Until approximately fifteen years ago, treatment advances in multiple myeloma stagnated. Patients had few treatment options, were powerless against its bone-eroding effects, and typically lived for two and a half years. Few ever achieved a complete remission. This situation changed with the demonstration that intensive chemotherapy given with the support of a patient’s own bone marrow or peripheral blood stem cells (called an autologous transplant) could result in much better responses than ever seen before.
More recently, the introduction of the drug thalidomide as an effective therapy for the disease has ignited research into the use of novel biologic agents for its treatment. As a result, multiple myeloma has been transformed into a hotbed of innovation and scientific breakthroughs that are extending the lives of many patients to beyond five years and some to more than ten years.
The culprit cell in myeloma is the plasma cell. Plasma cells are normal constituents of our immune system and reside mainly in the bone marrow, where they make up less than 5 percent of marrow cells. Their job is to generate antibodies, which are infection-fighting proteins that each plasma cell crafts to “form-fit” the target of its attack (for example, bacteria that cause infections). Every person’s blood contains a large variety of antibodies, each directed at a specific target.
Just as any cancer arises from one aberrant cell, myeloma is caused by one plasma cell that acquires the necessary genetic mutations to become a cancer. This one cell multiplies to form many more plasma cells.
Because all the plasma cells in myeloma are replicas (clones) of the first cancerous plasma cell, they all produce the same antibody molecule. This antibody is present in high enough amounts to be distinguished from all the other types of antibodies. It is detected in the blood and/or urine by a test called electrophoresis.
The antibody molecule found in myeloma is usually detected in the blood and is referred to as an M-protein (M stands for monoclonal, or one type of protein). Fragments of the M-protein, called light chains, may also be found in the urine in some patients, where they are called Bence Jones protein, after the renowned British physician Henry Bence Jones, who reported their discovery in 1847. A new test, called the freelite assay, can detect light chains in the blood with great sensitivity and is being increasingly used to both diagnose the disease and follow its course after treatment.
A physician may order an electrophoresis test that leads to the detection of an M-protein for many reasons. These include unexplained anemia, a high protein level in the blood, reduced kidney function, bone pain, or numbness and tingling in the feet (called peripheral neuropathy).
If an M-protein is detected, it is a sign, not a certainty, that myeloma may be present. A bone marrow biopsy is performed to look for excess plasma cells, and X-rays of all the bones (called a skeletal survey) are performed to examine them for damage caused by the disease; MRIs are often done to give a more precise picture of bone involvement. Myeloma cells create little holes in the bones called lytic lesions. All of these tests help determine the presence of myeloma, the stage of the disease, and whether treatment is necessary.
I wish to emphasize that a person found to have an M-protein does not necessarily have myeloma. In fact, one of the most common consultations I perform as a hematologist practicing in the community is the evaluation of a person whose blood tests show an M-protein but who is otherwise well. In these circumstances, it is not uncommon to have a normal skeletal survey and a normal bone marrow examination, without an excess of plasma cells.
The diagnosis in these situations isa disorder termed MGUS, which stands for monoclonal gammopathy of unknown significance. This is a convoluted way of saying that an Mprotein is present but everything else is normal, so the patient does not have myeloma. Because MGUS does have a 25 percent risk of progressing to a blood or lymph cancer over a thirty-year period, patients with MGUS need to have their M-protein, blood counts, and kidney function checked at least once a year.
A central question in trying to comprehend the effects of myeloma in the body is: Why do myeloma cells burrow into and destroy bone?
None of the other blood cancers commonly attack our skeleton. This bizarre behavior of myeloma is explainable by the observation that myeloma cells and bone cells support each other’s survival. Scientists have discovered that as cancerous plasma cells grow from the bone marrow into the hard bony cortex, they nuzzle up to bone cells called osteoclasts and stimulate them to eat away at the surrounding healthy bone. The bone cells, in turn, secrete chemicals that stimulate the growth and survival of the myeloma cells. This vicious cycle must be arrested or the result is severe bone weakening and fractures, which cause the pain and debilitation experienced by patients who are not responding to therapy.
Modern treatments for myeloma include not only those aimed at killing plasma cells but also those aimed at killing the destructive osteoclasts. Examples of osteoclast-killing drugs include pamidronate (Aredia) and zoledronic acid (Zometa). These medicines are given along with myeloma-fighting drugs because they are not sufficient to control the disease. The expanding spectrum of myeloma-fighting medicines includes chemotherapies (such as Doxil, melphalan, and Cytoxan), steroids (such as dexamethasone and prednisone), thalidomide (Thalomid), its derivative lenalidomide (Revlimid), and bortezomib (Velcade).
The revival of thalidomide as a cancer therapy nearly fifty years after it was banned for causing birth defects is a remarkable story of the human spirit, science, and serendipity.
Ongoing studies are defining the best sequence and combinations of myeloma-fighting agents to use to improve the control of the disease and long-term survival. Organizations such as the Multiple Myeloma Research Foundation (www.multiplemyeloma.org) and the International Myeloma Foundation (www.myeloma.org) are fueling the accelerated pace of progress in this disease.
