Description of underlying health problem

Multiple myeloma (MM) is a type of cancer. The cancer (myeloma) tends to be located at more than one site where there is bone marrow, such as the pelvis, spine and ribs, which is why it is known as MM.¹ MM occurs when a plasma cell begins to proliferate in an unregulated way. Plasma cells are a specialised component of the bone marrow and immune system and they normally produce specific antibodies to fight infection. In MM the myeloma cells produce large quantities of one type of abnormal antibody – monoclonal immunoglobulin protein (M-protein).² As the abnormal myeloma cells build in number, the normal functions of bone marrow become impaired to varying degrees of severity because the abnormal myeloma cells may disrupt the function of normal cells, and because the space available for normal bone marrow may be reduced.

In the early stages of MM there may not be any symptoms or a range of symptoms may be present, which are not specific to MM, such as fatigue, weight loss and increased infections. A common presenting symptom of MM is bone pain, and/or bone fracture due to lytic bone lesions. Lytic bone lesions are a typical feature of MM and are caused because the malignant plasma cells impair normal bone repair functions. MM cells both produce and influence chemokines and cytokines, which causes bone resorption to become uncoupled from bone formation such that resorption predominates.³

The most common finding on clinical investigation is anaemia.⁴ This occurs because the presence of proliferating myeloma cells in the bone marrow negatively impacts on the ability of the bone marrow to produce red blood cells, leading to a reduction in red blood cells in the circulation, which contributes to the symptom of fatigue. Likewise, circulating numbers of other cells produced in the bone marrow are also reduced. The reduction in normal white blood cells and the antibodies these produce (hypogammaglobulinaemia) leads to an increased risk of infection, while the reduction in platelets contributes to easy bruising and other bleeding.

Other common findings on clinical investigation are M-protein, which is secreted by the myeloma cells, and an excess of calcium in the blood (hypercalcaemia), which occurs as a result of bone destruction.⁵ The presence of M-protein in serum may increase blood viscosity, which is associated with an increased risk of thrombosis. A high level of serum protein (hyperproteinaemia), M-protein and light chains may also contribute to renal failure. The aetiology of this is generally multifactorial, and hypercalcaemia is another common contributing factor.

Multiple myeloma is one of a number of lymphoproliferative diseases classified by the World Health Organization (WHO) International Classification of Diseases 10th edition (ICD-10) as malignant neoplasms of lymphoid, haematopoietic and related tissue.⁶ The exact aetiology of MM is unknown but it is clear that the malignant cells arise from a single plasma cell. Therefore, research has focused on gaining an understanding of the chain of events that occurs between haematopoietic stem cells giving rise to B lymphocytes in the bone marrow, and these B cells subsequently differentiating to form plasma cells.^7,8

Normally, plasma cells would contain a pair of each of the ²² autosomal (non-sex) chromosomes. Myeloma cells, however, display a variety of genetic abnormalities. Common abnormalities of MM cells include aneuploidy (an abnormal number of chromosomes) and translocations (exchange of material between two different chromosomes). When aneuploidy is present, monosomies (one copy of a chromosome) are more common than trisomies (three copies of a chromosome). One of the most common monosomies is the loss of one copy of chromosome 13, which is associated with a shorter survival and lower response rate to treatment.^9,10 Of the translocations t(11;14)(q13;q32) and t(4;14)(p16.3;q32) are the most common; the former is associated with improved survival, whereas the latter is an indication of an unfavourable prognosis.^9,10 The genetic abnormalities underlying cases of MM can be identified by cytogenetic techniques, such as conventional karyotype analysis and fluorescence in situ hybridisation.

