Multiple Myeloma
Myeloma is a cancer of white blood cells found in the bone marrow, specifically called Plasma Cells. The bone marrow is the spongy tissue inside your bones that makes the different elements in the blood. Plasma cells are a critical part of the body’s immune system, producing antibodies that help the body fight infections. Myeloma is initiated when healthy plasma cells transform and grow out of control, resulting in multiple bone lesions that increase the risk of bone fractures hence, termed multiple myeloma.
In Multiple myeloma, when the healthy plasma cells change and grow out of control, they not only lower the individual ability to fight infections but also crowd and suppress the growth of other normal cells in the bone marrow; the red blood cells, the white blood cells and platelets resulting in anaemic conditions and bleeding tendencies.
Symptoms of Multiple Myeloma :
People with multiple myeloma experience various symptoms and signs, while a few do not exhibit any symptoms wherein the cancer is asymptomatic.
- 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 called osteoporosis, making the bones brittle and more likely to break. It affects bones in multiple places, but the back or ribs are the most common sites of bone pain, and the condition worsens with body movements and during the night. If the spine is affected by cancer, the vertebrae (the individual bones that make up the spine) can collapse which is called a compression fracture. In advanced multiple myeloma, individuals might lose inches from their height due to compressed vertebrae over the course of their illness.
- Frequent bouts of pain, numbness, and weakness occur when collapsed vertebrae press against the spinal cord or pinch a nerve coming out of the spine.
- A vital aspect that we need to be mindful of, is that too much M protein may lead to kidney damage or failure. Kidney damage in its early stages does not often exhibit symptoms and can only be diagnosed through blood and urine tests. When the functioning of kidneys fails, it starts exhibiting multiple symptoms like itching, weakness, fatigue, shortness of breath, muscle cramps, nausea, appetite loss, sleeping trouble, changes in urination, anaemia, and swelling of the legs, feet, or ankles.
- Hypercalcemia is a high level of calcium in the blood that occurs due to 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.
- Myeloma lowers immunity levels, which reduces the body’s capability to fight infections, resulting in fever and causing infection of the upper respiratory tract and lungs.
- Hyperviscosity or thickened blood and low platelets cause blood clots, nosebleeds, bleeding gums, bruising and cloudy vision, are some of the symptoms of multiple myeloma.
It is important to note that, like regular plasma cells, myeloma cells can produce antibodies. But myeloma cells are incapable of producing healthy functioning antibodies instead they make monoclonal protein, monoclonal immunoglobulin or M protein. M protein can build up in the blood and urine, potentially damaging the kidneys and other organs and reducing immunity.
- Myeloma causes structural bone damage, which results in weakened bones and leads to painful fractures or bone breaks over time. Myeloma, usually called multiple myeloma due to the presence of more than one bone lesion in more than 90% of individuals.
- Solitary plasmacytoma is a mass, or tumour, of myeloma cells that involve only 1 site in the bone or, less commonly, in other organs
- Extramedullary plasmacytoma describes myeloma that originates outside the bone marrow in the lymph glands, sinuses, throat, liver, digestive tract, or under the skin.
It is important to note that, like regular plasma cells, myeloma cells can produce antibodies. But myeloma cells are incapable of producing healthy functioning antibodies instead they make monoclonal protein, monoclonal immunoglobulin or M protein. M protein can build up in the blood and urine, potentially damaging the kidneys and other organs and reducing immunity.
- Myeloma causes structural bone damage, which results in weakened bones and leads to painful fractures or bone breaks over time. Myeloma, usually called multiple myeloma due to the presence of more than one bone lesion in more than 90% of individuals.
- Solitary plasmacytoma is a mass, or tumour, of myeloma cells that involve only 1 site in the bone or, less commonly, in other organs
- Extramedullary plasmacytoma describes myeloma that originates outside the bone marrow in the lymph glands, sinuses, throat, liver, digestive tract, or under the skin.
