Multiple myeloma

Multiple myeloma is a cancer affecting the plasma cells. Plasma cells are cells that produce antibodies that help the body fight against various infections.

In Multiple myeloma, when these healthy plasma cells change and grow out of control, they not only lower one’s ability to fight against infections but they also crowd and suppress the growth of other normal cells in the bone marrow; the red blood cells, the white blood cells and platelets, also resulting in anemia and bleeding tendencies.

The following factors can raise a person's risk of developing myeloma:

• Age: Myeloma occurs most commonly in people over 60. The average age at diagnosis is 70. Only 2% of cases occur in people under 40.
• Race: Myeloma occurs twice as frequently in black people than in white people. The reasons why are unclear, although the disease appears to also be more common in the Middle East, North Africa, and the Mediterranean.
• Exposure to radiation or chemicals: People who have been exposed to radiation or to asbestos, benzene, pesticides, and other chemicals used in rubber manufacturing may be at higher risk for developing myeloma. People often exposed to wood products, such as carpenters, furniture makers, and paper makers, are also at higher risk. There is also a high incidence of myeloma among professional firefighters and those exposed to herbicides, including Agent Orange.
• Personal history: People with a history of a solitary plasmacytoma of the bone are at greater risk for developing multiple myeloma.
• Monoclonal gammopathy of undetermined significance (MGUS): A person with a small amount of M protein in their blood has a 1% to 2% chance of developing myeloma, lymphoma, or another blood-related cancer called Waldenstrom’s macroglobulinemia per year.

Some people with multiple myeloma do not have any symptoms “asymptomatic”. Others may experience a number of different symptoms and signs.

• Anemia is a low level of red blood cells. This happens when myeloma plasma cells suppress or crowd out healthy red blood cells.
• Fatigue is usually caused by anemia or other factors associated with myeloma, such as abnormal cytokine production.
• Bone pain is a common symptom. Myeloma cells grow in the bone marrow and cortical bone, causing local bone damage or generalized thinning of the bone, which is called osteoporosis. This makes the bone more likely to break. The back or ribs are the most common sites of bone pain, but any bone can be affected. The pain is usually worse when someone moves and at night. If cancer is in the spine, the vertebrae (the individual bones that make up the spine) can collapse, which is known as a compression fracture. In advanced multiple myeloma, a person may lose inches from their height due to compressed vertebrae over the course of their illness.
• Pain, numbness, and weakness can sometimes happen when collapsed vertebrae press against the spinal cord or pinch a nerve coming out of the spine.
• Too much M protein may lead to kidney damage or failure, an important issue to be aware of. Kidney damage in its early stages often does not cause any symptoms and may only be diagnosed through blood and urine tests. When the kidneys begin to fail, symptoms include itching, weakness, fatigues, shortness of breath, muscle cramps, nausea, appetite loss, trouble sleeping, urination changes, anemia, and swelling of the legs, feet, or ankles.
• Hypercalcemia is a high level of calcium in the blood that can arise as a result of bone breakdown. It can cause drowsiness, constipation, and kidney damage.
• Symptoms of weight loss, nausea, thirst, muscle weakness, and mental confusion are related to kidney failure, hypercalcemia, or other imbalances in blood chemicals.
• Fever and infections, especially of the upper respiratory tract and lungs, may arise as a result of the lower immunity that people with myeloma have. This makes it harder to fight infection.
• Blood clots, nosebleeds, bleeding gums, bruising, cloudy vision caused by hyperviscosity, which is thickened blood, and low platelets are other symptoms of multiple myeloma.

Not all tests listed below will be used for every person. Your doctor may consider these factors when choosing a diagnostic test:

• The type of cancer suspected
• Your signs and symptoms
• Your age and general health
• The results of earlier medical tests

The following tests may be used to diagnose multiple myeloma:

Blood and urine tests: Myeloma cells often secrete the antibody monoclonal immunoglobulin, known as M protein. M protein levels in a patient's blood and urine are used to determine the extent of the disease and to monitor the effectiveness of treatment. In some people, the myeloma cells only secrete part of the antibody, which is called the light chain. The amount of M protein in the blood or urine is measured by serum protein electrophoresis (SPE or SPEP) or urine protein electrophoresis (UPE or UPEP).