Epidemiology

Multiple myeloma is the second most common haematological cancer after lymphoma in the UK. In 2007 there were 3357 new diagnoses of MM in England,¹³ with the highest incidence among those aged 75–79 years (Table 1). In Wales, in the 3 years from 2004 to 2006, an average of 252 new MM diagnoses were recorded.¹⁴ MM is rare before the age of 40 years. The average incidence rates were higher in men than in women, and higher for both sexes in Wales compared with England (Table 2). There are ethnic differences in incidence rates that have been observed in data from the USA; in black people (African American and other black people, but not Hispanic people) the incidence of MM is about twice that of white people, whereas in Asian people the incidence is lower than that of white people.¹⁵ The statistical information team at Cancer Research UK has used incidence and mortality data for 2001–5 to estimate the lifetime risk of developing MM, which is 1 in 148 for men and 1 in 186 for women in the UK.¹⁶ There are currently approximately 10,000–15,000 people living with MM in the UK.¹⁷

TABLE 1

Newly diagnosed cases of MM in England in 2007.

TABLE 2

Age-standardised incidence rates of MM per 100,000 of the population.

The risk factors for developing MM are not well defined but there is evidence for involvement of genetic factors because the first-degree relatives of people with MM are at greater risk of developing MM and related conditions than the first-degree relatives of people without MM.^8,18 Epidemiological studies have looked for evidence of a causal link between a range of potential environmental risk factors and MM but, in general, these have not produced consistent results.^4,8

Diagnosis and staging

Multiple myeloma is typically diagnosed in secondary care using a combination of tests such as urine tests, blood tests, bone marrow examination, imaging, plain radiograph and/or magnetic resonance imaging. If necessary, further tests can be conducted to find out the stage of disease.¹ There are two systems for staging MM. The Durie–Salmon¹⁹ (DS) staging system, which has been in use since 1975, is one of the systems but this is gradually being replaced by an updated system, the International Staging System (ISS).²⁰ This new system is based on measurement of two serum proteins, β₂-microglobulin and albumin (Table 3). A patient with stage I disease will not necessarily proceed linearly through disease stages. Stage III disease can be reached without a requirement to pass through stage II first. It is also noteworthy that staging does not have a significant influence on treatment. If MM is symptomatic, treatment is required irrespective of disease stage.

TABLE 3

Staging systems for MM.

Current service provision

The aim of treatment for MM is to extend the duration and quality of survival by alleviating symptoms and achieving disease control while minimising the adverse effects of the treatment.²¹ First-line treatment aims to achieve a period of stable disease (plateau phase) for as long as possible, prolonging survival and maximising QoL. In England and Wales the choice of first-line treatment depends on a combination of factors, including age, comorbidity, social factors and performance status of the patient. High-dose chemotherapy (HDT) with autologous stem-cell transplantation (SCT) will be offered if appropriate for the patient. However, the British Society for Haematology (BSH) guidelines on the diagnosis and management of MM (2005)²² state that (p. 428) ‘Although high-dose is recommended where possible, the majority of patients will not be able to receive such therapy because of age, specific problems or poor performance status’. For those patients who are not able to withstand such an intensive type of treatment, single-agent or combination chemotherapy (which is less intensive) may be offered as a first-line treatment. Patients eligible for HDT will get initial chemotherapy to reduce disease burden before transplant.

Typically, combination therapies include chemotherapy with an alkylating agent (such as melphalan or cyclophosphamide) and a corticosteroid (such as prednisolone or dexamethasone). The treatment recommended by the 2005 guidelines for patients who are unable to receive intensive treatment was either melphalan or cyclophosphamide, given either with or without prednisolone.²² More recent treatment options may also include drugs such as thalidomide^23–25 (Thalidomide Celgene^®, Celgene, Uxbridge, UK) and bortezomib²⁶ (Velcade^®, Janssen–Cilag, High Wycombe, UK). Such drugs are being investigated in ongoing clinical trials, such as the Medical Research Council (MRC)-funded Myeloma IX study,²⁷ which has compared thalidomide in combination with cyclophosphamide and dexamethasone (CTDa) against the standard drug combination of melphalan with prednisolone (MP).

The BSH guideline on the diagnosis and management of MM is being revised and updated. The draft of these revised guidelines²⁸ contains a recommendation that, for older and/or less fit patients in whom high-dose therapy is not planned, the initial therapy should consist of either a thalidomide-containing regimen in combination with an alkylating agent and steroid [such as thalidomide in combination with MP (MPT) or CTDa] or bortezomib in combination with melphalan and prednisolone (VMP). The draft revised guideline indicates that the choice of firstline therapy should take into account patient preference, comorbidities and the toxicity profile of the treatments.²⁸

After first-line treatment most patients will show a response. Response is usually assessed based on changes in serum levels of M-protein and/or urinary light chain excretion, and ranges from partial to complete remission, but almost all patients will eventually relapse. A minority of patients will have disease that proves resistant to primary treatment.

