no survival benefit for combination chemotherapy either for patients overall or in any prognostic subgroup (Level Ia evidence). Although this analysis did not include the MRC Myeloma V study, because this used melphalan alone rather than MP, it is unlikely that the efficacy of ABCM regimen differs significantly from that of regimens such as VMCP/VBAP (Kelly et al, 1998).
• Combination chemotherapy regimens offer no clear advantage over single alkylating agents (Level Ia evidence) but may be considered as an alternative to melphalan or MP for patients in whom it is not planned to proceed to HDT (Grade C recommendation; level IV evidence)
• The ABCM regimen is recommended if a combination regimen is to be used (Grade A recommendation; level Ib evidence)
• Possible benefits should be balanced against the increased side-effects, particularly in patients over the age of 65 years
• Treatment should be continued to plateau phase and then stopped (Grade A recommendation; level Ib evidence)
• These regimens should be used with caution in patients with renal impairment.
VAD and related regimens
VAD This comprises vincristine and doxorubicin (AdriamycinTM) given by continuous 4 d infusion together with high-dose dexamethasone (Barlogie et al, 1984). In newly diagnosed patients, VAD is associated with a high response rate of 60–80% and an appreciable CR rate of between 10% and 25% (Samson et al, 1989; Alexanian et al, 1990a; Abrahamson et al, 1996). Response is rapid with 90% of the maximum response reached after two courses of treatment.
VAD does not damage stem cells making it, or a similar regimen, the treatment of choice for patients proceeding to stem cell harvest and HDT. VAD is also suitable for patients with severe renal failure as no dosage modification is required and toxicity is not increased in these patients (Aitchison et al, 1990). The disadvantages are the requirement for a central line for administration and the high incidence of steroid-related side-effects. Remissions are not durable and there is no long-term survival advantage of VAD over MP or combination chemotherapy.
VAMP and C-VAMP In these regimens, high-dose dexamethasone is replaced by intravenous methyl prednisolone with a view to reducing steroid-related toxicity. C-VAMP includes weekly intravenous cyclophosphamide between courses of VAMP. There have been no randomized trials comparing VAMP, C-VAMP and VAD. Overall response and CR rates appear similar (Gore et al, 1989; Raje et al, 1997). In a non-randomized study comparing VAMP and C-VAMP, C-VAMP was associated with a higher CR rate than VAMP (24% vs. 8%) (Raje et al, 1997), while the CR rate with VAD has varied from 7% to 28% in different non-randomized series (Samson et al, 1989; Abrahamson et al, 1996).
Oral idarubicin with dexamethasone The introduction of oral idarubicin led to the development of a regimen in which idarubicin (ZavedosTM) is given daily for 4 d together with high-dose dexamethasone (Z-Dex). In a phase I/II study (Cook et al, 1996), 80% of newly diagnosed patients responded with a CR rate of 7%. Responses appeared to be as rapid as those observed with VAD. Stem cell harvesting was not affected by this regimen (Cook et al, 1997). There are no data on long-term outcome.
On the basis of current evidence it is not possible to make a firm recommendation for the use of Z-Dex; however, the regimen appears to offer a suitable alternative to VAD as initial therapy prior to stem cell harvest and HDT. It avoids the need for a central line with the associated risk of complications. A randomized trial comparing VAD and Z-Dex as induction therapy is in progress. Caution is required in patients with renal impairment (see below).
• A VAD-type regimen should be used as primary chemotherapy for patients in whom it is intended to offer HDT (Grade B recommendation; level IIa evidence)
• VAD is appropriate chemotherapy for patients presenting with renal failure and for patients in whom a rapid response is required (Grade B recommendation; level IIb evidence).
High-dose dexamethasone (HDD)
Historical comparison of the results in treating refractory patients with dexamethasone alone or with VAD suggested that dexamethasone alone is responsible for much of the efficacy of VAD (Alexanian et al, 1986). In a non-randomized trial, HDD alone was found to induce responses in 43% of newly diagnosed patients (Alexanian et al, 1992). Responses were rapid and the incidence of serious side-effects was only 4% compared with 27% in patients receiving VAD. Responding patients were then given interferon maintenance. Follow-up was not sufficient for accurate assessment of response duration or survival, although survival appeared similar to that achieved with VAD.