The amount of free light chains in the blood can be measured before the blood is filtered by the kidneys. This test is called a serum free light chain assay. When a light chain is found in the urine, it is called the Bence Jones protein.

The levels of serum albumin and serum beta-2 microglobulin (β2-M) are also measured using blood tests. These results are important for determining the stage of the myeloma. Blood tests are also used to measure kidney function, calcium levels, and blood cell counts for possible anemia and other low blood counts.

X-ray: X-rays taken as part of the doctor’s evaluation of the patient’s skeletal system are typically the first step in evaluating bones when myeloma is suspected or diagnosed.

Magnetic resonance imaging (MRI): An MRI can show if normal bone marrow has been replaced by myeloma cells or by a plasmacytoma, especially in the skull, spine, and pelvis. The detailed images may also show compression fractures of the spine or a tumor pressing on nerve roots.

Computed tomography (CT ) scan: A CT scan creates a detailed, cross-sectional view that shows any abnormalities or tumors in soft tissues. A computer then combines these pictures into a 3-dimensional image of the inside of the body.

Positron emission tomography (PET) or PET-CT scan: A PET scan is usually combined with a CT scan, called a PET-CT scan. But you may hear your doctor refer to this procedure just as a PET scan. A small amount of a radioactive sugar substance is injected into the patient’s body. This sugar substance is taken up by cells that use the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance to produce images of the inside of the body.

Bone marrow aspiration and biopsy: These 2 procedures are similar and often done at the same time to examine the bone marrow. Bone marrow has both a solid and a liquid part. A bone marrow aspiration removes a sample of the fluid with a needle. A bone marrow biopsy is the removal of a small amount of solid tissue using a needle. This is important for making a diagnosis of myeloma.

A pathologist then analyzes the sample(s). The genes in the myeloma are examined by cytogenetics and a special testing called fluorescent in situ hybridization (FISH). Cytogenetics is a type of genetic testing that is used to analyze a cell's chromosomes. These tests determine the genetic makeup of the myeloma and whether it is standard or high risk. A common site for a bone marrow aspiration and biopsy is the pelvic bone, which is located in the lower back by the hip.

Molecular testing of the tumor

Your doctor may recommend running laboratory tests on a tumor and/or bone marrow sample to identify specific chromosomes (cytogenetics), genes (FISH or genomic sequencing; see above), proteins, and other factors unique to the tumor as mentioned above. Results of these tests can help determine your treatment options.

• Cytogenetics: Cytogenetics, which is the study of genetic changes in cells, and molecular studies may be performed on a tissue sample removed during a biopsy to find out how aggressive the cancer is. In myeloma, the genes in plasma cells are routinely studied using the FISH test to identify standard and high-risk disease. This may help guide treatment.
• Minimal residual disease (MRD): As treatments have become increasingly effective in treating myeloma, new approaches to measure how well a treatment works have been developed, including MRD. The principle is that the harder it is to detect the disease, the better. If disease is found (called "MRD positive"), further treatment may be offered to suppress the disease further.

For myeloma, it is important to begin with whether the patient is experiencing symptoms. It is common to classify people with newly diagnosed myeloma as being either:

• Asymptomatic which means the person does not have symptoms and signs of the disease. Patients without symptoms are generally watched closely without specific treatment, although therapies are sometimes offered to stop the disease from growing or spreading. This is called active surveillance for smoldering myeloma
• Symptomatic, which means the person has symptoms and signs of the disease. Patients with symptoms, or who are about to develop symptoms, need treatment.

The symptoms related to myeloma are described with the mnemonic acronym "CRAB," with each letter corresponding to a symptom:

• Calcium levels are increased, which is known as hypercalcemia. This is defined as a serum calcium level greater than 11.0 mg/dL.
• Renal, or kidney, problems, identified as a creatinine greater than 1.3 mg/dL.
• Anemia is defined as having a low hemoglobin level, which is less than 10 g/dL.
• Bone pain or lesions, including:
  
  • Lytic lesions (areas of bone damage)
  • Osteoporosis (thinning of the bones)
  • Compression fracture of the spine

Other symptoms include symptomatic hyperviscosity (thickening of the blood), amyloidosis, and repeated serious bacterial infections (more than 2 episodes in 12 months). Patients with CRAB features require active treatment.

