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Multiple Myeloma: The Basics

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Eric Shinohara, MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: February 23, 2008

What is a plasma cell?

Plasma cells are a mature type of B lymphocyte that usually make up less than 5% of the cells in the bone marrow. The bone marrow is a spongy material found primarily in the center of long bones. Bone marrow is comprised of a variety of cells, which gradually mature to form:

• Red blood cells (also known as erythrocytes), which carry inhaled oxygen from the lungs to other organs and carry carbon dioxide from the organs to the lungs to be exhaled.
• Platelets (also known as thrombocytes), which form clots.
• White blood cells (also known as leukocytes), which are comprised of granulocytes, lymphocytes, and monocytes, each of which has a different role in the immune system. Lymphocytes are made up of B and T lymphocytes. Plasma cells are a mature form of B-lymphocytes, which produce antibodies.

There are a large number of different pathogens, such as bacteria or viruses, which can attack your body. When your immune system fights an infection, it needs to make an antibody that specifically targets the pathogen causing that infection. Each plasma cell can only produce one specific kind of antibody. Individual plasma cells can then divide repeatedly to form copies of themselves, known as clones. This group of clonal plasma cells can produce large amounts of a single kind of antibody to fight the infection. There are several thousand different populations of plasma cell clones, which then allow the immune system to make a wide variety of antibodies to target the many different kinds of pathogens. Antibodies coat the pathogen that they are built to attack, and thus make it easier for other immune cells to also attack the pathogen. Cancer of the plasma cells is called multiple myeloma.

What is multiple myeloma?

Multiple myeloma is a disorder in which one population of clonal (identical) plasma cells starts to reproduce uncontrollably. These cells are known as malignant plasma cells, or myeloma cells. Myeloma cells produce large amounts of one type of antibody, which is known as the monoclonal protein or M-protein. As the myeloma cell population grows, it begins to overcrowd the bone marrow and prevents normal reproduction of the other blood cell types in the bone marrow. This also negatively affects the immune system because the bone marrow now predominantly produces only one type of antibody, and can no longer effectively target all pathogens. Thus there is increased risk of infection in patients with multiple myeloma. Anemia results when multiple myeloma prevents the bone marrow from producing enough red blood cells. As the plasma cells continue to multiply, they can invade and damage other organs. The monoclonal protein produced by plasma cells can also damage organs, specifically the kidneys. The acronym “CRAB” is often used to describe symptoms associate with organ damage by multiple myeloma: Hyper Calcemia (High levels of calcium in the blood, caused by bone lesions), Renal insufficiency (kidney failure), Anemia (Low red blood cell counts), and Bone lesions.

Am I at risk for multiple myeloma?

Approximately 14,600 people are diagnosed with multiple myeloma a year in the United States. Multiple myeloma comprises approximately 1% of all cancers and comprises about 10% of all “blood cancers”. The rate of multiple myeloma in African Americans is twice that seen in white Americans. Rates appear to be lower in Asians. This disease occurs slightly more commonly in men than in women, and the average age at diagnosis is 60 and people younger than 40 rarely develop this disease.

At this time, the cause of multiple myeloma is not well established. However, there appear to be several factors which increase the risk of developing multiple myeloma, such as extensive exposure to radiation, chemical resins, organic solvents, pesticides, and herbicides. There is also a herpes virus, Human Herpes Virus 8 (HHV-8), which is thought to be related to the development of multiple myeloma. People with first-degree relatives, such as a mother or brother, who have multiple myeloma, may also be at increased risk for developing the disease. However, a clear genetic mutation related to multiple myeloma has not been discovered.

People who have a condition known as Monoclonal Gammopathy of Unknown Significance (MGUS) are at increased risk for developing multiple myeloma. People with MGUS develop an increased population of clonal plasma cells, but not to the degree seen in multiple myeloma; these patients do not otherwise have symptoms associated with multiple myeloma. However, people with MGUS do have a 1-2% annual risk of developing multiple myeloma or a related malignant disease, such as leukemia or lymphoma. In light of this risk, when someone is first diagnosed with MGUS, it is recommended that blood tests be performed to check for elevated monoclonal protein levels every three months initially.