The advantages of HDD alone for initial therapy include simplicity, absence of myelotoxicity, suitability for use in renal failure and rapidity of response. A schedule of dexamethasone 40 mg daily for 4 d every 2 weeks until response occurs then reducing to 4 weekly is widely used.
• HDD alone is recommended for initial treatment in patients in whom cytotoxic chemotherapy is contra-indicated, e.g. those with severe pancytopenia or those requiring extensive local radiotherapy (Grade C recommendation; level IV evidence)
• It is useful as initial therapy in patients presenting with renal failure (Grade B recommendation; level IIa evidence).
No recommendation can be made on current evidence as to specific subsequent therapy after initial dexamethasone.
High-dose therapy (hdt) with stem cell transplantion
HDT and autologous stem cell transplantation (ASCT)
The past decade has seen increasing use of HDT in an attempt to improve disease control and prolong survival. HDT usually comprises high-dose melphalan with or without other cytotoxic drugs or total body irradiation (TBI), and requires stem cell support with peripheral blood progenitor cells or bone marrow. It is normally given after establishing initial cytoreduction with VAD-based chemotherapy regimens. Peripheral blood stem cells (PBSC) are usually harvested after mobilization with a combination of chemotherapy and growth factors. Several phase II studies have demonstrated that HDT with ASCT is effective at differing stages of the disease (Lokhorst et al, 1999; San Miguel et al, 1999). As first line therapy it is associated with complete remission rates varying between 24% and 75%, and a median survival of 4–5 years. The procedure is not curative as > 90% of patients ultimately relapse. Procedure-related mortality is generally < 5%.
Only one prospective randomized trial comparing standard therapy with a high-dose approach as first-line therapy for newly diagnosed stage II/III myeloma patients has been published to date (Attal et al, 1996). Two hundred patients < 60 year of age were randomized between HDT with autologous bone marrow rescue and standard chemotherapy. At 5 years the event-free survival (28% vs. 10%) and overall survival (52% vs. 12%; P = 0·03) were significantly better for patients undergoing high-dose therapy analysed on an intention-to-treat basis. However, of the 100 patients randomized to the high-dose arm, only 74 patients underwent this treatment. A randomized study comparing transplant in first remission with chemotherapy followed by transplant at relapse has shown no significant survival difference but an advantage in duration of first remission and quality of life for early autograft (Fermand et al, 1998).
A systematic review of the available data concluded that the combined data favoured HDT as offering a potential survival gain, but emphasized the need to continue entry into clinical trials (Johnson et al, 1998). A historical case–control study of patients undergoing high-dose and standard-dose chemotherapy from the Nordic Myeloma Study group has also shown a survival advantage for HDT. Median survival was 44 months in the standard-dose group but was not yet reached in the HDT group; P = 0·001 (Lenhoff et al, 2000).
The majority of centres use intravenous high-dose melphalan (HDM) alone at a dose of 200 mg/m2. Some centres also give total body irradiation (TBI). However, available data indicate greater toxicity with TBI and no survival benefit (Lokhorst et al, 1999). Purging harvested stem cells with monoclonal antibodies and/or CD34+ stem cell selection does reduce marrow contamination with tumour cells. However, these approaches are expensive and there is currently no evidence to suggest that they reduce the risk of relapse (Morineau et al, 2000; Stewart et al, 2001), while the risk of infection post transplant may be increased (Goldschmidt et al, 2000). There is also no clear evidence that planned tandem autografting confers any benefit. Interim analysis of the French Intergroupe Francophone du Myelome (IFM) 94 study, comparing one with two procedures, has suggested a benefit in certain subgroups of patients but no survival difference overall (Attal et al, 2000), while preliminary data from similar studies in Italy and the Netherlands indicate no survival benefit for two procedures (Tosi et al, 1999; unpublished observations). Currently there is no evidence to support the use of tandem or double transplants outside a clinical trial. The use of HDT in patients with renal impairment is discussed below.
A cost–utility analysis comparing HDT with conventional chemotherapy in a non-randomized population-based study has been carried out by the Nordic Myeloma Study Group (Gulbrandsen et al, 2001). The intensive treatment yielded a significant increase in median survival time from 44 to 62 months, with a gain of 1·2 quality-adjusted life years (QALY). The cost per QALY gained was estimated at $27 000. A similar study in the UK showed that HDT provided a marginal benefit of 0·7 life years with an incremental cost per life-year gained of approximately £15 000 (Sampson et al, 2001).