People may also be treated, even if they do not have CRAB features, if any of the following conditions apply:

• More than 60% of the cells in the bone marrow are plasma cells.
• The involved-to-uninvolved free light chain ratio is greater than 100, based on serum testing, with absolute values greater than 100 mg/L or 10 mg/dL. The light chain is a fragment of an antibody and is the product of cancerous plasma cells. The light chains are classified as kappa or lambda. The plasma cells of myeloma will secrete excess amounts of either of these light chains.
• Bone lesions seen on MRI or PET-CT imaging.

International Staging System

The International Staging System (ISS) is now used more commonly to classify multiple myeloma. It defines the factors that influence patient survival. The ISS is based on data collected from people with multiple myeloma from around the world. The system has 3 stages based on the measurement of serum albumin and the levels of serum β2-M.

Recent efforts have been made to further classify myeloma based on patterns of gene expression in myeloma cells. This is an ongoing area of research.

Stage I: β2-M <3.5 mg/L with a serum albumin of 3.5 g/dL or more

Stage II: Either of these 2 criteria:

• β2-M between 3.5 mg/L and 5.5 mg/L
• Albumin <3.5 g/dL

Stage III: β2-M >5.5 mg/L

This system has recently been revised to include serum lactase dehydrogenase (LDH) and high-risk gene abnormalities defined by the FISH test. This is called the revised-ISS (or R-ISS). It is most commonly used to predict prognosis. Higher blood levels of LDH indicate a poorer prognosis. Abnormalities of chromosomes (as defined by the results of cytogenetic testing) in the cancer cells may also show how aggressive the cancer is and influence how the disease progresses.

Recurrent or relapsed myeloma: Myeloma that returns after a period of being in control after treatment is called recurrent myeloma or relapsed myeloma. If there is a recurrence, the cancer may need to be staged again (called re-staging) using one of the systems above.

Other classifications

Some people have no symptoms of myeloma, but they may have abnormal plasma cells producing M protein. Doctors generally monitor these people closely, and active treatment does not begin unless the person starts to experience symptoms and/or shows signs of damage to major organs, called end-organ damage; this is so-called symptomatic myeloma.

Monoclonal gammopathy of undetermined significance (MGUS)

This condition occurs when people have a low level of M protein, meaning there are small amounts of abnormal plasma cells but they do not have any other evidence of myeloma, such as bone damage, excessive plasma cells in the marrow, or low numbers of components of the blood count, such as red blood cells, white blood cells, and/or platelets. People with MGUS have a 1% chance per year of developing myeloma or, rarely, other types of blood problems such as chronic lymphocytic leukemia (CLL), lymphoma, Waldenstrom's macroglobulinemia, or amyloidosis. For this reason, a person with MGUS should be regularly monitored for health changes by their doctor.

Smoldering multiple myeloma (SMM) or asymptomatic myeloma

People who are diagnosed with SMM have higher levels of M protein and more plasma cells in the bone marrow than people with MGUS (10% to 60% of all cells in marrow are plasma cells). However, there is still no evidence of symptoms or signs of myeloma, such as significant bone disease or anemia. A person with SMM may be prescribed bisphosphonates for symptoms of osteoporosis or osteopenia and/or a new treatment being studied in a clinical trial. Osteopenia is a condition in which a person has a low density of bone minerals. Most people with SMM eventually develop myeloma. For this reason, the health of people with SMM should be closely monitored by their doctors, who may recommend starting treatment when there is progression of disease and especially to patients who are at risk of developing symptoms within 18 months to 2 years.

