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Myeloma: its diagnosis and treatment

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VOL: 98, ISSUE: 26, PAGE NO: 38

Ken Campbell, FIBMS, CertHMS, is clinical information officer, Leukaemia Research Fund, London

Myeloma, which is also known as multiple myeloma and myelomatosis, is the second most common form of blood cancer in the UK, after non-Hodgkin's lymphoma. It affects plasma cells in bone marrow and is characterised by marrow failure, paraproteinaemia (Box 1) and destructive bone lesions. Plasma cells are specialised B-lymphocytes (a type of white blood cell) that produce antibodies, so part of the symptom picture for myeloma is a compromised immune system.

Myeloma, which is also known as multiple myeloma and myelomatosis, is the second most common form of blood cancer in the UK, after non-Hodgkin's lymphoma. It affects plasma cells in bone marrow and is characterised by marrow failure, paraproteinaemia (Box 1) and destructive bone lesions. Plasma cells are specialised B-lymphocytes (a type of white blood cell) that produce antibodies, so part of the symptom picture for myeloma is a compromised immune system.

Myeloma is generally considered incurable. It is a slowly progressing disease with long periods of relative inactivity, yet the consequences, such as renal failure, bone destruction and immunosuppression, can be devastating.

Myeloma and MGUS
The condition known as monoclonal gammopathy of undetermined significance (MGUS) - where the presence of less than 3g/dL paraprotein is detected in the blood of patients with no evidence of myeloma or a related disorder - should not be confused with myeloma. Although a small percentage of people with MGUS go on to develop myeloma, most do not. It is important for nurses to realise this, particularly when giving health advice to patients. MGUS is not rare and is often detected on a routine screen: it occurs in 1% of people aged over 50 and in 3% of people aged over 70 (Kyle, 1999). The risk of MGUS progressing to myeloma or a related condition is low: 16% at 10 years, 33% at 20 years and 40% at 25 years (Kyle, 1999).

The presence of large numbers of plasma cells in the peripheral bloodstream is rare and usually indicates late-stage disease. Where plasma cells are primarily present in the blood and marrow without localised bone lesions, the condition is classified as plasma-cell leukaemia (Costello et al, 2001). Where there is a single tumour (in bone or soft tissue) containing plasma cells and the other features of myeloma are present, this is called a solitary plasmacytoma (Dimopoulos et al, 2000). Plasma-cell leukaemia and plasmacytoma are not discussed in detail in this article.

Epidemiology
Myeloma is a disease of later life, with 98% of patients aged 40 or older (Blade and Kyle, 1998). The incidence in the UK is about 40 per million per year, or about 2,500 new cases. At any one time there are about 10,000-15,000 patients with the disease (UK Myeloma Forum, 2001).

Plasma-cell tumours are unknown in childhood but may be seen in young adults (Geetha et al, 1999). The condition is rare in Asians, but roughly twice as common in Afro-Caribbean ethnic groups compared with Caucasians.

The only unequivocal cause of myeloma is exposure to high levels of ionizing radiation. Certain chemical exposures are reported to increase the risk, and an increased incidence is seen in agricultural workers (Nanni et al, 1998). It has been suggested that the latter may be the result of chronic antigenic stimulation.

Pathophysiology
There is a paradox in myeloma. The tumour is characterised by abnormal plasma cells (mature antibody-producing B-cells). However, these cells have a very low rate of cell division so they cannot be the source of the malignant cells. The nature of the source cells in myeloma remains controversial (Child et al, 1998). A wide range of chromosomal abnormalities is associated with myeloma and MGUS, which suggests that when the affected cell becomes malignant it is already committed to becoming a plasma cell (Bergsagel and Kuehl, 2001).

A striking feature of myeloma is the interaction between myeloma cells and bone cells (osteoblasts and osteoclasts) (Callander and Roodman, 2001). Osteoblasts are bone-forming cells, while osteoclasts remove unwanted or dead bone. Myeloma cells are capable of recruiting osteoclasts to tumour sites and increasing their bone-destroying activity. They also recruit osteoblasts, which help to create a microenvironment that is hospitable to the myeloma cells (Kanis and McCloskey, 2000) but inhibits the formation of new bone (Roodman, 2001). The breakdown of bone may lead to excessive amounts of calcium in the blood, which in turn affects several organ systems. Disruption of this positive-feedback loop can be exploited therapeutically, both to prevent destructive bone lesions and to treat the underlying illness (Anderson, 2001).

Renal impairment

Renal impairment is common in myeloma and affects up to half of all patients at some stage in their illness. Up to 20% present with renal failure while 3-12% experience advanced renal failure that requires dialysis or other intervention (UK Myeloma Forum, 2001). This may be a consequence of paraproteinaemia leading to proximal tubular damage or to protein cast nephropathy. Other possible causes include hypercalcaemia, dehydration, hyperuricaemia, infection or the action of nephrotoxic drugs. Unfortunately, several of the drugs that are used to treat myeloma have an adverse effect on kidney function.