• HDT with ASCT should be considered as part of the primary treatment strategy in newly diagnosed patients up to the age of 60 years. Initial induction therapy should be chosen accordingly (Grade A recommendation; level Ib evidence)
• Patients aged 60–70 years with good performance status may also be considered suitable candidates for this procedure (Badros et al, 1999; Sirohi et al, 2000), although there is no current evidence indicating a survival advantage in this age group. Decisions to offer HDT with ASCT in this age group must balance the probable risks and benefits of this approach for the individual patient. Further clinical data are needed for this age group. Whenever possible, HDT with ASCT should be offered as part of a clinical trial (Grade C recommendation; level IV evidence)
• There is no evidence to recommend HDT with ASCT for patients over 70 years of age for whom MP remains the recommended standard chemotherapy (Grade A recommendation; level Ib evidence)
• Conditioning should be with chemotherapy alone, e.g. melphalan 200 mg/m2 without TBI (Grade B recommendation; level IIa evidence)
• Double ASCT should only be considered in the context of a clinical trial (Grade B recommendation; level III evidence)
• Currently available methods of purging have not demonstrated clinical benefit and are not therefore recommended (Grade A recommendation; level Ib evidence)
• HDT and ASCT may be considered for patients with severe renal impairment (creatinine clearance < 50 ml/min) but should only be carried out in a centre with special expertise (Grade C recommendation; level IV evidence).
The role of allogeneic SCT in multiple myeloma is controversial because of high transplant-related mortality (TRM) and significant relapse rates after transplantation. TRM is higher in male patients and in those transplanted late in the course of the disease (Gahrton, 1996). An EBMT case–control study showed that the overall survival of patients receiving an allogeneic SCT was significantly shorter than that of patients undergoing autologous SCT (Bjorkstrand et al, 1996). However, more recent EBMT data show a reduction in TRM; early TRM has fallen from 38% before 1994 to 21% since that date (Gahrton et al, 2001). This improvement probably reflects better patient selection and earlier SCT.
Patients transplanted in first response have a 60% chance of entering CR and one-third of these patients are in persistent molecular remission with a very low risk of relapse (Corradini et al, 1999). The potential benefit of this outcome may justify the risks of allogeneic SCT in younger patients, particularly women. Patients relapsing after an allogeneic SCT have been shown to respond to donor lymphocyte infusions (DLI), while patients with persistent disease may achieve a complete remission following DLI (Lokhorst et al, 2000; MacKinnon, 2000; Salama et al, 2000; Kroger et al, 2001).
SCTs with matched unrelated donors (MUD) have an even higher TRM than matched sibling SCTs and cannot be recommended. They may be considered in exceptional cases and must only be carried out in accredited MUD transplant centres.
Recently, ‘low intensity’ or ‘mini’ allograft approaches have been developed which are associated with lower toxicity and TRM (Craddock et al, 2000; Kottaridis et al, 2000; Badros et al, 2001; McSweeney et al, 2001). Such an approach may increase the numbers of patients who are suitable for an allogeneic SCT. As yet such procedures are experimental and should only be carried out in studies in accredited transplant centres.
• Patients up to the age of 50 years of age may be considered for allogeneic SCT, the risks of which must be fully discussed with the patient (Grade B recommendation; level IIa evidence)
• Donor lymphocyte infusion should be considered for patients with persistent or progressive disease following transplantation (Grade B recommendation; level IIb evidence); this should preferably be carried out within the context of a clinical trial
• SCT should be carried out in EBMT accredited centres with extensive transplant experience and in which data is collected prospectively as part of international transplant registries (Grade C recommendation; level IV evidence)
• Low-intensity allografts are presently experimental and should be performed in the context of a clinical trial protocol (Grade C recommendation; level IV evidence).
The interferons are a family of compounds produced by leucocytes, fibroblasts and T lymphocytes which have antiproliferative activity against viruses and human tumour cells. The therapeutic effects of α-interferon (IFN-α) have been assessed in myeloma patients at induction, plateau phase, following HDT and in patients with relapse/refractory disease, both as monotherapy and combined with chemotherapy. Most studies have been with recombinant IFN-α; the two main types (α2a and α2b) appear clinically indistinguishable.