Diagnostics Facilities
Advanced Cancer Diagnostics
Advanced Cancer Treatment
General Diagnostic Facilities
Risk factors of Multiple Myeloma
The following factors can raise the individuals’ risk of developing myeloma:
- Age: Myeloma occurs most commonly in people over 60. The average age at diagnosis is 70, with a 2% possibility of occurrence in individuals under 40.
- Race: Myeloma occurs twice as frequently in black people than in white people. The reasons are unclear, although the disease is more common in the Middle East, North Africa, and the Mediterranean.
- Exposure to radiation or chemicals: People who have been exposed to radiation or 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 designers, and paper makers, are also at higher risk. There is also an increased 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): An individual with a small amount of M protein in their blood has a 1% to 2% chance of developing myeloma, lymphoma, or other blood-related cancers called Waldenstrom’s macroglobulinemia annually.
Diagnosis of Multiple Myeloma
Based on the patient’s requirements, the consultant recommends any of the following diagnostic procedures to diagnose multiple myeloma cancer:
- The type of cancer suspected
- Your signs and symptoms
- Your age and general health
- The results of earlier medical tests
- Blood and urine tests: Myeloma cells usually secrete the monoclonal immunoglobulin antibody known as M protein, and its levels in the patient’s blood and urine help the doctor determine the extent of the disease and monitor the effectiveness of treatment. In some people, the myeloma cells secrete only part of the antibody 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 serum-free light chain assay helps measure the amount of free light chains in the blood before the kidneys filter the blood, and the presence of light chains in the urine is called the Bence Jones protein.Blood analysis is performed to measure levels of serum albumin and serum beta-2 microglobulin (β2-M), calcium levels, and blood cells and also to measure the performance of kidneys.</p
- X-ray: X-rays are taken to evaluate the patient’s skeletal system and are typically the first procedure to examine the bones when myeloma is suspected or diagnosed.
- Magnetic resonance imaging (MRI): An MRI reveals if the normal bone marrow has been replaced by myeloma cells or plasmacytoma, especially in the skull, spine, and pelvis. The detailed images may also show compression fractures of the spine or a tumour pressing on nerve roots.
- Computed tomography (CT) scan: A CT scan creates a detailed, cross-sectional view that reveals any abnormalities or tumours in soft tissues. A computer then combines these pictures into a 3-dimensional image of the inside of the body.
- Computed tomography (CT) scan: A CT scan creates a detailed, cross-sectional view that reveals any abnormalities or tumours 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-CT scan, a combination of a PET scan and a CT CT scan, is usually referred to as a PET scan by doctors and is taken to determine the abnormalities inside the body. A small amount of radioactive sugars is injected into the patient’s body and consumed by cells that use the most energy. Since cancer tends to consume more energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance and produces images of the internal organs to help doctors determine the tumour’s location and spread.
- Bone marrow aspiration and biopsy: These two procedures are similar and often done simultaneously using a needle to examine the bone marrow and are crucial for making a myeloma diagnosis. Bone marrow has both solid and liquid components. A bone marrow aspiration helps collect the bone marrow fluid, whereas a bone marrow biopsy helps obtain a small mass of solid tissues.The pathologist then analyzes the collected samples. Cytogenetics and a special procedure called fluorescent in situ hybridization (FISH) help analyze the genes in myeloma. Cytogenetics is a type of genetic testing used to analyze the cell’s chromosomes. These tests determine the genetic makeup of the myeloma and its health risks. Bone marrow aspiration and biopsy are typically done in the pelvic bone located in the lower back by the hip.
Molecular testing of the tumour
Your doctor may recommend conducting multiple diagnostics on the tumour and/or bone marrow samples to identify specific chromosomes (cytogenetics), genes (FISH or genomic sequencing), proteins, and other factors unique to the tumour as mentioned above. The diagnostic outcomes can help determine your treatment options.
Stages of Multiple Myeloma
For myeloma, the staging process starts with whether the patient is experiencing symptoms. It is common to classify people with newly diagnosed myeloma as being either:
The symptoms related to myeloma are described with the mnemonic acronym “CRAB”, with each letter corresponding to a symptom:
- 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 severe bacterial infections (more than 2 episodes in 12 months), and patients with CRAB features require active treatment.
