Multiple myeloma

• What is Multiple Myeloma
• Statistics on Multiple Myeloma
• Risk Factors for Multiple Myeloma
• Progression of Multiple Myeloma
• Symptoms of Multiple Myeloma
• Clinical Examination of Multiple Myeloma
• How is Multiple Myeloma Diagnosed?
• Prognosis of Multiple Myeloma
• How is Multiple Myeloma Treated?
• Multiple Myeloma References

What is Multiple Myeloma

Multiple myeloma is a cancer of plasma cells in the bone marrow.

Normally, plasma cells form part of the immune system. They produce immunoglobulins (antibodies) which help fight infection. In multiple myeloma, abnormal plasma cells in the bone marrow multiply too fast. They take up too much space in the bone marrow and prevent the normal production of other blood cells, such as red and white blood cells. The plasma cells of multiple myeloma also produce large quantities of abnormal immunoglobulins, which cannot fight infection and which can cause damage to the kidneys.

The type of abnormal protein (called paraprotein) produced may be of any of the immunoglobulin types. (Immunoglobulins are specifically shaped antibodies made of protein.) The commonest are IgG (50%) and IgA (20%) with 20% also being of the “light chain” (part of the antibody) type. The rest are made up of a mixture of IgM, IgD and IgE myeloma while only 1 in 10 000 are non-secretory (i.e. has malignant cells in the bone marrow which do not produce any protein).

Statistics on Multiple Myeloma

Worldwide, the incidence of multiple myeloma is approximately 4 cases per every 100,000 people. In Australia, approximately 1200 new patients are diagnosed with multiple myeloma every year.

Multiple myeloma affects men more commonly than women. It is generally a disease of the elderly, with most patients being diagnosed at around 60 years of age. Multiple myeloma is rare before the age of 40.

Multiple myeloma is found more commonly in black African populations, and only rarely in Asian populations.

Risk Factors for Multiple Myeloma

There are a number of associations with multiple myeloma. Most of these are observed, rather than explained.

Occupations which may be associated with a higher risk of multiple myeloma include:

• Farming
• Woodworking
• Leather working
• Any occupation involving exposure to petroleum products.

In addition, exposure to high levels of ionising radiation may predispose to the development of multiple myeloma.

One factor which has been associated with a definite increase in risk of multiple myeloma is the presence of monoclonal gammopathy of undetermined significance (MGUS) in the blood. This is a condition which is seen in approximately 3-5% of people over 80 years of age. It is normally benign (not cancerous), but the presence of MGUS carries an annual 1-1.5% risk of developing active myeloma.

Progression of Multiple Myeloma

There are three major features of multiple myeloma:

• Bone destruction: the expansion of the abnormal plasma cells in the bone marrow causes destruction of normal bone. This causes bone pain, and may lead to fractures where the bone has been weakened.
• Bone marrow infiltration: the bone marrow is infiltrated by plasma cells. This means that normal blood cells cannot be produced, leading to low levels of red blood cells (anaemia), white blood cells (neutropaenia) and platelets (thrombocytopenia). Patients with multiple myeloma are at increased risk of developing infections, partly due to their impaired white cell production.
• Kidney impairment: the kidneys may be damaged in multiple myeloma in a number of ways. Bone destruction by plasma cells leads to increased levels of calcium in the blood (hypercalcemia), which is harmful to the kidneys. In addition, the abnormal immunoglobulins produced by the plasma cells can be deposited in the kidney tubules and cause damage. Overall, kidney failure occurs in approximately one quarter of multiple myeloma patients.

Tumour spread in multiple myeloma is usually confined to the bones and bone marrow only. Rarely, the tumour may spread to the spleen, lymph nodes, or other organs.

Symptoms of Multiple Myeloma

Common symptoms of multiple myeloma include:

• Bone pain
• Symptoms of anaemia, such as fatigue or dizziness
• Recurrent infections
• Symptoms of hypercalcemia (excess calcium in the blood), such as nausea, vomiting, constipation or confusion
• Symptoms of renal failure, such as fatigue, weakness, breathlessness or ankle swelling.

Some patients have no symptoms, and are diagnosed incidentally on routine blood tests.

How is Multiple Myeloma Diagnosed?

For the diagnosis of multiple myeloma to be made, 2 out of the following 3 criteria have to be met:

1. Monoclonal immunoglobulin in the blood and/or urine. (An abnormal single protein produced by abnormal plasma cells. The protein is of the type which in normal circumstances would be an antibody).
2. Infiltration of bone marrow by malignant plasma cells.
3. Osteolytic bone lesion (holes eroded in bone by the malignant cells).