IFN-α cannot be recommended as monotherapy. Response rates are lower than with alternative therapy (Peest et al, 1996). IFN-α has been combined with standard induction chemotherapy in a number of studies and results show no benefit (Cooper et al, 1993) or are conflicting (Avvisati et al, 1995). A meta-analysis (Myeloma Trialists' Collaborative Group, 2001) has evaluated individual patient data from 2469 patients: in 12 induction trials, complete (17% vs. 14%, P = 0·08) and complete plus partial (58% vs. 53%, P = 0·01) response rates were slightly better with IFN-α. Median progression-free survival (PFS) was increased by about 6 months with IFN-α (P = 0·0003), but overall survival (OS) was prolonged by only 2 months, and this difference was not statistically significant. A meta-analysis using published data rather than individual patient data yielded similar results, with prolongation of median PFS by about 5 months and OS by 3 months (Fritz & Ludwig, 2000). In a large randomized study, the Nordic Myeloma Group showed no gain in survival for IFN-α in induction and maintenance (Wisloff et al, 1996), and this study also showed a significant reduction in quality of life during the first year of therapy for patients receiving IFN-α.
A number of studies have examined the therapeutic role of IFN-α maintenance therapy following induction chemotherapy (Mandelli et al, 1990; Browman et al, 1995; Westin et al, 1995; Joshua et al, 1997; Drayson et al, 1998) and autologous transplantation (Cunningham et al, 1998; Bjorkstrand et al, 2001). A meta-analysis has evaluated individual patient data on 1543 patients in 12 trials (Myeloma Trialists' Collaborative Group, 2001). PFS was again significantly improved in IFN-α-treated patients (P = 0·00001), with a prolongation of about 6 months in median PFS, and median OS was also prolonged by about 7 months. Similar results were obtained in the meta-analysis of published data on IFN trials (Fritz & Ludwig, 2000). Median PFS was prolonged by 4 months and OS by 7 months. Retrospective case–controlled data from the EBMT registry have suggested significant gains in PFS and OS for interferon-treated patients; however, such data are non-randomized and subject to selection bias (Bjorkstrand et al, 2001).
Overall, the data do not show significantly better response or survival in any particular patient groups. Trials generally show a greater gain in progression-free survival (PFS) than in overall survival, suggesting that survival following progression is shorter among interferon-treated patients. Dosages of IFN-α have varied, but no benefit for doses greater than 3 MU/m2, 3 × week, subcutaneously, has been shown. There are no data on duration of therapy.
Relapsed and refractory disease
IFN-α does have activity in primary refractory disease and in relapsed patients. However, response rates are low, and there are no good clinical trial data to guide therapy.
Most patients experience some side-effects, which are significant in up to one-third. Flu-like symptoms are common a few hours after each of the initial injections and generally resolve after the first 2–3 weeks of therapy. The symptoms will respond to paracetamol, which should be taken at the time of each initial injection.
Fatigue and depression are recognized side-effects of longer term interferon therapy and will resolve on cessation of interferon. Some 20–25% of patients may prove intolerant of interferon therapy.
IFN-α has a role in multiple myeloma. Small, statistically significant increases in PFS and OS of up to 6 months are identified in meta-analysis, most clearly observed for patients receiving maintenance therapy following chemotherapy or autologous transplant. However, published data suggest that only 5–10% of myeloma patients achieve a significant gain in survival from IFN-α (Blade & Esteve, 2000). Potential benefits must be balanced against possible toxicity and the financial costs of interferon. Cost–utility analysis of IFN-α therapy suggests a cost of $50 000–100 000 per quality-adjusted life year gained (Wisloff et al, 1999). There are no clear data on which patients are most likely to benefit, on optimum dose or duration of therapy.
• Interferon therapy is not indicated during induction therapy (Grade A recommendation; level Ia evidence)
• Interferon therapy has activity as maintenance therapy during plateau phase following conventional chemotherapy or following HDT (Level Ia evidence) but an unfavourable cost per QALY
• No recommendation can be made regarding duration of treatment
• Careful consideration should be given as to whether interferon should be continued in the face of side-effects which impair quality of life (Grade C recommendation; level IV evidence).
Bone pain, hypercalcaemia and pathological fractures are a major cause of morbidity and mortality in patients with multiple myeloma. Randomized placebo-controlled studies with both pamidronate and clodronate have shown a significant benefit for bisphosphonate treatment (Delmas et al, 1982; Lahtinen et al, 1992; Berenson et al, 1996, 1998; McCloskey et al, 1998). Long-term therapy with bisphosphonates has been shown to reduce skeletal morbidity, improve quality of life, and reduce the need for surgery and radiotherapy.