In addition to chemotherapy, patients also require concomitant supportive therapy to control the symptoms of the disease, including bisphosphonates to treat bone disease, erythropoietin to treat anaemia, antibiotics to treat infections and various types of pain medication. Prophylaxis against thrombosis is recommended in the thalidomide summary of product characteristics (SPC) for the first 5 months that patients receive thalidomide.²⁹ In the UK this recommendation for prophylaxis against thrombosis is followed, but there is less agreement about whether to continue with prophylaxis for the entire duration of thalidomide therapy. Therefore, clinical practice is likely to vary. Side effects of treatment may result in discontinuation or change of chemotherapy treatment.

UK clinical experts have indicated that the most common combination therapy used as a first-line treatment for patients who are not able to withstand high-dose therapy is CTDa. The second most common therapy is MPT, with the ratio of patients on CTDa to those on MPT being approximately 2 : 1, although in some areas the ratio may be nearer 3 : 1. Intolerance to thalidomide limits its use in some patients, and occurrence of peripheral neuropathy limits the duration of treatment in some patients (clinical opinion expert advisor). VMP is not widely used as a first-line treatment, but may be used in the subgroup of patients who have renal impairment or failure at presentation. Use of MP is declining, but this is still used in patients who cannot tolerate thalidomide or where the use of thalidomide is contraindicated (clinical opinion expert advisor).

As noted above (see Description of underlying health problem) there is some evidence that myeloma that is characterised by a high-risk cytogenetic abnormality can demonstrate a poor response to conventional treatment. However, although there is interest in the use of cytogenetic data as a prognostic indicator, the incorporation of cytogenetic data into decisions about treatment choice is not currently supported in the UK.^22,28

When patients relapse after first-line treatment most will receive a second-line treatment. The choice of second-line treatment is individualised to the patient and, in theory, a patient could receive the same therapy that they received as a first-line treatment, particularly if this had been effective and the remission had lasted a long time. However, in current UK practice many patients will receive bortezomib monotherapy as a second-line treatment because, as noted below, this has been recommended by the National Institute for Health and Clinical Excellence (NICE). Similarly when patients relapse after second-line treatment the treatment recommended by NICE for this patient group is lenalidomide.

In addition to the BSH guidelines on the diagnosis and management of MM,²² two NICE technology appraisals have been completed for MM. NICE (TA129³⁰) has previously recommended bortezomib monotherapy for relapsed MM as a possible treatment for progressive MM for people:

• whose MM has relapsed for the first time after having one treatment, and
• who have had a SCT, or who are unsuitable to receive one.

The National Institute for Health and Clinical Excellence has also recommended lenalidomide (a structural derivative of thalidomide) when used in combination with dexamethasone as a possible treatment for MM when people have already received at least two other treatments (TA171³¹). Neither of these NICE appraisals considered first-line therapy for MM.

One technology appraisal is in development – denosumab for the treatment of bone metastases from solid tumours and MM – but the scope of this appraisal was not available at the time of writing (January 2010). A draft scope for consultation was issued in March 2010.

The National Institute for Health and Clinical Excellence has also published Guidance on Cancer Services – Improving Outcomes in Haematological Cancers – The Manual.³² This document covers all haematological cancers, including MM, and makes recommendations for service delivery and organisation. Some information about current service costs are included but these relate to the haematological cancer service as a whole.

Description of technology under assessment

Two interventions are being considered in this assessment:²¹ bortezomib in combination therapy with an alkylating agent and a corticosteroid, and thalidomide in combination therapy with an alkylating agent and a corticosteroid. The scope of this review allows for the inclusion of bortezomib or thalidomide when used in combination with any alkylating agent and any corticosteroid. This may therefore include drug combinations that are not covered by the licences for bortezomib and thalidomide, for example CTDa.