New treatments are helping people with multiple myeloma live longer after diagnosis.
Each year in the United States, nearly 27,000 people are diagnosed with multiple myeloma, a cancer of the bone marrow. Bone marrow contains plasma cells, a type of white blood cell that is an important part of the immune system, which protects the body from infection.
Normally, plasma cells make up less than 5 percent of the blood cells in the bone marrow. For reasons not completely understood, plasma cells can grow out of control. When they do, they are referred to as myeloma cells. These myeloma cells can fill up the bone marrow and damage the bone. Over time, they collect and form tumors in several (multiple) areas of the bones. That is why this cancer is called “multiple” myeloma.
Most people diagnosed with multiple myeloma have symptoms such as bone pain, fatigue, or weight loss. In early stages, however, multiple myeloma does not cause obvious symptoms. About 20 percent of people have either mild or no symptoms at the time of diagnosis. Often, people are diagnosed when a doctor is looking at another health problem. But as multiple myeloma progresses, it begins to affect the bone and other parts of the body. (See sidebar for a list of possible symptoms.)
Over the past 20 years, new medications approved by the U.S. Food and Drug Administration (FDA) have transformed the way multiple myeloma is treated. This progress is unmatched in any other type of cancer. Doctors report that some patients have gone into remission (a state in which all signs and symptoms of cancer have disappeared) for 10 or even 20 years. Researchers expect the picture for people with multiple myeloma to improve even more as new drugs and drug combinations are studies in clinical trials.
Diagnosing Multiple Myeloma
Patients are considered to have multiple myeloma when at least 10 percent of their bone marrow is made up of myeloma cells or when doctors detect a tumor containing myeloma cells. Tests used to detect multiple myeloma include:
Bone marrow biopsy. This is the most important test used to figure out the percentage of myeloma cells in the bone marrow. Blood cells are removed from the bone marrow and examined under a microscope. Doctors use high-tech tests to check the cells' genetic material for anything out of the ordinary.
Bone X-rays. X-ray films are examined to find any areas of the bone that have been damaged by myeloma cells. Other tests may provide a more detailed picture. For instance, MRI (magnetic resonance imaging) or PET (positron emission tomography) scans are used to locate and identify tumors that may be affecting tissues outside of the bone, pressing on the nerves or the spinal cord.
Blood tests. Blood samples are taken to measure kidney and liver outlook, as well as the amount of calcium in the blood (which rises when the bones are affected), and to look for changes in the blood cells such as anemia. Other blood tests also help doctors find and measure abnormal proteins produced by myeloma cells.
Urine tests. Like blood tests, urine tests can identify abnormal proteins produced by myeloma cells.
A number of advances have made treatment of multiple myeloma much more effective. Over the past 10 years, drugs for multiple myeloma have been able to target not only the tumors in the bones but also the bone marrow where the tumors begin. Medications that help the body’s immune system destroy myeloma cells are now being used. And we are learning more about how the genetic makeup of myeloma differs from one patient to another. This will help pinpoint the right treatment for the right person.
Doctors do not usually recommend treatment for people with multiple myeloma who have no symptoms. But once patients do experience symptoms, treatment should be started. Some cancer drugs approved to treat multiple myeloma include:
Thalidomide (Thalomid) works with the body’s immune system to fight cancer. It prevents myeloma cells from binding to bone and forming tumors. It also blocks the growth of blood vessels that tumors need to grow. Thalidomide is used as a treatment for people with advanced cancer that continues to grow despite other treatments. In 2006, the FDA approved the use of thalidomide with a type of steroid called dexamethasone for newly diagnosed multiple myeloma. This combination is an effective first treatment for people with multiple myeloma, including those who later may have a stem cell transplant (discussed on page 10).
Thalidomide also is an effective treatment for older people with newly diagnosed multiple myeloma. In these patients, thalidomide is combined with the steroid prednisone and melphalan (Alkeran and others).
Possible side effects of thalidomide include blood clots, which can be prevented with low-dose aspirin and prescription blood thinners such as warfarin (Coumadin and others). Other possible side effects include constipation and fatigue. Thalidomide may also lead to nerve damage, which causes tingling, weakness or numbness, usually in the hands and feet. This condition, called peripheral neuropathy, can be treated with medications that include gabapentin (Neurontin and others), duloxetine (Cymbalta) and pregabalin (Lyrica and others). Vitamin supplements, especially B vitamins, and physical therapy also may help.
