What is Multiple Myeloma? What are its symptoms? How is it treated?

Multiple Myeloma is a cancer affecting the plasma cells of our immune system. In this article:

• Plasma cells
• What is Multiple Myeloma?
• What causes Multiple Myeloma?
• What are the symptoms of Multiple Myeloma?
• Which tests diagnose Multiple Myeloma?
• What are the stages (extent of disease spread) of Multiple Myeloma?
• How is Multiple Myeloma treated?

are the topics you can find. Before detailed information about Multiple Myeloma, we will explain plasma cells, where this disease originates, to help understanding.

Plasma Cells

Plasma cells are a type of immune cell: mature B lymphocytes. B cells activate, for example during infection, and become plasma cells. Plasma cells produce antibodies for the body’s defense.

What is Multiple Myeloma?

Multiple myeloma is cancer of plasma cells. Cancerous plasma cells form a tumor called a plasmacytoma . These tumors are usually in bone and rarely in other tissues. A single plasma cell tumor is called an isolated plasmacytoma . If tumors are multiple, the disease is called multiple myeloma.

Multiple Myeloma is examined in 3 classes:

• Monoclonal gammopathy of undetermined significance (MGUS): Abnormal plasma cells produce too much of the same antibody, but do not form tumors or adversely affect health. The number of plasma cells in the blood is within normal limits. This category may later develop into multiple myeloma in some people.
• Early (asymptomatic) myeloma: There is a subcategory called smoldering myeloma. As the name suggests, symptoms may be absent, and patients may live for years without treatment.
• Active (symptomatic) myeloma: An advanced stage of Multiple Myeloma requiring treatment.

Multiple Myeloma accounts for %1 of all cancers and %10 of blood cancers (hematologic malignancies). In 2014, 3677 patients were newly diagnosed in Türkiye.

What causes Multiple Myeloma?

Factors increasing the likelihood of cancer are called risk factors. Some cancers have clearly defined causes and risks (such as smoking for lung cancer and the sun’s UV rays for skin cancer). For others, identifying a single or clear cause is difficult. Multiple Myeloma is among them, although some risk factors exist. These factors for Multiple Myeloma include:

• Genetic factors
• The extent of monoclonal gammopathy of undetermined significance
• Occupational factors
• Age
• Race
• Sex

Some research suggests links with immune dysfunction, certain occupations and exposure to chemicals and radiation. Agricultural workers, petroleum workers, leather-industry workers and cosmetologists, for example, have higher risks. This does not mean everyone in these industries will become ill. Most Multiple Myeloma patients have none of these risk factors. The most important risk factor is age. Of cases, %96 occur in individuals aged 45 and older, and more than %63 in those over 65. Abnormal chromosome number or structure is also associated with Multiple Myeloma.

What are the symptoms of Multiple Myeloma?

Multiple Myeloma may generally remain asymptomatic until an advanced stage, making early diagnosis difficult. Possible symptoms include:

1. Bone problems:
   • Bone pain, usually in the back, hips and skull
   • General bone weakness (osteoporosis) or weakness at the plasmacytoma site
   • Bone fractures sometimes caused by only minor injury
2. Low blood counts:
   • Fatigue, breathlessness and dizziness from anemia
   • Reduced immunity to infections such as pneumonia due to leukopenia (markedly reduced white blood cell count)
   • Even small injuries causing serious bleeding due to thrombocytopenia (markedly reduced platelet count)
3. Hypercalcemia (increased blood calcium): This may cause the following symptoms:
   • Drinking a lot of water
   • Frequent urination
   • Thirst
   • Kidney problems progressing to kidney failure
   • Severe constipation
   • Abdominal pain
   • Loss of appetite
   • Weakness
   • Drowsiness
   • Confusion
   • Coma (if calcium becomes extremely high)
4. Nervous system problems: If Multiple Myeloma weakens the spine’s bones, they can collapse and compress nerves, causing:
   • Sudden, severe back pain
   • Numbness, usually in the legs
   • Muscle weakness, usually in the legs
   • Seek medical help immediately if you have these symptoms.
5. Nerve damage: Sometimes proteins produced by myeloma cells harm nerves, causing numbness and weakness in various body parts.
6. Hyperviscosity (reduced fluidity due to increased thickness): In some patients, excess blood myeloma proteins thicken the blood and reduce fluidity, called hyperviscosity. This slows blood flow to the brain, potentially causing confusion, dizziness and some stroke symptoms (such as one-sided weakness and speech difficulty). Patients with these symptoms should consult a doctor immediately. Plasmapheresis can remove the excess proteins causing these symptoms, reducing complaints.
7. Kidney problems: Myeloma proteins may damage the kidneys. Initially asymptomatic, this can be detected through blood or urine tests. Failing kidneys cannot filter excess salt, fluid and metabolic waste, potentially causing weakness, breathlessness, itching and leg swelling.
8. Infections: Myeloma patients are much more likely to develop infections than healthy individuals. Pneumonia is the most common infection.
9. Symptoms of light-chain amyloidosis: Antibodies from plasma cells consist of light and heavy chains. In light-chain amyloidosis, abnormal plasma cells produce excess short chains, which accumulate in tissues as amyloid . Excess deposits in organs may prevent proper function; kidney deposits can cause kidney failure. Other problems include:
   • Heart problems
   • Enlarged spleen and liver
   • Enlarged tongue
   • Skin problems (such as easy bruising and bruising around the eyes)
   • Diarrhea
   • Carpal Tunnel Syndrome

How is Multiple Myeloma diagnosed?