Prognosis

The ISS of myeloma gives information about prognosis and predicts the person’s chance of recovery. Researchers are also looking at other ways to predict prognosis for people with multiple myeloma. Some of the current approaches for evaluating prognosis include:

• High levels of β2-M may indicate that a large number of myeloma cells is present and that kidney damage has occurred. The level of this protein increases as myeloma becomes more advanced.
• Lower amounts of serum albumin may indicate a poorer prognosis.
• Higher blood levels of LDH indicate a poorer prognosis.
• Abnormalities of chromosomes (cytogenetics) in the cancer cells may show how aggressive the cancer is. This approach to testing the genetics of the myeloma include FISH and even the testing of individual gene mutations.
• A plasma cell labeling index can be done in a specialized laboratory using bone marrow samples to find out how fast the cancer cells are growing.

In cancer care, different types of doctors often work together to create a patient’s overall treatment plan that combines different types of treatments. This is called a multidisciplinary team. Cancer care teams also include a variety of other health care professionals, including physician assistants, nurse practitioners, oncology nurses, oncology social workers, pharmacists, counselors, dietitians, and others.

The treatment of multiple myeloma depends on whether the patient is experiencing symptomsand the patient’s overall health. In many cases, a team of doctors will work with the patient to determine the best treatment plan. The goals of treatment are to eliminate myeloma cells, control tumor growth, control pain, and allow patients to have an active life. While there is no cure for multiple myeloma, the cancer can be managed successfully in many patients for years.

The information below is divided into treatment options for people without symptoms and for people with symptoms. In addition, treatment options may depend on whether the patient is newly diagnosed with myeloma or is experiencing a recurrence of the disease.

Active surveillance for people without symptoms

People with early-stage myeloma and no symptoms, called SMM, may simply be closely monitored by the doctor through checkups. This approach is called active surveillance or watchful waiting. As noted previously, if there is evidence of bone thinning, or osteoporosis, periodic infusions of bisphosphonates to reverse this process may be recommended. If symptoms appear, then active treatment starts. Two clinical trials in high-risk SMM have shown that early treatment can slow the progression to myeloma with symptoms for some patients, but whether this helps people live longer is not known.

Overview of treatment options for patients with symptoms

Treatment for people with symptomatic myeloma includes both treatment to control the disease as well as supportive care to improve quality of life, such as by relieving symptoms and maintaining good nutrition. Disease-directed treatment typically includes drug therapy, such as targeted therapy and/or chemotherapy, with or without steroids. Bone marrow/stem cell transplantation may be an option. Other types of treatments, such as radiation therapy and surgery, are used in specific circumstances. Each type of treatment is described below.

The treatment plan includes different phases.

• Induction therapy for rapid control of cancer and to help relieve symptoms.
• Consolidation with more chemotherapy or bone marrow/stem cell transplant.
• Maintenance therapy over a prolonged period to prevent cancer recurrence.

Therapies using medication

Systemic therapy is the use of medication to destroy cancer cells. This type of medication is given through the bloodstream to reach cancer cells throughout the body. Systemic therapies are generally prescribed by a medical oncologist, a doctor who specializes in treating cancer with medication.

Common ways to give systemic therapies include an intravenous (IV) tube placed into a vein using a needle or in a pill or capsule that is swallowed (orally).

The types of systemic therapies used for multiple myeloma include:

• Chemotherapy
• Targeted therapy
• Immunomodulatory drugs
• Steroids
• Bone-modifying drugs

Combination regimens are an important part of the treatment of multiple myeloma. Combining different treatment effects from different types of drugs – such as a combination of an immunomodulatory drug, a proteasome inhibitor, and a steroid – can be an effective way of managing the disease. In addition, other targeted treatments may be added, depending on the individual's specific situation.

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by keeping the cancer cells from growing, dividing, and making more cells.

A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a set period of time. A patient usually receives combinations of different drugs at the same time.

Combination chemotherapy has been used successfully for the treatment of myeloma. These drugs include cyclophosphamide (available as a generic drug), doxorubicin (available as a generic drug), melphalan (Alkeran, Evomela), etoposide (available as a generic drug), cisplatin (available as a generic drug), carmustine (BiCNU), and bendamustine (Bendeka). Chemotherapy drugs like these may be used in certain situations. For example, melphalan is most commonly used when a bone marrow transplantation is part of the treatment plan. A high dose of melphalan is used to suppress the myeloma for a long time, and the patient's own bone marrow cells are used to recover from this treatment.

