Multiple Myeloma

Multiple Myeloma

  • Multiple Myeloma is a relatively rare, non-curable form of cancer that affects plasma cells, one of the components of blood.
  • It most commonly affects individuals between the ages of 65 and 74.
  • Each year 16,400 men and 14,370 women will be diagnosed with multiple myeloma
  • Although multiple myeloma is non-curable cancer, it is possible to manage and maintain the disease at bay while living an active life with long periods of remission.

 

Blood Plasma and Multiple Myeloma

Blood plasma is a pale yellow blood cell found in the body that holds blood cells in suspension. Plasma cells are found in the bone marrow along with white blood cells and platelets. This plasma substance makes up about 55% of blood volume and contains different components including electrolytes, glucose, proteins such as albumin and fibrinogen, growth hormones, and antibodies. These components are important for providing the body with proteins, modulating blood pressure, growing of bone and muscle among others. Plasma also serves to get rid of waste and help to clot by delivering clotting factors to the site of cuts and lesions.

One important function of plasma is to fight infection. There are two main types of cells that the immune system uses to fight infection, T cells and B cells. Plasma develops out of mature B cells that respond to infection. Plasma cells then make antibodies, also known as immunoglobulin’s, that attach to infection and act as a maker for the body to attack and destroy the foreign germs. There are five types of antibodies that a plasma cell can: IgA, IgD, IgE, IgG, and IgM.

Multiple myeloma is the third most common form of hematological malignancy after non-Hodgkin’s lymphoma and leukemia and is characterized by uncontrolled proliferation of a clone of plasma cells within the bone marrow. There are four mechanisms by which multiple myeloma affects the body: First, the cancer cells produce abnormal proteins also referred as a monoclonal production of immunoglobulins or M protein. In this mechanism, there is rapid growth and replication of one cell that contains a particular antibody. This can be identified by an increased presence of that particular antibody which can cause damage to the kidneys. Another mechanism is increased bone turnover. In this mechanism, cancer cells release damaging substances that affect the bone causing it to break down at a faster than normal rate. This results in lytic bone lesions that increase the chance for fractures. The breakdown of the bones also leads to the release of calcium which causes hypercalcemia to occur. The third mechanism of multiple myeloma is crowding of the bone marrow. Bone marrow produces different types of blood cells but in multiple myeloma, cancer cells crowd the bone marrow preventing it from creating red blood cells and platelets. The lack of blood and platelets can lead to anemia and thrombocytopenia. Lastly, the last mechanism is the decreased production of normal antibodies which can lead to increased risk of infection.

How Prevalent is Multiple Myeloma?

Multiple myeloma is the 14th most diagnosed cancer in the United States and it accounts for 1.8% of new cancer cases. There are about 30,770 new diagnoses of multiple myeloma each year with 16,400 men and 14,370 women. Myeloma is a relatively uncommon cancer with each person having a less than 1% chance of obtaining it in a lifetime. Among those diagnosed with multiple myeloma there is a 50.7% chance of surviving 5 years or more.

Fortunately over the last 20 years, the survival rates of cancer have almost doubled a trend that continues to improve with each passing year due to the advancements in treatment and medical care.

 

What Causes Multiple Myeloma?

 Age- Multiple myeloma is most frequently diagnosed among people between the ages of 65 and 74 with 29.8% of cases falling under this category.

Gender- This cancer also tends to affect men at a slightly higher rate than women.

Race- African Americans men have the highest rate of diagnosis with 15.9 men out of 100,000.

 Genetic Factors- There is a small number of cases in which family history of the disease increases the risk of the being diagnosed with Multiple Myeloma. Particularly, there is a slightly higher chance of being diagnosed with multiple myeloma of a parent or sibling is also diagnosed.

Other risk factors- Chances of getting this cancer increase if there are other plasma cell diseases present:

  • Monoclonal Gammopathy of Undetermined Significance (MGUS)- this type of inactive myeloma is known is having benign characteristics. In MGUS abnormal cells make an abnormal protein but do not result in any symptoms. Typically, this type of multiple myeloma is not treated unless symptoms occur such as damage to the kidneys and the chance of becoming active myeloma increases by 1% every year.
  • Smoldering Myeloma (SMM)- this type of inactive myeloma is more aggressive then MGUS. It is characterized by a more abnormal protein present in blood as well as more cancel cells present in the bone marrow. Therefore, there is a 50% chance that SMM will turn into active myeloma after 5 years. This type of myeloma is very closely monitored with PET-CT scans and X-rays since patients benefit from early treatment.
  • Solitary Plasmacytoma- This type of cancer refers to single tumor found usually at the bone. This type of active myeloma responds to treatment well and must be closely monitored due to a higher risk of being developed into multiple myeloma.