Three randomized studies have compared oral clodronate with placebo. In 30 patients, Delmas et al (1982) reported a reduction in bone pain and progression of skeletal lesions. The Finnish clodronate study randomized patients to clodronate 2400 mg/d or placebo (Lahtinen et al, 1992; Laakso et al, 1994). There was a reduction in biochemical markers of bone turnover and a 50% reduction in the incidence of new osteolytic lesions in the clodronate group. No significant effect was seen on progression of vertebral and non-vertebral fractures. Vertebral fractures were reduced (38% vs. 55%, P = 0·01) and a decrease in non-vertebral fractures (6·8% vs. 13·2%, P = 0·04) observed in the UK MRC clodronate trial in which 536 patients were randomized between clodronate 1600 mg p.o. and placebo (McCloskey et al, 1998). Height loss was less and the incidence of hypercalcaemia reduced in patients who received clodronate; similarly, analgesic usage was reduced and at 24 months back pain and poor performance status were improved for clodronate-treated patients. Subgroup analysis in both the Finnish and MRC studies showed that patients without overt skeletal disease at entry benefited from bisphosphonate treatment, and in the MRC study these patients benefited most, supporting the use of bisphosphonates early in the evolution of the disease.
Pamidronate is also effective in myeloma. Berenson et al (1996, 1998) evaluated the efficacy of intravenous pamidronate 90 mg monthly in 392 patients with stage III myeloma who had been stable for over 3 months on chemotherapy. This study showed a significantly reduced incidence of bone pain, analgesic usage, fewer skeletal events, together with less deterioration in performance status, in patients who were randomized to receive pamidronate. Subgroup analysis of those patients undergoing chemotherapy of first relapse suggested a possible survival advantage for those who received pamidronate.
There have been no randomized studies comparing different doses of clodronate or comparing clodronate with pamidronate. Oral pamidronate has not been shown to be effective (Brincker et al, 1998). Oral etidronate is ineffective in myeloma and may cause demineralization (Belch et al, 1991). There are no data on the effectiveness in myeloma of any other oral bisphosphonate.
Zoledronate is a new, more potent bisphosphonate in vitro. It is given intravenously and requires only a 10-min infusion in comparison with 90 min for pamidronate. It is currently undergoing clinical trial evaluation. It has been shown to be more effective than pamidronate in the treatment of tumour-related hypercalcaemia (Major et al, 2001) and to be as effective as pamidronate in reducing skeletal-related events in patients with osteolytic lesions owing to myeloma or breast carcinoma (Berenson et al, 2001).
Health economic data on long-term bisphosphonate use are conflicting. In the Finnish study clodronate did not increase overall cost of treatment (Laakso et al, 1994), whereas analysis of data from the MRC trial suggested a 17% overall increase in treatment costs with the additional costs of clodronate set against the reduction in cost owing to skeletal-related events (Bruce et al, 1999). Formal quality-of-life data are lacking in all studies but the evidence for reduction in bone pain and analgesic usage as well as fewer skeletal-related events would suggest that quality of life is improved.
• Long-term bisphosphonate therapy is recommended for all patients with myeloma requiring treatment for their disease, whether or not bone lesions are evident (Grade A recommendation; level Ib evidence)
• Both oral clodronate (1600 mg/d or equivalent dosage according to formulation) and intravenous pamidronate are effective (Grade A recommendation; level Ib evidence). The choice of therapy will depend on patient and physician preference
• Etidronate should be avoided (Grade A recommendation; level Ib evidence)
• Caution is required in moderate to severe renal failure.
Management of relapsed and refractory disease
Primary refractory disease
There is a lack of evidence from randomized controlled trials on the optimum approach to treating primary refractory disease. Patients refractory to alkylating agents may respond well to VAD-type regimens (Barlogie et al, 1984). Conversely, younger patients treated with VAD as primary therapy who fail to respond prior to planned SCT may still respond to high-dose melphalan (Rajkumar et al, 1999; Vescio et al, 1999).
For the majority of patients in this category, attempts to influence the course of the disease with chemotherapy will be, by definition, unsuccessful so that the focus of management for these patients should be on control of symptoms and maximizing the quality of their survival.