The high incidence of MGUS in people aged over 70 and the low incidence of myeloma suggests that most, possibly all, cases of myeloma represent the progression of undiagnosed MGUS (Bergsagel and Kuehl, 2001). This is true, even though there is a low probability of a patient with MGUS developing myeloma.

Clinical features
Myeloma may present in any of a number of guises. Some patients are asymptomatic, with abnormalities being identified as a result of routine screening or investigations in connection with another illness. Where symptoms are present these may include (singly or together):

- Bone pain;

- Recurrent or persistent infection;

- Anaemia;

- Symptoms of renal impairment.

Symptoms that require urgent specialist referral are:

- Bone destruction symptoms, such as persistent, unexplained backache associated with loss of height and osteoporosis (especially in men and premenopausal women) and symptoms suggestive of spinal cord/nerve-root compression;

- Compromised immunity and/or bone marrow function, such as recurrent or persistent bacterial infections, anaemia (typically normochromic), leukopenia and/or thrombocytopenia;

- Persistent elevation of erythrocyte sedimentation rate (ESR) or plasma viscosity;

- Evidence of impaired renal function;

- Hypercalcaemia.

Diagnosis
A GP with a list of 2,000 patients might expect to see one new myeloma patient every 10 years (Department of Health, 2001). Over that 10-year period the same GP will have dealt with thousands of cases of back pain, anaemia and persistent malaise in patients aged over 40, so many patients with myeloma have a history of chronic symptoms before being diagnosed.

A panel of tests, consisting of full blood count, ESR, serum calcium, and urea and electrolytes (U&Es), is relatively inexpensive and will indicate whether myeloma is a likely diagnosis for chronically ill patients. The routine screening of patients for the presence of a paraprotein is probably not appropriate. Given that 1% of people aged over 50 and 3% of those aged over 70 have MGUS, screening could generate anxiety in many patients who will never develop a malignancy.

There are no specific signs or symptoms of myeloma; destructive bone lesions are highly suggestive of myeloma but are not unique to this disease and are not always present. Common presenting features of myeloma are listed in Table 1.

Diagnosis is based on laboratory and radiographic findings and depends on three abnormal results:

- Bone marrow containing more than 15% plasma cells (normally no more than 4% of the cells in the bone marrow are plasma cells);

- X-rays showing generalised thinning of the bones and/or punched-out lesions;

- Blood serum and/or urine containing an abnormal protein.

Treatment
The UK Myeloma Forum (2001), with the support of the British Committee for Standards in Haematology, has published a set of guidelines on all aspects of the diagnosis and treatment of myeloma. These should be regarded as the preferred source of detailed guidance on treatment and are available on the forum's website (www.ukmf.org.uk), where they will be updated regularly.

Bisphosphonates

Historically, the most serious morbidity invariably resulted from destructive bone lesions, which cause severe intractable pain, pathological fractures, and often deformity and disability. The introduction of a new class of drugs called bisphosphonates has transformed this aspect of the condition (Berenson, 2001). They bind to bone at sites of active bone remodelling (Theriault and Hortobagyi, 2001) and can therefore inhibit myelomatous bone damage.

Thalidomide

In recent years thalidomide has been recognised as a valuable drug for the treatment of a number of serious conditions, including myeloma (Barlogie et al, 2001; Rajkumar, 2000; Sirohi and Powles, 2001). A number of studies are under way to identify thalidomide derivatives that have more acceptable side-effects and lack teratogenicity. Until such derivatives are available it is imperative that any nurse administering thalidomide should be fully aware of the rigorous safety precautions necessary for the use of this drug.

Stem-cell transplantation

Most patients who are diagnosed with myeloma are too old to undergo a standard stem-cell transplant from a donor. In the few younger patients who have had the procedure, the results have been historically poor and are usually worse in men. With improved conditioning regimens, however, transplant-related mortality has reduced and this option should be considered for patients aged under 50, particularly women.

Autologous transplantation, in contrast, has an established place in the treatment of myeloma. It is the treatment of choice for patients age under 60 and should be considered for those aged between 60 and 70 who have a good performance status. It is not recommended for patients over the age of 70.

Prognosis
Myeloma continues to be regarded as incurable, certainly in the conventional sense. Although most patients will achieve prolonged symptoms-free periods, relapse occurs in virtually all cases. Median survival with conventional therapy is about three years, while stem-cell transplant can achieve a median survival of more than five years (Zaidi and Vesole, 2001).

Operational cure

An important new concept of an 'operational cure' has been proposed in relation to myeloma. In this state a patient's bone marrow is clear by microscopy, no paraprotein is present in the blood or urine, bony lesions have resolved or are stable and the patient is leading an essentially normal life. What distinguishes operational cure from conventional concepts of cure is the continuing presence of myeloma cells, albeit at such low numbers that only the most sophisticated laboratory tests can detect them. These patients are, in essence, living with cancer rather than free of it (Sirohi and Powles, 2001).

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