The side effects of chemotherapy depend on the individual and the dose used, but they can include fatigue, risk of infection, nausea and vomiting, hair loss, loss of appetite, and diarrhea or constipation. Other side effects include peripheral neuropathy (tingling or numbness in feet or hands), blood clotting problems, and low blood counts. These side effects usually go away once treatment is finished. Occasionally an allergic reaction such as skin rash may occur and the drug may have to be stopped.

The length of chemotherapy treatment varies from patient to patient and is usually given until the myeloma is well controlled.

Targeted therapy

Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells and limits damage to healthy cells.

• Proteasome inhibitors: Bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro) are classified as proteasome inhibitors. They target specific enzymes called proteasomes that digest proteins in the cells
• Histone deacetylase inhibitors: Panobinostat (Farydak), an inhibitor of the enzyme histone deacetylase (HDAC), also treats recurrent myeloma.
• Monoclonal antibodies: Elotuzumab (Empliciti) and daratumumab (Darzalex) are monoclonal antibodies that bind to myeloma cells and label them for removal by the person's own immune system.
• Nuclear export inhibitors: Selinexor (Xpovio) is a targeted therapy that is given in combination with dexamethasone, a steroid available as a generic drug. This combination is used to treat adults with multiple myeloma that has come back after at least 4 previous treatments.
• B-cell maturation antigen (BCMA): Belantamabmafodotin-blmf (Blenrep) is an antibody-drug conjugate to treat adults with recurrent or refractory multiple myeloma who have received at least 4 previous treatments.

Thalidomide, lenalidomide, and bortezomib can also be effectively used as maintenance therapy to extend the disease's response to the initial therapy or after a bone marrow/stem cell transplant.

Immunomodulatory drugs

Thalidomide, lenalidomide (Revlimid), and pomalidomide (Pomalyst) are classified as immunomodulatory drugs, which stimulate the immune system. These drugs also keep new blood vessels from forming and feeding myeloma cells. Thalidomide and lenalidomide are approved to treat newly diagnosed patients. Lenalidomide and pomalidomide are also effective for treating recurrent myeloma.

Steroids

Steroids, such as prednisone and dexamethasone, may be given alone or at the same time as other drug therapy, such as with targeted novel therapy or chemotherapy. Steroids are very effective at reducing the burden of plasma cells, but this effect is only temporary.

Bone-modifying drugs

Most people with myeloma receive treatment with bone-modifying drugs. These drugs help strengthen the bone and reduce bone pain and the risk of fractures.

There are 2 types of bone-modifying drugs available for treating bone loss from multiple myeloma. The choice of drugs depends on your overall health and your individual risk of side effects.

• Bisphosphonates, such as zoledronic acid (Zometa) and pamidronate (Aredia), block the cells that dissolve bone, called osteoclasts.
• Denosumab (Xgeva)is an osteoclast-targeted therapy called a RANK ligand inhibitor. It is approved to treat multiple myeloma and may be a better option for people with severe kidney problems.

Treatment with a bone-modifying drug is recommended for up to 2 years. At 2 years, treatment may be stopped if it is working. If the myeloma comes back and new bone problems develop, treatment with a bone-modifying drug is usually started again.

Bone marrow transplantation/stem cell transplantation

A bone marrow transplant is a medical procedure in which bone marrow that contains cancer is replaced by highly specialized cells, called hematopoietic stem cells, that develop into healthy red blood cells, white blood cells, and platelets in the bone marrow. Hematopoietic stem cells are blood-forming cells found both in the bloodstream and in the bone marrow. This procedure is also called a stem cell transplant. This is because it is the stem cells in the blood that are typically being transplanted, not the actual bone marrow tissue.

There are 2 types of stem cell transplantation depending on the source of the replacement blood stem cells: allogeneic (ALLO) and autologous (AUTO). ALLO uses donated stem cells, while AUTO uses the patient’s own stem cells. For multiple myeloma, AUTO is more commonly used. ALLO is being studied in clinical trials. In both types, the goal is to destroy all of the cancer cells in the marrow, blood, and other parts of the body using high doses of chemotherapy (usually melphalan) and then allow replacement blood stem cells to create healthy bone marrow and better immunity.