As almost all patients with myeloma will relapse, the overall management strategy should include plans to treat relapse. In most cases the therapeutic objectives will still be to achieve disease control, ameliorate symptoms, improve quality of life and prolong survival. Early relapse carries a poor prognosis and is likely to respond poorly to most chemotherapy. Patients who relapse or progress after a long stable plateau phase are likely to respond well to further treatment.
Possible treatment regimens for relapsed myeloma therefore include no further antineoplastic treatment, repeating initial chemotherapy or high-dose therapy. There are also a number of novel and experimental therapies available.
Current options include:
• No further antineoplastic treatment
• Melphalan with or without prednisolone
• Combination chemotherapy
• VAD and similar regimens with or without resistance modification agents (e.g. PSC 833)
• Oral idarubicin alone or in combination
• High-dose dexamethasone
• High-dose therapy with stem cell transplantation
• Hemibody irradiation.
Available evidence suggests that, if the patient was initially treated with MP and achieved stable plateau, MP is appropriate treatment as a further response can be achieved in 50% patients (Belch et al, 1988). Patients who have been treated previously with alkylating agents may respond well to VAD or related regimens (Barlogie et al, 1984) or an idarubicin-based regimen (Cook et al, 1996; Parameswaran et al, 2000). HDT and stem cell transplantation may be considered in patients who have not had a prior stem cell transplant. A second HDT may also be appropriate in selected patients who relapse after an initial autograft (those with a low β2-microglobulin, one prior transplant and late relapse) (Tricot et al, 1995b; Mehta et al, 1998; Lokhorst et al, 1999). Steroids alone may be useful in patients at second or later relapse or in patients in whom chemotherapy is contra-indicated (Alexanian et al, 1990a).
Thalidomide has been recently shown to produce responses in at least 30% of relapsed/refractory patients (Singhal et al, 1999; Juliusson et al, 2000; Barlogie et al, 2001). Higher response rates have been observed with the combination of thalidomide and dexamethasone (Dimopoulos et al, 2001; Palumbo et al, 2001). On current evidence it is reasonable to offer thalidomide to relapsed/refractory patients pending the results of clinical trials which are currently evaluating the role of thalidomide at earlier stages of the disease. A position paper from the UK Myeloma Forum on the use of thalidomide in myeloma is in preparation and will be available on the UKMF and BSH/BCSH websites (anticipated late 2001).
Double hemibody irradiation is useful in patients with widespread bone pain and in those who are refractory to chemotherapy and steroids (Singer et al, 1989). Caution is required as it can cause significant myelosuppression.
• The most appropriate management must be determined on an individual basis depending on the timing of relapse, age, prior therapy and other clinical circumstances
• For the majority of patients who relapse after plateau or remission, the most appropriate chemotherapy is oral melphalan ± prednisolone (Grade B recommendation; level III evidence)
• When possible the patient should be treated in the context of a clinical trial
• Good supportive therapy is essential.
The management of patients with renal failure
A degree of renal impairment occurs in up to 50% of patients with myeloma at some stage of the illness (Alexanian et al, 1990b). Up to 20% of patients will present with renal failure. Advanced renal failure requiring dialysis or other major intervention occurs in 3–12% (Clark et al, 1999). A modest increase in the serum creatinine indicates a substantial degree of renal impairment. Urgent intervention is required to correct early renal impairment and prevent long-term renal damage (Winearls, 1995). Patients with suspected myeloma and abnormal renal function need to be seen as a matter of urgency.
The pathogenesis of renal failure in myeloma is multifactorial. Immunoglobulins, particularly the light chain component, can damage the kidney directly causing proximal tubular damage and myeloma cast nephropathy. Other factors include dehydration, hypercalcaemia, hyperuricaemia, infection, nephrotoxic drugs [e.g. non-steroidal anti-inflammatory drugs (NSAIDs) and some antibiotics]. Less frequently, amyloid, light chain deposition disease, and plasma cell infiltration may occur (Clark et al, 1999).
When not otherwise specified, the following recommendations are based on clinical experience of haematologists and renal physicians. Published evidence in this field is limited and the recommendations are predominantly Grade C based on level IV evidence.
Responsibility for the overall management of myeloma patients with chronic renal failure will usually rest with the specialist haematological oncology team, but there needs to be clear communication and liaison with the specialist renal teams to optimize the care and outcome for the individual patient.
