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March 1, 2010

Newer Treatments Hold Hope for Multiple Myeloma Patients          
By Carolyn Gutierrez
For The Record
Vol. 22 No. 4 P. 24

New treatment options developed within the last seven years for multiple myeloma patients are accelerating disease-free survival rates. The immunomodulatory drug lenalidomide in particular has been shown in several studies to consistently stall the progression of myeloma longer than in those given a placebo when used in patients who received a blood stem cell transplant. In addition, proteasome inhibitors, such as bortezomib, combined with chemotherapy agents and corticosteroids continue to play a significant part in the treatment of multiple myeloma. Trials experimenting with combinations of new and existing therapies for multiple myeloma are more promising than ever, improving response rates and enhancing the quality of life for those suffering with the disease.                  

Background and Overview
Multiple myeloma is caused by an overproliferation of mutated plasma cells. Cells that assist the body’s immune system originate in the bone marrow from stem cells. Some stem cells evolve into lymphocytes, or small white blood cells. There are two groups of lymphocytes: B cells and T cells. Plasma cells, found mainly in bone marrow, are developed from B cells. When these plasma cells encounter germs, they produce proteins known as immunoglobulins that function as antibodies, defending the body from germs and infection. In a healthy body, plasma cells develop in the lymph nodes in a direct response to infection. In multiple myeloma, through a series of genetic changes, the plasma cells become malignant, dividing again and again unchecked. These malignant plasma cells are known as myeloma cells.

Eventually, the myeloma cells traverse the bloodstream and accumulate in the bone marrow, destroying healthy tissue. The myeloma cells attach themselves to the structural cells within the bone marrow, known as stromal cells, eventually infiltrating the solid bone and leading to structural damage, tumors, and bone pain. The term multiple myeloma applies when there is widespread accumulation of myeloma tumors and lesions throughout the bone structure.            

Myeloma cells produce large amounts of the immunoglobulin Monoclonal (M) proteins that block out normal immunoglobulins. These M proteins can disrupt normal kidney function, resulting in damage and kidney failure. In addition, the overgrowth of plasma cells can affect normal blood-forming cells, causing anemia in many patients. Thrombocytopenia, a condition in which the platelet levels in the blood become dangerously low and results in increased bleeding and bruising in patients, is also common. Leukopenia, or the shortage of white blood cells in those with multiple myeloma, can seriously compromise a patient’s ability to fight infection.

According to the American Cancer Society, multiple myeloma is relatively rare; the lifetime risk of the average American getting the disease is 1 in 161. Yet it is a devastating form of cancer, with a five-year survival rate hovering at about 35%. More men develop the disease than women. African Americans have the highest reported number of cases of multiple myeloma, while Asian Americans have the lowest number of cases. The average age of a myeloma patient is 65 to 70, and it is unusual for those under the age of 35 to get the disease. Some studies suggest that those who have family members with multiple myeloma may be at a higher risk of developing the disease.

Symptoms and Diagnosis
The symptoms of multiple myeloma can be elusive. According to Vivek Roy, MD, an associate professor of medicine in the hematology/oncology department at the Mayo Clinic in Florida, “The symptoms are variable. … In some patients, if they are diagnosed at an early stage, the only abnormality may be when they have a routine physical, someone may notice there is something not right in their blood test … or they may be weak, they may be tired, they may be getting frequent infections, they may be getting bone pains—these kind of symptoms. There is not one specific symptom that leads to the diagnosis of myeloma.”       

Multiple myeloma patients may experience bone pain from minute fractures in the bone caused by the accumulation of malignant plasma cells. The back and the ribs are especially vulnerable to this type of pain. Osteoblasts, or cells that help create new bone in the body, are compromised by myeloma cells, leading to a general weakness in the bone structure that results in fragile bones that are easily broken. Clinicians may suspect the disease when examining a patient’s x-ray for a fracture.   

While a multiple myeloma patient’s fatigue may be brought about by anemia (the suppression of red blood cells in the marrow), the body’s lack of white blood cells also increases a patient’s susceptibility to bacterial pneumonia and urinary tract infections. Other possible symptoms include weight loss, nausea, constipation, frequent urination, and increased thirst. These are most likely due to either excess M protein in the blood or hypercalcemia (increased calcium in the blood due to the myeloma cells dissolving bone).

If multiple myeloma is seriously considered, notes Roy, “usually we start with bloodwork. Most patients also need a urine test, they may need x-rays, we may need to do a bone marrow biopsy. In fact, most of the patients with myeloma will need to do a bone marrow biopsy. That’s where the abnormal cells are, so we need to look at that to make the diagnosis.”

Fine or core needle bone marrow biopsies are generally taken from the marrow of the hip bone or another large bone. CT scans and MRIs are ordered, and immunoglobulin tests are performed to assess the patient’s antibody levels.  

Patients with few symptoms whose multiple myeloma is in an early stage (referred to as smoldering myeloma) can often go years without treatment. For those whose illness is more advanced, there are several options.

“The mainstay of treatment is some type of chemotherapy, [but treatment] has evolved over the last five to seven years and has improved a lot, so we have many more agents now available to treat myeloma than we used to have,” Roy says. “There are agents that are within the category of conventional chemotherapy. There are more targeted agents (sometimes also called biological agents) that work against myeloma. They tend to have less side effects than the conventional chemotherapy regimen, and sometimes we combine the conventional chemotherapy with the more modern regimen to have the best benefit. On top of this, many patients require radiation, depending on what their specific symptom or problem is, and many patients with myeloma will also need a stem cell transplant.”