How can I prevent multiple myeloma?

Unfortunately, because the exact cause of multiple myeloma is unknown, there are no specific guidelines for the prevention of multiple myeloma. Limiting exposure to radiation, chemical resins, organic solvents, pesticides, and herbicides may decrease the risk for developing multiple myeloma.

People with MGUS should see their physician regularly to check for progression to multiple myeloma.

What Screening Tests are Available?

Multiple myeloma is very rare, accounting for only 1% of all cancers diagnosed in the United States, and thus there are no effective screening tests available. However, there are some basic tests which can help with the diagnosis of multiple myeloma. Almost all people with multiple myeloma have monoclonal proteins in their blood or urine, and there are effective tests available to check for them. Other blood tests to check for kidney disease, high calcium levels, and low red blood cell counts (anemia) can also be used to test for the disease. X-rays can be used to detect erosions in bones caused by multiple myeloma.

What are the Signs of Multiple Myeloma?

The increased number of myeloma cells, as well as the high levels of monoclonal protein that they produce, can cause several symptoms in people with multiple myeloma:

Bone Pain: Multiple myeloma appears to increase the activity of osteoclasts (which break down bone) and decrease the activity of osteoblasts (which help to build new bone). Up to 60 % of people with multiple myeloma have bone pain at the time of diagnosis, which is typically in the back or chest, but can occur in the leg or arm bones. Pain is usually associated with movement and is not present at night, unless the person moves. Multiple myeloma can cause osteoporosis, or generalized weakening of the bone. This makes people with multiple myeloma more vulnerable to fractures. Often fractures can occur with little or no trauma due to the weakening of the bone. A common place where these types of fractures can occur is at the vertebral bodies, which make up the spine. Fractures of the spine can lead to a decrease in height as well as pain or numbness if nerve roots coming out of the spinal cord are injured. Multiple myeloma can also cause bone erosions, which occur when small areas of bone are eaten away. On x-ray, erosions can make the bone appear patchy with the areas of bone loss appearing darker. At diagnosis, about 75% of people with multiple myeloma will have evidence of fractures, bone erosions, or osteoporosis on x-ray. Bisphosphonates, a class of medication which strengthens bone, can be used to help improve bone weakness.

High Calcium Levels: Bones have high calcium content and as they are broken down, a large amount of calcium is released into the blood. This condition is also known as hypercalcemia and can occur in up to 30% of people with multiple myeloma. High level of calcium in the blood can cause GI symptoms, such as nausea, vomiting, and constipation. It can affect the urinary system and cause increased urination as well as kidney stones due to the higher calcium concentration in the urine. In can also affect how you feel generally by causing headaches, fatigue, weakness, confusion, and depression.

Low Red Blood Cell Count: Also known as anemia. About 70% of people with multiple myeloma will have anemia at the time of diagnosis. As the bone marrow becomes overcrowded with myeloma cells, red blood cells cannot be produced in adequate numbers. There are not enough red blood cells in the blood, and this decreases the body's ability to transport oxygen to the tissues and to transport carbon dioxide to the lungs. Due to this, people with anemia often appear pale and have weakness and fatigue.

Increased Blood Thickness: Also known as hyperviscosity syndrome. The myeloma cells produce a large amount of monoclonal protein, which can thicken the blood to the point where the blood has problems circulating properly in smaller blood vessels. The most common symptom associated with hyperviscosity syndrome is an increased risk of bleeding. People may have spontaneous bleeding of their gums, nose, or bowel during bowel movements. People may also notice continued bleeding after minor procedures, such as dental work. People may also notice that they bruise easier than they do normally. Symptoms related to the neurological system are also frequently seen in hyperviscosity syndrome. These include changes in vision, such as blurriness or loss of vision, hearing loss, numbness, difficulties with balance, headache, tingling, sleepiness, and even seizures. The thicker blood can also affect the heart and cause symptoms of heart failure, where the heart cannot pump blood well. People with heart failure often have fatigue and difficulty breathing.

