Thalidomide and Newer Analogues for Multiple Myeloma

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Multiple Myeloma

Multiple myeloma is a cancer of plasma cells. Plasma cells are a type of white blood cell that develop in the bone marrow. Normally, they fight infection by releasing antibodies (also known as immunoglobulins) that attack foreign bodies such as bacteria. In multiple myeloma, the plasma cells become cancerous and are subject to uncontrolled growth. This causes overcrowding in the bone marrow, and prevents the growth of normal blood cells. In addition, the antibodies that myeloma cells release have no useful function. These dysfunctional antibodies are called M-protein (previously known as paraprotein), and can be used for disease diagnosis and to monitor disease progression.

Approximately 1,200 Australians are diagnosed with multiple myeloma each year, and about 5,000 Australians are currently living with it. It predominately affects people over 60 years of age, with approximately 5-10% of multiple myeloma patients under 40 years old.

The most common symptoms of multiple myeloma are consistent with the pathophysiology of the disease. Bone pain can occur due to the build-up of myeloma cells in the bone marrow. The bones affected are those which have active marrow, i.e. spine, skull, pelvis, rib cage, shoulders and hips. The hands and feet are not usually affected, and therefore normally retain full function. Multiple myeloma can also cause weak bones or fractures because of the secretion of substances which increase the action of osteoclasts (the cells responsible for bone breakdown). This bone resorption can also result in hypercalcaemia due to the release of bone calcium into the blood stream. Overgrowth of myeloma cells causes a lack of space in the bone marrow for functioning red and white blood cells to grow. This results in a decreased ability to fight infection, and increased fatigue due to anaemia. Multiple myeloma can also cause kidney damage; high levels of M-protein in the blood cannot be excreted efficiently by the kidneys and hence impact on the functionality of the kidney (myeloma kidney).

Currently, treatments for multiple myeloma are not curative, once a patient is diagnosed, medical surveillance will be required for life. However, treatment can control symptoms, and slow or halt the disease progression. Stem cell transplantation (SCT) is a standard treatment option for those who can tolerate it (generally patients less than 65 years old with little or no co-morbidity). Patients who are eligible for transplant will receive extensive chemotherapy followed by SCT while other patients who are ineligible for transplant are treated with chemotherapy alone. There are many different chemotherapy regimens which may be used to treat multiple myeloma. This includes traditional cytotoxic chemotherapy (e.g. doxorubicin or cyclophosphamide with dexamethasone), immunomodulator drugs (e.g. thalidomide), and proteasome inhibitors (e.g. bortezomib). These can be used individually or in combination. In addition, there are supportive therapies used to treat the symptoms of multiple myeloma. For example, bisphosphonates are used to slow bone breakdown.

The remainder of this article will focus on the immunomodulator class of drugs (IMiD).

Thalidomide

Approved for the treatment of multiple myeloma in the 1990’s, thalidomide was the first immunomodulator to be used in this setting. The exact mechanism of action of thalidomide in treating multiple myeloma is unknown, but there are several mechanisms which may contribute. It is thought to directly inhibit myeloma cell growth and survival. It also appears to interfere with the cytokines involved in myeloma cell survival and proliferation, such as inhibition/down-regulation of TNF-alpha, a pro-survival cytokine which favours tumour cell survival, and enhancement/up-regulation of IL-2 and IL-6, which counteract TNF-alpha. Furthermore, thalidomide seems to have a stimulating effect on T cells (immune cells which attack myeloma cells) and cause inhibition of angiogenesis through inhibition of VEG-F and bFGF-2, angiogenic cytokines released by myeloma cells. It is also possible that thalidomide causes reduction (neutralisation) of free radicals that cause DNA damage.

Thalidomide was initially used as a sedative and an analgesic to treat insomnia and headaches. It was also found to be an effective antiemetic, particularly for morning sickness. The teratogenic effect of thalidomide became well known, during the late 1950’s and early 1960’s, when thousands of babies were born with major limb deformities, often also associated with internal organ malformations. There are multiple possibilities which explain this mechanism; the most widely accepted is that inhibition of angiogenesis in the development of limb buds causes the limb malformation.

As a result of the severe consequences of such history, there are now rigorous controls around prescribing and dispensing of thalidomide. Both the prescribing doctor and the dispensing pharmacist, along with the patient, must be registered with the risk management program run by the manufacturer, Celgene. In addition, approval is required from the manufacturer prior to each supply of the medication. Thalidomide is subsidised by the Pharmaceutical Benefits Scheme (PBS) for the treatment of multiple myeloma.

Thalidomide therapy is also associated with other adverse effects. Thalidomide can increase the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), so an anti-platelet (usually aspirin) is often co-prescribed. Sedation is another common side effect, and as such it is generally recommended that thalidomide be taken at night. Thalidomide can also cause peripheral neuropathy; this is felt by patients as numbness or tingling in the hands and feet. However other myeloma treatments, and myeloma itself, can also cause this symptom, so it can be difficult to determine the exact cause. Other common side effects include dizziness (particularly on standing up), nausea, vomiting, skin rash, constipation, and leukopenia/increased risk of infection.

Numerous studies have established the effectiveness of thalidomide in the treatment of multiple myeloma. Despite the adverse effect profile, thalidomide remains a justified treatment option for this disease.

Lenalidomide and Pomalidomide

Lenalidomide and pomalidomide are newer analogues of thalidomide. They have a more potent action, particularly with regards to inhibition of TNF-alpha and stimulation of T cells. They also have a more tolerable adverse effect profile, with fewer incidences of sedation, neuropathy and constipation. However, due to the similarity in structure to thalidomide, both drugs are thought to have the potential to cause severe teratogenic effects. As a result, restrictions in place regarding prescribing and dispensing are similar to those of thalidomide. Lenalidomide is listed on the PBS, but only for patients who meet certain strict clinical criteria, including treatment failure following a trial of thalidomide. Pomalidomide, the newest of the IMiD’s, is still undergoing clinical investigation and is not listed on the PBS. Patients may be able to access it via a clinical trial, or via the access program run by the manufacturer Celgene.

Looking toward the future, there are several drugs currently being studied for the treatment of multiple myeloma, including both new drugs and drugs that are currently registered for other indications. These include drugs which inhibit the enzymes that myeloma cells need to develop and survive, and drugs that target receptors specifically expressed on the surface of myeloma cells.

Management and treatment of multiple myeloma is continually improving. There are multiple treatment options, and the immunomodulator class of drugs plays an important role in treatment of this uncommon but significant disease.