Originally approved by the FDA in 2006, lenalidomide (Revlimid) is used in combination with dexamethasone to treat people whose myeloma returns after at least one previous treatment. Doctors have found that these two drugs together can also be effective as an early treatment for young people with newly diagnosed multiple myeloma who are able to have a stem cell transplant. After treatment, low doses of lenalidomide have been shown to be effective at keeping tumors from growing. This use is known as maintenance therapy.
Side effects of lenalidomide may include low blood cell counts, which can be corrected by adjusting the dose. Like thalidomide, lenalidomide may cause blood clots.
A new form of the drug thalidomide, pomalidomide (Pomalyst), is effective when combined with dexamethasone. This combination has been studied in a number of large clinical trials and has shown long-lasting effects in about one third of people whose multiple myeloma does not respond to any other drugs. Pomalidomide stops the growth of blood vessels that feed tumors. It also boosts the immune system and may kill cancer cells directly. Pomalidomide is the most recently approved drug for treatment of multiple myeloma.
Bortezomib (Velcade) not only kills myeloma tumor cells but also overcomes the tumors’ resistance to chemotherapy. In 2005, bortezomib was approved by the FDA for the treatment of multiple myeloma tumors that have returned or do not respond to other medications. The drug is especially effective when added to other medications such as cyclophosphamide plus dexamethasone, melphalan plus prednisone or lenalidomide plus dexamethasone.
Side effects of bortezomib may include peripheral neuropathy. But in the past few years, doctors have found a way to greatly reduce the risk of nerve damage by injecting the drug under the skin. Another way to reduce side effects is to give bortezomib once a week instead of twice a week.
In 2012, the FDA approved carfilzomib (Kyprolis) to treat people whose multiple myeloma comes back or does not respond to at least two previous treatments, including bortezomib and thalidomide. Carfilzomib is the same type of drug as bortezomib, but researchers consider it to be more potent. It is given intravenously (in a vein) and does not cause neuropathy. The most common side effects of carfilzomib are fatigue, low blood cell count and blood platelet levels, shortness of breath, diarrhea and fever. In rare cases, it can cause a heart attack, so patients must be watched closely.
The Role of Stem Cell Transplants for Multiple Myeloma
Stem cell transplants are an important treatment option for people with multiple myeloma. Transplants often lead to long remissions and long survival.
For this procedure, stem cells are taken from either the person with multiple myeloma or from a donor. Keeping the stem cells on hold, doctors then give the patient high doses of chemotherapy to destroy as many myeloma cells as possible. The stem cells are then transplanted to the patient to grow into healthy blood cells, forming new blood cells and boosting the person’s defense against infection.
When a person with multiple myeloma receives his or her own stem cells, the procedure is called an autologous stem cell transplant. For some people, two autologous transplants given within six months of each other (called tandem transplants) are more effective than single transplants. When a patient gets stem cells from a donor (usually a brother or sister), the procedure is known as an allogeneic stem cell transplant.
To figure out whether a stem cell transplant is right for a patient, doctors weigh several factors: the type of myeloma, the cancer stage, how aggressive the cancer is and how it has responded to treatment before. A patient’s age and general physical health also are taken into account.
Allogeneic transplants tend to lead to the longest remissions, but they also are linked with more risks. For example, in some people, transplanted cells from the donor’s bone marrow see the patient’s body tissues as “foreign” and attack them. This serious complication in the skin, mouth, digestive system and liver is called graft-versus-host disease (GVHD). Steroids often are given to treat GVHD.
The Latest in Multiple Myeloma Research
Researchers are developing a number of new drugs to treat multiple myeloma. Some of the most promising of these new medications include:
Immunotherapy There are new antibodies and drugs becoming available that can help reveal cancer cells to the body’s immune system by blocking receptors on the T cells and in the bone marrow. Ongoing trials in myeloma will help determine which of these drugs work best and in which combinations. One type of immunotherapy is monoclonal antibodies. It’s likely there will be a monoclonal antibody for myeloma approved within the next year.
Monoclonal antibodies. Often compared to guided missiles, monoclonal antibodies zero in on cancer cells whose surface has a “target molecule.” For example, elotuzumab blocks SLAMF7, which is a substance on the surface of myeloma cells. This drug has been shown to kill myeloma cells, including those that resist other treatments.
Researchers are combining elotuzumab with lenalidomide. In clinical trials, these two medications together are showing promise in people whose multiple myeloma has come back after previous treatment.