Neurologic Impairment: The spinal cord communicates with the body through a network of nerves. Nerve roots are large bundles of nerves which conduct signals into and out of the spinal cord. Compression can lead to irritation and inflammation of the nerve roots, which is also known as radiculopathy. Multiple myeloma can weaken bones leading to fractures of the vertebral bodies, which in turn can compress the nerve roots and cause radiculopathy. These nerves control body movement as well as sensation, thus symptoms of radiculopathy are numbness, tingling, shooting pains, and weakness. The spinal cord, which is protected by the surrounding vertebral bodies, can be compressed by collapsing bone or by the growth of a tumor into the spinal canal. This can occur in 5-10% of patients with multiple myeloma. Compression of the spinal cord is a medical emergency, and immediate medical care is necessary to decompress the cord and prevent permanent nerve damage. The most common symptom associated with cord compression is severe back pain. Other symptoms include weakness, numbness, tingling, and loss of bowel or bladder control.

Increased Risk of Infection: Myeloma cell overgrowth in the bone marrow prevents normal plasma cells from producing antibodies. It also prevents adequate numbers of other white blood cells from being formed in the bone marrow. Due to this, people with multiple myeloma are more susceptible to infections, most commonly by bacteria such as streptococcus pneumoniae.

Plasmacytoma: A plasmacytoma is a collection of myeloma cells that builds up either in the bone or other tissues. The skin can develop plasmacytomas, which can cause purplish lumps. Reports have shown that about 12% of people can develop plasmacytomas in the ribs. Very rarely, plasmacytomas can develop in the brain.

Kidney Failure: Kidney function can be measured by checking the level of a compound called creatinine in the blood. About 25-50% of people with multiple myeloma have an increased level of creatinine in their blood, indicating kidney failure. Multiple myeloma causes kidney failure due to the large amount of monoclonal protein produced by myeloma cells. Renal failure can also be caused by fragments of antibodies improperly building up in the kidneys, causing a condition known as primary amyloidosis. These proteins collect in the kidneys and prevent the kidneys from properly filtering blood to create urine. High blood levels of calcium caused by bone breakdown can also cause kidney failure. Caution should be used when receiving scans, as contrast material from these scans can cause or worsen renal failure in patients with multiple myeloma.

How is Multiple Myeloma Diagnosed?

There are a specific set of criteria for the diagnosis of multiple myeloma, to help distinguish it from other blood disorders that have similar characteristics to multiple myeloma, such as MGUS, smoldering myeloma, primary amyloidosis, and metastatic carcinoma. The following are the minimal criteria required for diagnosis of multiple myeloma in patients who have symptoms consistent with multiple myeloma as described above:

• The presence of monoclonal protein in the blood and urine. As many as 97% of people with multiple myeloma will have monoclonal protein in their blood or urine during the course of their disease. Blood and urine samples can be tested for the presence and amount of monoclonal proteins.
• Bone marrow biopsies from people with multiple myeloma must show that at least 10% of the bone marrow cells are plasma cells. Alternatively, if a plasmacytoma is found, this criterion can also be met. Bone marrow biopsies can usually be preformed as an outpatient procedure without general anesthesia. It involves inserting a needle, usually into the hipbone, and the removal of a small sample of bone marrow.
• Bone lesions seen on X-Ray. Radioactive scans such as bone scans and PET scans appear to be inferior to X-rays in finding lesions.

Often, when people first present with multiple myeloma, all of these criteria are not met. Hence tests to check for these criteria may need to be repeated to confirm the diagnosis of multiple myeloma.

There are additional tests which can be used to help diagnose multiple myeloma. In addition to detecting plasma cells in the bone marrow, up to 80% of people with active multiple myeloma will have myeloma cells in their blood stream. A plasma cell labeling index (PCLI) test can also be used to help determine if someone has multiple myeloma, but it is not always positive.