 

Symptoms of Multiple Myeloma

Persons with multiple myeloma may feel a series of seemingly unrelated symptoms such as:

  • Gastrointestinal issues and constipation
  • Increased thirst
  • Fatigue and loss of appetite
  • Bone pain or back pain
  • Fever
  • Kidney damage
  • Weight loss
  • Hypercalcemia
  • Blood clots
  • Bruising and bleeding gums

These symptoms are all related to each mechanism of myeloma. As mentioned, the breakdown of bones caused by the myeloma can result in bone pain, fractures, and hypercalcemia, or an increase of calcium to the body. Hypercalcemia often results in gastrointestinal issues such as constipation. Moreover, the increase of abnormal proteins damages the kidneys causing renal failure and increased thirst. Since the bone marrow is crowded with cancer cells, it can no longer create red blood cells, leading to anemia, which is characterized by fatigue; it also prevents the production of platelets which can lead to easy bruising, bleeding and other clotting issues. Lastly, since the body no longer has the ability to make normal antibodies, the patient becomes prone to infection leading to fevers and other related problems.

 

Types of Multiple Myeloma

 There are two different types of multiple myeloma each with several subgroups; inactive myeloma and active myeloma. There are also two types of inactive myeloma, hyperdiploid and hypodiploid.

Hyperdiploid myeloma refers to cells that have more chromosomes than normal. This type accounts for 45% of cases and is generally less aggressive.

Hypodiploid myeloma occurs when the cells have fewer chromosomes than necessary. This type accounts for 40% of cases and tends to be more aggressive.

 Immunoglobulin Types are myelomas that produce an abnormal about of light chains relative to heavy chains. Light and heavy chains are the components of normal antibodies. The propensity of light chains can be measured by a blood essay and normally, more light chains found in the blood indicate a more aggressive multiple myeloma.

There are certain genetic classifications that about 60% of patients with multiple myeloma fall under. It is important to establish which genetic mutations, a translocation or deletion, are present in a patient with multiple myeloma. This is because treatment varies depending on which mutation is present. A translocation indicates that the genetic material of two chromosomes gets swapped. There are three types of translocations that affect multiple myeloma: Cyclin D Translocations, MMSET Translocations, and MAF Translocations. Multiple myelomas resulting from a cyclin D translocation tend to be less aggressive and account from 1% to 16% of cases. MMSET translocations are more aggressive and account for 15% of cases. Lastly, MAF translocations cause the most aggressive type of multiple myeloma. A deletion occurs when part or all of a chromosome is deleted. This is the most aggressive type of multiple myeloma since it does not easily respond to treatment.

 

Diagnosis

The diagnosis of multiple myeloma is done through a series of lab tests, biopsies, and imaging tests. A doctor may order a complete blood count in order to ascertain the levels of red blood, white blood cells, and platelets. A patient with multiple myeloma will have a decreased count of all three of these cells. It is important to note that low counts of red blood cells, white blood cells, and platelets alone may not necessarily indicate multiple myeloma.

Another test a doctor can perform is a blood chemistry test. This test can determine the levels of important plasma components such as albumin, creatinine, and calcium. As mentioned. Multiple myeloma affects the kidneys, creatinine levels can determine kidney function, and a higher level indicated kidney dysfunction. Therefore persons with multiple myeloma may have increased levels of creatinine. The level of albumin is the protein that is found in blood. Since plasma cells are damaged, a person with multiple myeloma may have lower levels of albumin. Lastly, calcium levels can indicate if a person has hypercalcemia which is a symptom of multiple myeloma.

Urine tests are also used to determine if there is myeloma proteins present. Since the myeloma proteins are filtered through the kidneys their presence indicate multiple myeloma.

Since multiple myeloma affects the plasma and antibodies, a test to measure which type and how many antibodies are present in the body is necessary. Patients with multiple myeloma will have a high level of one of the five antibodies and low levels of the rest. The antibody that has a high level in the blood is then known as the M protein. Electrophoresis can then be used in urine and blood samples to identify which antibody is in abundance. Finding which antibody is being overproduced is an important step in the diagnosis of multiple myeloma.