Two other monoclonal antibodies, daratumumab, which blocks a molecule called CD38, and tabalumab, which blocks B-cell activating factor, also are showing promise. Early clinical trials suggest that these drugs can effectively destroy myeloma cells in people whose cancer has returned or did not respond to previous treatment. However, further study of these drugs is needed.
Elotuzumab and daratumumab have both been awarded “breakthrough therapy” status by the FDA, meaning that they can be approved more quickly and may be available for multiple myeloma treatment soon.
Histone deacetylase (HDAC) inhibitors. This class of drugs works by killing cancer cells or stopping their growth. Because combinations of drugs often are so much more effective than single drugs, the HDAC inhibitor vorinostat (Zolinza) has been combined with bortezomib, lenalidomide and dexamethasone in clinical trials. Ongoing studies also are testing the HDAC inhibitor ACY-1215 in combination with lenalidomide and bortezomib.
Proteasome inhibitors. Proteasomes are proteins that play a role in the development of cancer and can make myeloma cells resist chemotherapy. Proteasome inhibitors block the action of these proteins and allow chemotherapy to kill the cancer cells. Bortezomib is a proteasome inhibitor, and now there are new generations of this type of drug being studied in clinical trials.
The proteasome inhibitor ixazomib (MLN9708) has shown positive results in a clinical trial. It is taken in pill form and does not have many side effects. Oprozomib is another new oral proteasome inhibitor being studied in clinical trials. Also in this class is marizomib, which is being tested in multiple myeloma patients whose cancer has returned or has resisted other treatments.
Frequently Asked Questions
Q. Do the newer treatments cause fewer cases of neuropathy (nerve damage)?
A. Yes, the newer drug carfilzomib (Kyprolis) does not cause neuropathy. There are other newer drugs not yet approved by the FDA, such as MLN9708, that do not cause as much nerve damage as some currently approved treatments. Lenalidomide (Revlimid) and pomalidomide (Pomalyst), which are approved for treatment of multiple myeloma, also cause less neuropathy than some other drugs. It’s worth noting that a protein produced by myeloma cells can lead to neuropathy in some people. However, treatments are available that can help.
Q. How do doctors treat older people with multiple myeloma who can’t tolerate a stem cell transplant?
A. All patients with multiple myeloma can benefit from combinations of very effective newer drugs. For example, the combination of lenalidomide, bortezomib and dexamethasone at slightly lower doses can achieve remarkable success, even in older people with multiple myeloma. For the past 50 years, melphalan (Alkeran and others) and prednisone have been given to multiple myeloma patients. Today, we add newer drugs to that combination— either thalidomide (Thalomid), lenalidomide or bortezomib. There are exciting studies showing that people of all ages with multiple myeloma live much longer when treated with these drugs. So whether you’re younger and a transplant candidate or older and cannot have a stem cell transplant, everyone with multiple myeloma should be receiving these newer drugs as part of their first treatment as well as long term.
Q. Is the hope for a vaccine against multiple myeloma any closer to becoming a reality?
A. There are a couple of different kinds of vaccines that are showing great promise in people with multiple myeloma. In early studies, one type of vaccination seems to stop the myeloma cells from growing. But the most exciting work being done in this area is focusing on people with smoldering multiple myeloma—that is, cancer in the earliest stages that doesn’t need treatment yet. Because a patient with smoldering myeloma still has a strong immune system, the goal of this research is to help the patient’s own body destroy the myeloma cells. These vaccines are tailored to each person to make it much more likely that he or she will be able to fight off the cancer. The hope is that doctors can delay or even prevent the development of active myeloma.
Q. Can you suggest ways to cope with some of the side effects of my treatment?
A. As in many types of cancer, people with multiple myeloma may experience fatigue and weight loss. Some causes of fatigue, such as anemia, can be treated. There are also practical things you can do to cope with fatigue, including taking short naps, doing light exercise if possible and asking for help with tasks you find difficult or tiring. If you are experiencing weight loss, talk to your doctor about working with a registered dietitian. These professionals can suggest ways to maintain your weight with nutritious foods. If your treatment is causing nausea that discourages you from eating, your doctor can treat that symptom with medication.
Noopur Raje, MD
Associate Professor of Medicine, Harvard Medical School, and Director, Center for Multiple Myeloma, Division of Hematology and Oncology, Massachusetts General Hospital