What are the Treatments for Multiple Myeloma?

There are several factors which can predict how aggressive the multiple myeloma will behave. Blood tests for two proteins, beta-microglobulin and albumin, are used to determine severity of disease. High levels on beta-microglobulin and low levels of albumin usually indicate more aggressive multiple myeloma. Levels of other compounds in the blood such as lactate dehydrogenase (LDH), C-reactive protein, red blood cell levels, and calcium levels, among others, can also be measured to determine the severity of disease. There are tests known as cytogenetic tests which can check for several chromosomal abnormalities, which are abnormalities in how the DNA is structured. Some of these abnormalities have been associated with a better prognosis and some with a worse prognosis. A staging system is used to combine multiple test results to predict how aggressive the disease may be in someone with multiple myeloma and which treatments will work best. There are two staging systems used in Multiple Myeloma:

• The International Staging System for multiple myeloma is broken into 3 stages based on albumin and beta-microglobulin levels:
  • Stage I: albumin greater than or equal to 3.5 g/dl and beta-microglobulin level of less than 3.5 mg/dl
  • Stage II: albumin less than 3.5 g/dl and beta-microglobulin less than 3.5 mg/gl or beta-microglobulin 3.5-5.5 mg/dl
  • Stage III: beta-microglobulin > 5.5 mg/dl
• The Durie-Salmon staging system uses a more complex system taking into account several test results, and is broken into Stage I (low), Stage II (intermediate), and Stage III (high).

People who develop multiple myeloma can present with smoldering multiple myeloma, which is characterized by increased plasma cells in the bone marrow and the presence of monoclonal proteins, without the symptoms of multiple myeloma. Often it can be 2-3 years before symptoms develop, and there have been no studies that have shown a benefit to early treatment. Therapy is usually not started in patients with smoldering multiple myeloma or asymptomatic stage I disease. Generally, therapy for Stage II or III multiple myeloma starts with “conventional chemotherapy”, which is traditional chemotherapy. Stem cell transplantation is a mainstay of treatment now as well, usually after conventional chemotherapy, but some studies have shown it may be beneficial as initial therapy. The preferred initial treatment for people who are thought to be potential transplant is with thalidomide and dexamethasone or lenalidomide and dexamethasone. Prior regimens used Melphan, an alkylating chemotherapywhich can damage the stem cells, causing problems with collection of stem cells for future transplant.

Thalidomide was originally used as a sedative until it was found to cause birth defects when used during pregnancy. Clinical trials initially demonstrated that thalidomide was highly effective when used alone to treat multiple myeloma relapses, and recently studies have shown that it works even better when combined with other drugs, such as dexamethasone and melphan. Thalidomide is now an integral part of the treatment of multiple myeloma relapses and now, as mentioned above, is an important component of initial treatment of multiple myeloma. However, there are several side effects associated with thalidomide, including fatigue, constipation, neuropathy, and rash. A serious complication associated with thalidomide is Deep Vein Thrombosis (DVT), which only happens in 1-3% of people on thalidomide. However, when used in combination with dexamethasone, this can increase to 10-15%, and if used in combination with dexamethasone and doxorubicin, (another chemotherapeutic drug), this number can increase to 25%. DVT in the leg is concerning because the blood clot in the leg can travel to the lungs, causing a serious condition called pulmonary embolus. A pulmonary embolus can cause cough, chest pain, shortness of breath, and even death. Lenalidomide is a derivative of thalidomide, without some of the side effects, such as fatigue, constipation, neuropathy, and birth defects. Early studies have shown that it may be more potent than thalidomide.

In people who are 65-75 years old and who are not candidates for transplant, treatment with Melphan, prednisone and thalidomide is recommended. If this is not tolerated well, treatment can be performed with Melphan and prednisone. In people older than 75 and who are not candidates for transplant Melphan and prednisone is recommended. People with certain types of genetic mutations which are known as 13q14, among others, generally do not respond well to chemotherapy or transplant and clinical trials are generally recommended for these people.