Blood tests:

• Full blood picture: haemoglobin, white cell count and platelet counts are normal to low.
• ESR / CRP: raised.
• Urea and electrolytes: may show evidence of kidney impairment.
• Calcium: normal or raised.
• Uric acid: normal or raised.
• Serum B2 microglobulin, serum LDH: these may be useful when predicting the course of disease (prognosis).
• Total protein: normal or raised. Serum albumin will be normal or low.
• Serum protein electrophoresis: a monoclonal band is usually seen.

Imaging investigations:

• A skeletal survey is required for baseline evaluation. Additional x-ray imaging of specific areas of concern, such as ribs, may be helpful.
• CT: to investigate areas of concern, particularly if radiotherapy or surgery is being considered.
• MRI: this may be used to assess disease bulk, or if spinal cord compression is suspected.

A bone marrow biopsy may also be necessary.

Prognosis of Multiple Myeloma

There are a number of features which have been identified as being associated with a poor prognosis in multiple myeloma:

• Older age at diagnosis
• Poor performance status.
• Anaemia or low platelet count at presentation.
• Renal failure.
• Raised B2-microglobulin.

Overall, approximately 15% of patients will die within 3 months of diagnosis, with a subsequent death rate of 15% per year. Causes of death include progression of myeloma, renal failure, or sepsis (overwhelming infection). With treatment, the average survival is approximately 5 years. One in ten patients will have a very slow (indolent) course, with only gradual progression of disease.

How is Multiple Myeloma Treated?

Treatment depends upon the stage and form of myeloma, but most people require both systemic chemotherapy and supportive symptomatic care.

Chemotherapy

The standard treatment chemotherapeutic regime for multiple myeloma includes an alkylating agent (melphalan, cyclophosphamide or chlorambucil) and prednisone administered for 4 to 7 days every 4 to 6 weeks. This is continued for one to two years.

While around 50% of patients respond well to this treatment, relapse of disease usually occurs within a year of stopping treatment.

In patients under 65 years who are otherwise healthy, autologous bone marrow transplant is a standard treatment option. This involves 3-6 months of ‘induction’ chemotherapy, designed to reduce the number of myeloma cells in the body, and remove myeloma cells from the blood. Healthy bone marrow stem cells are then ‘harvested’ from the patient’s blood, before intensive high-dose chemotherapy is given to kill any remaining cancer cells. The patient’s own harvested stem cells are then returned to the patient to ‘rescue’ the depleted bone marrow.

Newly developed drugs offer alternative treatment options, particularly for patients with relapsed refractory disease. Bortezomib is a new type of drug which is able to kill myeloma cells which are resistant to dexamethasone, alkylating agents, and anthracycline. When used alone in the treatment of refractory disease, bortezomib has a response rate of approximately 30%; when combined with dexamethasone, the response rate is 60-70%.

Thalidomide is an older drug which has found a new role in the treatment of multiple myeloma. When combined with dexamethasone in treating refractory myeloma, thalidomide has a response rate of 26-48%. With chemotherapy, the response rate is higher, at 44-86%.

Supportive care

Supportive care includes treatment of anaemia, pathological bone fractures, bone pain (eg. by radiation therapy), strengthening the skeleton (vitamin D, calcium and fluorides), treatment of electrolyte disturbances and antibiotics to prevent infections. Information on other types of leukaemia:

• Chronic Myeloid Leukaemia
• Promyelocytic leukaemia
• Myelodysplastic syndrome
• Chronic lymphocytic leukaemia
• Acute lymphoblastic leukaemia
• Acute myeloid leukaemia

Multiple Myeloma References

1. Braunwald, Fauci, Kasper, Hauser, Longo, Jameson. Harrison’s Principles of Internal Medicine. 16th Edition. McGraw-Hill. 2001
2. Cotran RS, Kumar V, Collins T. Robbins Pathological Basis of Disease Sixth Ed. WB Saunders Company 1999.
3. Durie BGM et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematology Journal 2003; 4(6): 379-98.
4. Joshua DE. Multiple myeloma: the present and the future. MJA 2005; 183(7): 344.
5. Kumar P, Clark M. Clinical Medicine. WB Saunders 2002.
6. Sirohi B, Poles R. Multiple myeloma. Lancet. 2004. 363: 875-87.