Another protein that is indicative of myeloma is beta2-microglobulin. This protein is linked with the prognosis of multiple myeloma as higher levels indicate a more advanced cancer.

In rare cases where no m protein is identified as a Serum free light chain blood test can be performed. As mentioned, antibodies are made of two light chains and two heavy chains. The light chains, kappa, and lambda, are normally equally present in the blood, therefore if one is found in higher abundance than the other, it can be an indication of multiple myeloma.

Imaging is also used for diagnosis. X-rays are used to identify the state of the patients skeletal system since multiple myeloma can cause lytic lesions in the bones. An MRI which uses magnetic fields, can identify which areas of the bone marrow have been overtaken my myeloma cells or if there are any plasmacytomas (tumors). A CT scan can also be used to obtain a 3-dimensional view of the body and any tumors. Lastly, there is a PET-CT scan. First, a small amount of radioactive substance is inserted into the body.  The radioactive particle attaches to cells that use a lot of energy. Since cancer cells use a lot of energy, this scan is used to track the location of cancer cells.

A bone marrow aspiration and biopsy can also be useful for the diagnosis of multiple myeloma. With bone marrow aspiration a small amount of liquid from the bone marrow is extracted using a needle. In a biopsy, a small amount of the solid substance from the bone marrow is collected. Normally, both procedures are done at the same time. Once the samples are collected, they are examined by a pathologist who determines, through a series of tests, whether the patient has multiple myeloma. If a multiple myeloma diagnosis is made, then the cancer cells are sent for genetic testing to determine which type of mutation they have.

 

Staging

Once all of the testings is completed and a diagnosis of multiple myeloma is confirmed, a doctor will proceed with staging. Staging is a way to classify the spread and growth of any cancer. In this case, there are two staging methods that a doctor can follow. The Durie-Salmon System consists of three stages and depending on how the kidneys are affected they each stage can be classified as A or B. This system looks at the levels of hemoglobin, blood calcium, the presence of bone lesions, amount of M protein and kidney function.

  • Stage 1- is characterized by having a hemoglobin level greater than 10.5 g/dL, a normal calcium level or less than 12 mg/dL, normal bone structure with no lesions or a single plasmacytoma, low M protein production and low presence of light chains in the urine (4g/24 hours)
  • Stage 2- occurs when levels of the described above rise or fall beyond the predetermined markers but do not meet stage 3 criteria. This stage is classified as A if there is no renal failure or B if there is renal failure.
  • Stage 3- is characterized by having a hemoglobin level less than 8.5 g/dL, a calcium level greater than 12 mg/dL, three or more bone lesions, high M protein production and high presence of light chains in the urine (12g/24 hours)

Another staging system a doctor can follow is the International Staging System. This system looks at the level of beta2-microglobulin and albumin in blood. This system is based on international data in order to improve accuracy and is the most commonly used.

  • Stage 1- is characterized by an albumin and beta2-microglobulin lever greater than 3.5 g/dL.
  • Stage 2- occurs when levels are greater than stage 1 but do not meet stage 3.
  • Stage 3- is characterizes by a level of beta2-microglobulin of more than 5.5 mg/L.

Treatment

Diagnosis is based on laboratory and radiographic findings and depends on three abnormal results:

  • Bone marrow containing more than 15% plasma cells (normally no more than 4% of the cells in the bone marrow are plasma cells)
  • Generalised osteopenia and/or lytic bone deposits on plain film radiography
  • Blood serum and/or urine containing an abnormal protein.
  • Genetic abnormalities

There are several treatments available to those diagnosed with multiple myeloma. These are chemotherapy and drug therapy, stem cell transplantation/bone marrow transplant, radiation therapy, surgery and supportive care. The right combination of these options is essential for treatment and will usually involve a team of doctors, nurses, counselors, social workers and more. For individuals that do not have symptoms the best course of treatment is active surveillance since these patients have a higher risk of developing multiple myeloma. Individuals diagnosed with smoldering myeloma may see benefit from getting targeted therapy to lower this risk.

Multiple myeloma is not a cancer that can be cured however it can be successfully managed. The ultimate goal of treatment is to rid the body of cancer cells. However, there is a large focus in treating to reduce symptoms like bone pain and anemia, slow the progression of the disease, reduce tumor size, provide long periods of remission, and lengthen survival time. In order to achieve these goals, a team of doctors will decide the best course of treatment based on several factors that include the type of genetic mutations present, how aggressive the cancer is, if there are other unrelated health issues, and age. These are important factors when trying to decide how intense the treatment will be.