Initial management of renal failure
• Rehydrate with intravenous fluid to achieve a urine flow of over 3 l/d (MRC, 1984; MacLennan et al, 1989; Ganeval et al, 1992). It may be of benefit to include bicarbonate in the intravenous fluid regimen to achieve a urine above pH 7·0. Volume replacement should be guided by monitoring of central venous pressure
• Avoid potentially nephrotoxic drugs, including NSAIDs; it is important to check on usage of over-the-counter NSAIDs
• Treat infection rapidly and vigorously with appropriate antibiotic therapy, intravenously if necessary
• Correct hypercalcaemia with intravenous bisphosphonate in those patients not responding to rehydration alone. The kidney is the only route of excretion for bisphosphonates. However, it appears from pharmacokinetic studies that no dose adjustment of pamidronate is necessary in patients with moderate to severe renal failure [glomerular filtration rate (GFR) > 10 ml/min but < 20 ml/min]. With GFR < 10 ml/min, dosage is determined by the uncorrected serum calcium level; with Ca2+ levels > 4·0 mmol/l give 60 mg pamidronate; Ca2+ < 4·0 mmol/l give 30 mg. Alternatively, 30 mg of pamidronate, repeated after 24 h if no improvement is seen, is used in many units and appears to be safe. A 50% reduction in the dosage of clodronate is recommended in mild to moderate renal failure (GFR 10–50 ml/min); it is contra-indicated if creatinine clearance is less than 10 ml/min (ABPI, 1999; Bunn & Ashley, 1999)
• Seek the advice of a nephrologist if renal function does not improve within 48 h
• Renal biopsy is desirable but not essential. It will help guide management, identifying those patients with: acute tubular necrosis, which will usually improve with time alone; amyloid and light chain deposition disease, which do not respond to measures other than control of myeloma; and cast nephropathy which may improve with rapid reduction of light chain concentration
• Plasma exchange is theoretically beneficial in cast nephropathy but, because the evidence from the only two small randomized trials is conflicting, plasma exchange should preferably be used in a trial setting (Zucchelli et al, 1988; Johnson et al, 1990)
• Dialysis should be offered to patients when appropriate for the management of the renal failure
Choice of chemotherapy regimen
The theoretical benefit of the rapid reduction of paraprotein and light chains and the need for dosage reduction owing to impaired excretion both influence the choice of therapy.
• Melphalan is hydrolysed and excreted via the kidneys so bone marrow suppression may develop when full doses are used. The extent of drug accumulation is variable in each individual and cannot be predicted from the degree of renal impairment (Osterborg et al, 1989b). Initial doses should be reduced to 50% if the GFR is below 40–50 ml/min and titrated against bone marrow toxicity in subsequent courses. Melphalan should not be used in patients in whom the GFR is below 30 ml/min
• Cyclophosphamide metabolites are excreted in the urine. Caution in renal impairment with dose reduction is recommended by the manufacturers and if the GFR is 10–50 ml/min, the dose should be reduced by 25%, and by 50% if GFR is less than 10 ml/min
• Vincristine, adriamycin and dexamethasone do not require dosage adjustment in the presence of renal impairment and can be safely used in patients with severe renal failure (Aitchison et al, 1990)
• High-dose dexamethasone alone is effective as a single agent in this setting (Alexanian et al, 1992) and is practical as initial therapy because it can be given ‘immediately’ without the need to wait for central line insertion to administer VAD
• Idarubicin toxicity is potentially increased in patients with renal impairment as the kidneys excrete its active metabolite, idarubicinol. Most available data are on patients with creatinine levels below 200 µmol/l. A number of current trials allow inclusion of patients with higher levels of serum creatinine, but there are presently insufficient data to recommend routine use of oral idarubicin or to guide dose modification in patients with creatinine levels above 200 µmol/l.
• VAD or dexamethasone alone are recommended for initial treatment (Grade B recommendation; level IIa evidence)
• Dexamethasone alone should be given as initial immediate treatment pending decisions on subsequent chemotherapy and the outcome of full supportive measures (Grade C recommendation; level IV evidence).
General points in management
• NSAIDs should be avoided because of their adverse effect on renal blood flow
• Use opiates (from morphine to dextropopoxyphene) with caution because they accumulate rapidly leading to problems with drowsiness and respiratory depression
• Consider the early use of radiotherapy for bone pain
• Dosage adjustment of bisphosphonates may be required in renal failure
• Patients with chronic renal impairment and anaemia should receive erythropoietin therapy.