The most common transplant is known as autologous stem cell transplantation, which gained momentum as a treatment in the late 1980s and 1990s involving the use of a patient’s own stem cells. Ira Braunschweig, MD, director of the Bone Marrow Transplantation Program at Montefiore Medical Center and an assistant professor of medicine at the Albert Einstein College of Medicine in New York City, notes that patients undergoing this procedure “can expect about a 40% chance of going into a complete remission. Those that do will have a prolonged survival. Landmark studies have shown that this therapy prolongs survival in myeloma patients.”         

To begin this procedure—which carries a price tag around $100,000—patients are given a standard dose of chemotherapy, causing the blood count to decrease. After two weeks of recovery, stem cells ordinarily found in bones travel into the bloodstream. Once there, they can be collected. Then, according to Braunschweig, “The patient is hooked up to a machine by an IV, and the machine processes the blood and collects the portion of the blood rich in stem cells. If you saw someone having it done, it looks like a fancy blood donation or dialysis. The stem cells are frozen. About a week or two later, the patient is readmitted. They get high doses of chemotherapy that are very effective against the myeloma, and after the chemo is cleared from their bodies (a day later), the stem cells are thawed and infused like a blood transfusion into a vein. It then takes about two weeks’ time for the cells to find their home in the bones and grow again.”                

The best candidates for this procedure are patients aged 65 and younger, although Braunschweig maintains that they “typically offer this therapy to a patient in their early 70s if they are in good health otherwise.”

“It’s a strong treatment and therefore the person has to be in a reasonable state of health to be able to undergo this treatment safely,” Roy notes. “So age in itself is not selection criteria or exclusion criteria, but I think it is fair to say a younger person is more likely to be suitable to undergo this transplant than somebody who is an advanced age.”

In this course of treatment, because the patient’s immune system is vulnerable until new blood cells grow again, infection is a major concern. Despite this vulnerability, however, the overall “severe morbidity/mortality of the procedure is about 2%,” according to Braunschweig, who adds the procedure’s effectiveness is heightened when it is combined or “used in symphony with” modern drug regimens that are gaining popularity.       

Perhaps the regimen causing the biggest stir in the medical community surrounds the use of lenalidomide. “Lenalidomide is a close cousin of thalidomide. It has a lot of activity against myeloma and has become the preferred treatment for myeloma in most of the cases now,” says Roy.

Lenalidomide, otherwise known as its brand name Revlimid, is an immunomodulatory agent that inhibits the adhesion of myeloma cells to bone marrow stromal cells. Most often it is combined with the steroid dexamethasone, a drug combination that was approved by the FDA in 2006 for treating patients who had received at least one prior therapy for their multiple myeloma.

In December 2009, the National Cancer Institute released findings from a study that showed patients who received lenalidomide after autologous blood cell transplantation had a 58% decrease in disease progression compared with patients on placebo. Because of these results, the study, which involved 460 randomized patients, was stopped early. Although the study has not yet shown proof of overall survival benefit, these results are significant since it is the first phase 3 trial to demonstrate the advantage of lenalidomide following stem cell transplantation for multiple myeloma.         

Thalidomide itself has shown promise in treating patients with multiple myeloma. Notorious in the late 1950s for causing severe birth defects in infants born from women using the agent as a morning sickness treatment, thalidomide has since been found to be helpful in affecting cell activity in patients with numerous diseases, including myeloma. Although not completely understood, thalidomide seems to assist the body’s immune system in fighting cancer cells by blocking the blood supply to malignant tumors and stopping the tumors from growing larger. Thalidomide’s side effects can include neuropathy, pulmonary embolism, and deep vein thrombosis, but it is considered to be the safer of the two drugs for myeloma patients. Both lenalidomide and thalidomide are oral agents, making them more tolerable and less invasive.

The proteasome inhibitor bortezomib, marketed as Velcade, is also commonly used to treat multiple myeloma. Approved by the FDA in 2003, bortezomib is recommended for multiple myeloma patients who have had at least two prior therapies. The drug works by blocking the proteins that myeloma cells need to multiply, slowing down tumor growth. Bortezomib alone and its use in combination with other agents are still being explored in clinical trials, yet it is currently considered to be a strong treatment option.

However, despite its effectiveness, “it tends to cause nerve irritation more frequently than lenalidomide,” notes Roy. “It has to be given as an injection, as an infusion really, whereas the lenalidomide is a pill. So there are some drawbacks with [bortezomib] in the sense that it can have more side effects. It’s a more tedious treatment, if you will. Patients have to come to the clinic to get the injections twice a week.” The costs, too, are not trivial for these drugs: Many of the newer multiple myeloma drugs cost thousands of dollars per month.

Older drugs such as bisphosphonates can be helpful in aiding the bone erosion that takes place with myeloma. A bisphosphonate is used intravenously and, according to Roy, it “counteracts [the bone erosion] of myeloma and then it seems to also slow down the myeloma in addition to strengthening the bone.” However, the use of a bisphosphonate can have drawbacks as well. “One of the potential problems with bisphosphonate is that it can cause kidney dysfunction, so patients that have kidney damage from myeloma may not always be able to receive this drug,” Roy says.

— Carolyn Gutierrez is a freelance writer based in New York City.