Individuals who do not exhibit CRAB features may also be treated if any of the following conditions apply:
International Staging System
- The International Staging System (ISS), now used more commonly to classify multiple myeloma, illustrates the factors critical for the best patient outcomes and is based on data collected from people worldwide with multiple myeloma. The system has 3 stages based on the measurement of serum albumin and the levels of serum β2-M.
- Efforts to further classify myeloma based on patterns of gene expression in myeloma cells are underway and are 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 the following two 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 and 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 in chromosomes (as defined by the results of cytogenetic testing) of the cancer cells may also indicate the aggressiveness of the cancer 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. In case of a recurrence, the cancer staging process has to be repeated (called re-staging) as explained above.
Other classifications
Some people exhibit no myeloma symptoms but 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 decreased blood components, 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 leukaemia (CLL), lymphoma, Waldenstrom’s macroglobulinemia, or amyloidosis. For this reason, a person with MGUS should be regularly monitored for health changes by their doctor.
Smouldering multiple myeloma (SMM) or asymptomatic myeloma
People 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 anaemia. A person with SMM may be prescribed bisphosphonates for symptoms of osteoporosis or osteopenia, with clinical trials for new treatment procedures. 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, doctors monitor the health of individuals with SMM and may commence treatment as the disease advances, especially for patients with an increased risk of developing symptoms within 18 months to 2 years.
Prognosis
The ISS of myeloma gives information about the prognosis and predicts the individual’s chances 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 the presence of a multitude of myeloma cells along with kidney damage. 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 indicates poorer prognosis.
- Abnormalities in chromosomes (cytogenetics) of the cancer cells may indicate the aggressive state of the cancer. This approach to testing the genetics of the myeloma includes FISH and even the testing of individual gene mutations.
- A plasma cell labelling index can be done in a specialized laboratory using bone marrow samples to understand the progress of cancer.
Treatment for Multiple Myeloma
In cancer care, a multidisciplinary team of doctors collaborate to devise the patient’s overall treatment plan that combines different treatment strategies. Cancer care teams comprise healthcare professionals from different specialities, including physician assistants, nurse practitioners, oncology nurses, oncology social workers, pharmacists, counsellors, dietitians, etc.
The treatment of multiple myeloma depends on the symptoms the patient exhibits symptoms and the patient’s overall health. In most cases, a team of doctors work with the patient to determine the best treatment strategy. The treatment objective is to eliminate myeloma cells, control tumour growth, control pain, and encourage patients to lead an active life. While there is no cure for multiple myeloma, the cancer can be managed successfully in majority of the cases for several years, enhancing survival prospects.
Treatment strategies vary based on symptomatic or asymptomatic myeloma and whether the individual is recently diagnosed with myeloma or is experiencing a disease recurrence.
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 periodical checkups. This approach is called active surveillance or watchful waiting. As noted previously, if there is evidence of bone thinning or osteoporosis, periodical 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 does not provide a clear indication of enhancing an individual’s longevity.
Overview of treatment options for patients with symptoms
Treatment for people with symptomatic myeloma includes both treatments to control the disease and supportive care to improve quality of life, like relieving symptoms and maintaining good nutrition. Disease-directed treatment typically includes drug therapy, like targeted therapy, chemotherapy or steroids (optional). Other treatment procedures like, bone marrow/stem cell transplantation, radiation therapy and surgery are used in specific circumstances as per the patient’s health requirements. Let’s look at the treatment procedures in detail:
The treatment plan comprises multiple 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 about destroying cancer cells using medicinal drugs injected through the bloodstream to reach cancer cells throughout the body. Medical Oncologist, a doctor specializing in treating cancer with medication, generally prescribes systemic therapies.
Systemic therapies typically include injecting medicines via an intravenous (IV) tube inserted into the vein using a needle or taking oral medication like a pill or capsule.