Radiation therapy

Radiation therapy is the use of high-energy x-rays or other particles to destroy cancer cells. A radiation therapy regimen (schedule) usually consists of a specific number of treatments given over a set period of time.

Doctors may recommend radiation therapy for patients with bone pain when chemotherapy is not effective or in order to control pain.

Surgery

Surgery is not usually a disease-directed treatment option for multiple myeloma, but it may be used to relieve symptoms. Surgery is used to treat bone disease, especially if there are fractures, and recent plasmacytomas, especially if they occur outside the bone.

Physical, emotional, and social effects of cancer

Cancer and its treatment cause physical symptoms and side effects, as well as emotional, social, and financial effects. Managing all of these effects is called palliative care or supportive care. It is an important part of your care that is included along with treatments intended to slow, stop, or eliminate the cancer.

Palliative care focuses on improving how you feel during treatment by managing symptoms and supporting patients and their families with other, non-medical needs. Any person, regardless of age or type and stage of cancer, may receive this type of care. It often works best when it is started right after a cancer diagnosis. People who receive palliative care along with treatment for the cancer often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional and spiritual support, and other therapies. You may also receive palliative treatments similar to those meant to get rid of the cancer, such as chemotherapy, surgery, or radiation therapy.

Refractory myeloma

The disease is called relapsed and refractory myeloma if the cancer no longer responds to the most recent treatment. If this happens, it is a good idea to talk with doctors who have experience in treating refractory myeloma. Doctors can have different opinions about the best standard treatment plan. Also, clinical trials might be an important option.

Sometimes drugs that have gone through advanced phases of clinical trial and are awaiting approval, are made more readily available to patients with refractory myeloma through Clinical Trial Program. For example, daratumumab was first approved in 2015 to be used alone to treat relapsed and refractory myeloma after other treatments had failed. In November 2016, the FDA approved the use of daratumumab in combination with lenalidomide and dexamethasone or with bortezomib and dexamethasone to treat people who have already received at least 1 previous treatment. Since then, daratumumab has received 5 more approvals from the FDA and is now approved in combination with bortezomib, thalidomide, and dexamethasone to treat newly diagnosed patients with multiple myeloma who may also receive an AUTO stem cell transplant.

Remission and the chance of recurrence

A remission is when cancer cannot be detected in the body and there are no symptoms. A remission may be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. The possibility of the cancer returning, which is almost certain with myeloma, despite recent advances in therapy. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return.

If the cancer returns after the original treatment, it is called recurrent myeloma or relapsed myeloma. When this occurs, a cycle of testing will begin again to learn as much as possible about the recurrence. After testing is done, you and your doctor will talk about the treatment options. Often the treatment plan will include the treatments described above such as targeted therapy and chemotherapy, but they may be used in a different combination or given at a different pace. Recent advances in targeted, newer therapy mean that the chances of effective treatment for relapsed disease are increasing.

Watching for recurrence

One goal of follow-up care is to check for a recurrence, which means that the cancer has come back. Over time, myeloma recurs and arises because small areas of this cancer may remain undetected and resistant to treatment in the body. In turn, these cells may increase in number until they show up on test results or cause signs or symptoms. During follow-up care, a doctor familiar with your medical history can give you personalized information about your risk of recurrence. Your doctor will also ask specific questions about your health. Some people may have blood tests or imaging tests as part of regular follow-up care, but testing recommendations depend on several factors, including the type and stage of cancer first diagnosed and the types of treatment given. For myeloma, this typically includes blood tests, periodic imaging scans, and bone marrow evaluation every 1 to 3 months. Treatment usually continues in myeloma, so this is usually integrated with ongoing surveillance.

Managing long-term and late side effects

Most people expect to experience side effects when receiving treatment. However, it is often surprising to survivors that some side effects may linger beyond the treatment period. These are called long-term side effects. In addition, other side effects called late effects may develop months or even years afterwards. Long-term and late effects can include both physical and emotional changes.