Both haemodialysis and peritoneal dialysis are equally effective long-term renal replacement therapies. Renal transplantation is an option for only a very small number of highly selected patients with good prognosis disease and who have achieved plateau after treatment of their myeloma (Humphrey et al, 1975; Walker & Bear, 1983). As regards further treatment of the myeloma, HDT with autologous SCT can be undertaken in patients with moderate to severe renal failure, but the available data suggests that the risks of HDT are increased and therefore transplant should take place only in a centre with appropriate expertise.
Patient information and support
Provision of information and support for patients and their carers is essential to assist patients in making informed choices on treatment options, as well as understanding the importance of compliance with treatment regimens which, at times, can be very demanding.
It is important for patients and their families to understand that, although treatment is not curative, it will relieve symptoms and prolong survival and its quality; the positive aspects of treatment need to be stressed. Patients with myeloma should be aware of support networks in the community; the specialist team should be able to provide patients and their families with information on local support networks, whether these are specific to myeloma or in relation to cancer generally. The specialist team also needs to have information available for the patient and family on State benefits, e.g. Disability Living Allowance and Attendance Allowance. Bone problems may result in long-term disability and preclude many patients returning to work. High-dose and conventional chemotherapy regimens also make employment impractical for periods of several months. Patients therefore commonly need advice on socio-economic problems, which result from the condition and its treatment.
• The diagnosis needs to be communicated honestly to the patient with the minimum of delay. Uncertainty about the condition is generally more distressing to a patient and his or her family. The 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
• 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
• At the end of a consultation it is recommended that patients and their family/carers have written information, which provides information on the condition. It should also guide patients and their family/carers on access to information services. CancerBACUP, the IMF (UK) and the Leukaemia Research Fund (see below) produce useful, patient-orientated booklets on the condition and its treatment
• 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
• The management plan needs 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 multidisciplinary specialist team
• Patients and their families should be cautioned about the amount of unregulated information accessible on the Internet; they should be given recommendations on appropriate sites. An appropriately trained person, normally a specialist nurse, should be available to discuss/inform patients on information materials including guidance for using the Internet as an information source
• Patients should be given the opportunity of receiving more than one medical opinion.
Useful information sources
The IMF (UK) is a UK-based patient support group of the International Myeloma Foundation. The main office is in Edinburgh with a help and advice line for patients, (0800) 9803332. It produces useful written material on myeloma and runs a series of patient and family seminars during the year in the UK and Ireland.
CancerBACUP is a UK-based support organization for patients with all types of cancer. They produce a range of disease-specific patient-orientated information, as well as excellent information on specific symptoms and other aspects of living with cancer. A help line will deal with patient and family enquiries on (0808) 8001234.
The Leukaemia Research Fund (LRF) supports research in myeloma and also provides patient information booklets. For further information telephone (020) 7405 0101.
The UK Myeloma Forum Guidelines Working Group
• Dr Alastair Smith (Chairman), Southampton University Hospitals NHS Trust
• Dr Judith Behrens, St. Helier Hospital NHS Trust, Carshalton, Surrey
• Dr Mark Drayson, University of Birmingham
• Dr Neil Iggo, Brighton Healthcare NHS Trust
• Dr Graham Jackson, Royal Victoria Infirmary, Newcastle upon Tyne
• Ms. Julia Liddi, CancerBACUP UK
• Mr Eric Low, International Myeloma Foundation (UK)
• Dr Atul Mehta, Royal Free Hospital, London
• Dr Steve Schey, Guys and St Thomas NHS Trust London
• Dr Charles Singer, Royal United Hospitals NHS Trust, Bath
• Dr Richard Soutar, Western Infirmary, Glasgow.
• Dr Diana Samson, Faculty of Medicine, Imperial College, London (Chairman UK Myeloma Forum)
The authors are greatful to the following for consultation and advice: Dr Stuart Ralston, Department of Medicine, Aberdeen Royal Infirmary on behalf of the Bone and Tooth Society, Dr Tim Illidge, Dept of Clinical Oncology, Southampton University Hospitals NHS Trust.
This guideline was produced with the support of an educational grant from the International Myeloma Foundation (UK).
The UK Myeloma Forum
The UKMF is a registered charity (No 1082702). The website address is http://www.ukmf.org.uk and the postal address is Clinical Trials Office, Department of Haematology, 4th Floor Guy’s Tower, Guy’s Hospital, St. Thomas Street, London SE1 9RT.