The types of systemic therapies used for multiple myeloma include:
- Chemotherapy
- Targeted therapy
- Immunomodulatory drugs
- Steroids
- Bone-modifying drugs
Combination regimens are a critical aspect of the treatment process for multiple myeloma. Combining multiple treatment strategies like, a combination of immunomodulatory drugs, proteasome inhibitors, and steroids, can be effective in controlling and managing the disease. Depending on the patient’s specific requirements, other targeted treatment procedures may be included as part of combination regimens.
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 over a defined period, wherein the doctor prescribes different drug combinations that can be taken orally or injected through the bloodstream.
Combination chemotherapy has been used successfully for the treatment of myeloma. 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) are examples of chemotherapy drugs used in specific situations as per need and after doctor recommendation. 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 bone marrow cells are used to recover from this treatment.
Depending on the individual’s health and dosage the chemotherapy side effects may include fatigue, risk of infection, nausea and vomiting, hair loss, loss of appetite, and diarrhoea 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 subside after the treatment process is completed. Occasionally an allergic reaction such as skin rash may occur, and the treatments have to be discontinued for a while. The length of chemotherapy treatment varies from patient to patient and is continued until the myeloma is well controlled.
Targeted therapy
- In this approach, the specific cancer genes, proteins, or the tissue environment that contribute to cancer growth and survival are targeted. 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, which target specific enzymes called proteasomes that digest cell protein
- 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 individuals’ 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 made a recurrence after at least four treatment cycles.
- B-cell maturation antigen (BCMA): Belantamabmafodotin-blmf (Blenrep) is an antibody-drug conjugate to treat adults with recurrent or refractory multiple myeloma after undergoing at least four treatment cycles.
- Thalidomide, lenalidomide, and bortezomib can also be used effectively as maintenance therapy to extend the disease’s response to the initial therapies the patient has received or after a bone marrow/stem cell transplant.
Immunomodulatory drugs
Thalidomide, lenalidomide (Revlimid), and pomalidomide (Pomalyst) classified as immunomodulatory drugs, stimulate the immune system. These drugs control 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: Steroids like prednisone and dexamethasone may be given alone or with other drug therapies, like targeted novel therapy or chemotherapy. Steroids are very effective at reducing the burden of plasma cells but provide only temporary relief.
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 two 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 encountering 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 using bone-modifying drugs is recommended for up to 2 years; if successful can be discontinued after two years. If the myeloma reappears, causing new bone problems, treatment with a bone-modifying drug is initiated again.
Bone marrow transplantation/stem cell transplantation
A bone marrow transplant is a medical procedure in which the bone marrow that contains the 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 because the process involves transplanting the stem cells in the blood and not the actual bone marrow tissues.
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 stem cells. For multiple myeloma, AUTO is more commonly used. ALLO is being studied in clinical trials. In both types, the goal is to completely eliminate 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 construct 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 defined period.
Doctors may recommend radiation therapy for patients with bone pain when chemotherapy is not effective or 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 the formation of plasmacytomas, with occurance 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 the critical aspect 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 cancer treatment often experience less severe symptoms and enhanced well-being, and report satisfaction with the treatment process.
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 procedures meant to eliminate cancer, like chemotherapy, surgery, or radiation therapy.
Follow up
Periodical monitoring for cancer recurrence
The objective of periodical follow-up care is to check for a recurrence. Over time, myeloma recurs and arises because cancer cells in certain areas of the body may remain undetected and resistant to treatments. 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 the risk of recurrence and get to know about your current health condition. Some people may have blood tests or imaging tests as part of regular follow-up care, and the testing recommendations depend on several factors, including the type and stage of cancer first diagnosed and the treatment process. For myeloma, this typically includes blood tests, periodic imaging scans, and bone marrow evaluation performed every 1 to 3 months. In the case of myeloma, the treatment process is continual and integrated with continuous 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 comprise both physical and emotional aspects.
Doctors
Dr. Deepan Rajamanickam