It may take 6-12 months to see if there is a response to treatment using blood tests. Generally, 50-60% of patients have at least a partial response to this treatment with an average survival of 3 years after treatment. Side effects include reduced blood counts, which can cause increased risk of infection, bleeding, and fatigue. Fibrosis of the lungs can also occur and cause shortness of breath. Some people report skin sensitivity while on this treatment.

Recently, more aggressive chemotherapy regimens have been developed and have shown a faster response, but do not appear to increase survival. They are used in the event that a person has advanced disease with severely debilitating symptoms and needs a rapid response. In these cases, there are several treatment options, including treatment with vinblastine, doxorubicin, and dexamethasone (VAD) among others. However, these treatments tend to be more toxic and as more effective multiple myeloma regimens have become available, there use has declined. The goal of chemotherapy is to induce a plateau phase, or a period where the disease shows no signs of progressing. It is not clear whether consolidation chemotherapy, after a plateau phase has been achieved, helps slow progression of the disease or increase survival. Generally all of these treatments do not cure multiple myeloma, but can prolong survival with the disease. Hence, even after chemotherapy it is felt that some malignant cells remain. It is possible that maintenance chemotherapy may not be of benefit and simply cause resistance of these remaining malignant cells. Stem Cell or Bone Marrow transplant: In this type of treatment, physicians attempt to destroy as many myeloma cells in the body as possible, and then replace them with normal stem cell harvested from the bone marrow or the blood. People who are able to have a transplant are generally younger than 70 and in good health; however, it can be considered in those older than 70 who are healthy. People who have early stage multiple myeloma are usually not candidates for transplant. Unfortunately, like intensive chemotherapy, transplants do not appear to cure the disease, but can prolong survival.

There are two types of transplants: autologous transplants, where the stem cells to be transplanted come from the person with multiple myeloma, or allogeneic transplants, where stem cells are harvested from a donor who has been matched with the person with multiple myeloma. It is important to note that autologous transplants increase the chances of what is called a complete response compared with chemotherapy alone, but rarely lead to cure.

Autologous transplants have been shown to increase survival and the amount of time that people are free of symptoms. Up to 50% of people with multiple myeloma may be candidates for autologous transplant, but it should be noted that autologous transplants have serious side effects, with a mortality rate of approximately 1-2%. About 50% of people can make it through transplantation as an outpatient. Generally, survival is increased by about 12 months with autologous transplant, as compared with chemotherapy alone. People who have had prior treatment for a long period of time using a class of chemotherapy drugs know as alkylating agents may not be candidates for allogeneic transplant. This is because it may not be possible to harvest enough stem cells in these people for transplant. Hence, it is important to have stem cells harvested prior to any therapy with alkylating agents.

Some people may be eligible for a double transplant, or tandem transplant. Here, after the first stem cell transplant, a second one is done within six months. It has been suggested that this can lead to greater complete response rates and longer survival compared with a single transplant. Up to 51% of people can have a complete response, and there appears to be increased long-term survival with the tandem transplant as compared with the single transplant, however this is still being studied. The development of mini-transplants, where low doses of chemotherapy are used after stem cell harvest to kill myeloma cells prior to autologous transplant, have been found to be most effective when used in tandem after a regular autologous transplant.