The first step in the treatment of multiple myeloma is induction therapy. This therapy uses a combination of targeted therapy, chemotherapy, and corticosteroids to reduce the number of myeloma cells. Targeted therapy uses molecules that specifically target cancer cells. This can result in stopping or slowing down the progression of multiple myeloma. Targeted therapy can improve the outcome of a stem cell transplant and reduce the risk of relapse among others. The goal of induction therapy is to rapidly lower the amount of cancer cells in the body.

If a patient meets the criteria, they may choose to get stem cell transplantation. Stem cells are non-differentiated cells, this means that these cells can develop into any kind of cells depending on their environmental cues. Stem cell transplantation works by taking these non-differentiated cells and placing them in bone marrow so that they develop more bone marrow cells. If an individual meets the criteria to receive a stem cell transplant the first step is to kill all the bone marrow and myeloma cells in the bone with a high dose of chemotherapy or targeted therapy. Then, healthy stem cells from a donor are placed in the dead bone marrow. These cells grow and develop into healthy bone marrow. There are three types of transplants that can be used for multiple myeloma. Autologous transplant occurs when stem cells are collected from the patient’s own body after induction therapy and are the preferred transplant for individuals older an 50 years of age. For those younger than 50 allogenic transplants can be used since side effects may be too severe. These transplants originate from a donor who may or may not be related to the patient. However, these transplants are considered experimental and are usually given during clinical trials. Lastly, syngeneic transplants are transplants that are given from one identical twin to the other.

Once a transplant is performed it is followed by consolidation therapy. This therapy involves an intense, short course of chemotherapy following the transplant. Research indicates that chemotherapy and targeted therapy after stem cell transplant can increase the effectiveness of the transplant and increase remission time.

After consolidation therapy, maintenance therapy is used to prevent the reoccurrence or slow down the development of multiple myeloma. It involves administering a drug for a long period of time at a low dose. Targeted therapy the main type of maintenance therapy and can be given corticosteroids to reduce inflammation caused by the drugs. This therapy can also be given to individuals who do not qualify to get stem cell transplantation.

In some cases, radiation therapy and surgery can be used effectively to treat or remove a solitary plasmacytoma, relieve pain and control symptoms, and prevent compression of the spinal cord and bone fractions.

The last course of treatment for multiple myeloma is supportive therapy and active monitoring. Supportive care can include medicine to support bone growth, reduce inflammation, increase the production of red blood cells, and prevent infections. This care is given to mitigate both the symptoms of the myeloma and the side effects of the therapy. It is also crucial for those individuals with high risk of getting multiple myeloma and those in remission to constantly monitor for the development, re-development, or progression of the disease.

Median survival with conventional therapy is about 3 years, whilst stem-cell transplant can achieve a median survival of more than 5 years [. Overall, the prognosis is poor with the most recent statistics from the USA showing a relative 5-year survival of 29 %. Death results from bacterial infection, renal insufficiency and thromboembolism.

 

Complications

The complications of multiple myeloma can be summarised as

  • Spinal cord compression
  • Pathological fractures
  • Secondary amyloidosis
  • Renal impairment
  • Predilection for recurrent pneumonia due to leucopaenia
  • Thromboembolism.

A pathological fracture affects about 50% of patients at some time with many of the fractures affecting the vertebral bodies. Spinal cord compression resulting from vertebral body fracture may occur in up to 25% of patients and has been described as the presenting feature in 12% of patients. Magnetic resonance is the imaging investigation of choice.

The Takeaway

­The symptoms of multiple myeloma, to the untrained eye, may seem unrelated therefore it is important for an individual to not ignore their body, especially past the age of 65. Early detection is vital to the management and survival of this cancer. Although multiple myeloma is a non-curable cancer, it is possible to manage and maintain the disease at bay. With the advancement of medicine, it is possible to live an active life with long periods of remission. However, patients that have a high risk of getting multiple myeloma have a responsibility to closely monitor their health. Though there are no environmental health risks to obtaining multiple myeloma, health issues like diabetes or kidney disease can affect an individual’s options for treatment. Due to the complexity of the disease, it is crucial to have any and all avenues of treatment open.

 

The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.

Sources:

  • American Cancer Society
  • The National Cancer Institute
  • National Comprehensive Cancer Network
  • American Academy of Gastroenterology
  • National Institute of Health
  • MD Anderson Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • American Academy of Hematology

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