About 5-10% of people with multiple myeloma may be candidates for allogeneic stem cell transplants. One advantage of allogeneic over autologous transplant is that even after induction chemotherapy, there are often still malignant cells in the blood. Inevitably, during harvesting of stem cells, some of the remaining malignant cells are accidentally collected. Allogeneic cells come from a donor with no malignant cells; hence the stem cells contain no malignant cells. Allogeneic cells also cause graft versus host disease, which can be good and bad. The grafted stem cells form the new immune system for the person receiving the transplant. Unfortunately, this new immune system may perceive the host tissues (the organs of the patient who received the transplant) as foreign and attack them. However, the new immune system also recognizes the myeloma cells as foreign and can attack any myeloma cells that are left. Hence, there has to be a careful balance when suppressing the new immune system to protect organs but also allow the new immune system to destroy left over myeloma cells. Another complication of allogeneic transplants is that the donor tissue must be matched to the recipient. Sometimes family members can be donors, but in the event that is not possible, the national registry of bone marrow donors can be searched for a match. Graft versus host disease can cause organ failure, and immunosuppression to control graft versus host disease can increase the risk of infection.

Treatment is given in three phases for transplants: induction therapy -> consolidation therapy-> maintenance therapy:

• Induction therapy: Several combinations of various agents can be used as induction therapy. Dexamethasone, vincristine and doxorubicin can be used in combination, or else Dexamethasone with thalidomide or Dexamethasone alone can be used. Occasionally total body radiation can be used. These treatments are used to try to decrease the number of myeloma cells prior to harvesting stem cells from the blood or bone marrow.
• Consolidation therapy: People are then treated with high dose chemotherapy, such as melphan to destroy as many myeloma cells as possible. The harvested stem cells are then infused and take root in the bone marrow and begin to grow and replace the old marrow.
• Maintenance therapy: Used to try to maintain remission, people can be treated with steroids, thalidomide, or no treatment may be necessary.

Almost all patients with multiple myeloma are at risk for an eventual relapse. Generally, for relapses that occur within the first six months, another cycle of the same initial chemotherapy is given. Alternatively, in people who have had stem cells harvested and saved, an autologous stem cell transplant can be used as salvage therapy..

Clinical trials have shown that bortezomib is effective in treating unresponsive multiple myeloma or relapses of multiple myeloma. Bortezomib is approved for use for people who have already had prior treatment with first line therapies (conventional chemotherapies), but has not been approved for first line use as of yet. Trials to see if it can be used effectively with thalidomide and other chemotherapies, as well as if it can be used as initial therapy, are ongoing. Side effects include GI symptoms, fatigue, low blood counts, and nerve damage.

Recent studies have focused on interferons, which are proteins normally produced by the body in response to infection. Early studies suggested that if a person responded well to chemotherapy, interferon could prolong the response to treatment and improve survival. However, other studies have not confirmed this.

Radiation therapy can be used for local treatment to relieve bone pain or to prevent fractures. Orthopedic surgery may also be required to fix bones, which are fractured or weakened. Radiation can also be used to shrink plasmacytomas which are causing symptoms. Generally, a fairly low dose of radiation can be used to good effect.

Follow-up Testing

Follow up appointments to check for recurrence are very important in people with multiple myeloma. Generally, after completion of treatment your doctor may ask you to follow up every one to three months. The follow up visit usually entails a physical exam, X-Rays, blood tests and urine tests. X-Rays are used to check for bone disease and blood and urine tests are used to check for the level of monoclonal proteins. Blood tests to check kidney function, calcium levels, and cell counts are also done routinely. Repeated bone marrow biopsies may also be needed to check for myeloma cells in the bone marrow.

References

Abeloff M., Armitage J., Niederhuber J., et al. (Eds): Clinical Oncology 3 rd Edition. (2004). Elsevier Churchill Livingstone, Philadelphia, Pennsylvania.

The American Cancer Society Multiple Myeloma and Other Plasma Cell Neoplasms. www.cancer.org

Kyle R., Rajkumar S. (2004) Multiple Myeloma. The New England Journal of Medicine, 351:1860-1873.

The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Myeloma. www.nccn.org.

Rajkumar S., Gertz M., Kyle, R. et al. (2002) Currrent Therapy for Multiple Myeloma. Mayo Clinic Proceedings, 77:813-822.

Rajkumar S., Kyle R. (2005) Multiple Myeloma: Diagnosis and Treatment. Mayo Clinic Proceedings, 80:1371.