1. Laboratory tests

• Blood count
• Quantitative Immunoglobulins: This measures various blood antibodies. In Multiple Myeloma, one type may be more abundant than others.
• Electrophoresis: Serum protein electrophoresis (SPEP) measures blood antibodies and identifies those produced in excess. Urine protein electrophoresis (UPEP) detects Bence Jones Protein in urine as a result of this disease.
• Free light chain: Measures blood light-chain amounts and can identify Short-Chain Amyloidosis.
• Beta-2 Microglobulin: A protein produced by cancer cells. It does not itself cause a problem but is useful for monitoring disease course.
• Blood chemistry tests: Blood urea nitrogen (BUN), creatinine (Cr), albumin, calcium and other electrolytes are assessed. Elevated BUN and Cr are common in Multiple Myeloma and indicate kidney failure. Low albumin and high calcium may indicate advanced disease.
• Bone marrow biopsy: The back of the pelvic bone is numbed with local anesthesia, and a syringe withdraws a small amount of marrow fluid. Microscopic examination determines whether it contains myeloma cells. It may also undergo immunohistochemistry, flow cytometry or chromosome analysis.
• Immunohistochemistry: The biopsy sample is exposed to special antibodies. If cell surfaces contain particular proteins bound by them, the sample changes color, detectable microscopically. This helps identify myeloma cells.
• Flow Cytometry: Like immunohistochemistry, this identifies cell-surface proteins, but examines more cells and a wider variety simultaneously. Different cell types marked with different antibodies can be examined together.
• Cytogenetics: Microscopy examines structural and numerical chromosome abnormalities, which may occur in myeloma cells.
• Fluorescence In Situ Hybridization (FISH): Unlike cytogenetics, chromosomes are stained with special fluorescent dyes to detect abnormalities.

2. Amyloid biopsy tests

Amyloid can accumulate in any tissue, and a biopsy from any affected tissue can diagnose the disease.

3. Other biopsy tests

If an X-ray shows an abnormal area, biopsy may be needed to determine whether it is a plasmacytoma:

• Fine-needle aspiration biopsy: A normal syringe attached to a very fine needle collects a sample from abnormal-looking tissue.
• Core needle (trucut) biopsy: A thicker needle than in the method above collects a larger tissue sample.

4. Imaging tests - Radiology

• Bone X-ray
• Tomography
• MRI
• PET scan
• Echocardiogram: This may be requested if amyloid formation is suspected of affecting heart function.

What are the grades (stages) of Multiple Myeloma?

Multiple Myeloma can be classified using the Durie-Salmon System . However, new diagnostic methods have reduced its value. Recently, the International Staging System for Multiple Myeloma was developed, based mainly on blood albumin and beta-2-microglobulin levels. We will discuss both methods.

1. Durie-Salmon System

This system is based on four factors:

• Amount of abnormal monoclonal antibody in blood or urine: High blood monoclonal antibody levels indicate many plasma cells producing these antibodies.
• Blood calcium amount: High blood calcium results from disease-related bone damage.
• Degree of bone damage: Multiple bone lesions on X-ray indicate advanced Multiple Myeloma.
• Blood hemoglobin amount: Low hemoglobin results from myeloma cells occupying excessive marrow space, leaving insufficient room for normal marrow cells to produce red blood cells.

This system divides Multiple Myeloma into three stages:

1. Stage 1: Myeloma cells are few. All the following findings occur:
   • Hemoglobin slightly below normal.
   • Bone X-rays appear normal or show damage in one area.
   • Normal calcium levels.
   • Very little monoclonal antibody in blood or urine.
2. Stage 2: Myeloma cells are at an intermediate level, with features between stages 1 and 3.
3. Stage 3: Very many myeloma cells. One or more of the following findings occur:
   • Low hemoglobin (below 8,5 g/dL)
   • High calcium (above 12 mg/dL)
   • Bone damage in three or more areas
   • High monoclonal antibody levels in blood or urine

2. International Staging System

• Stage 1: Serum beta-2 microglobulin is below 3,5 mg/L. Serum albumin is 3,5 g/dL or higher.
• Stage 2: Serum beta-2 microglobulin is between 3,5 and 5,5 mg/L with any albumin level. Or albumin is below 3,5 g/dL
while beta-2 microglobulin is also below 3,5 mg/L.
• Stage 3: Serum beta-2 microglobulin is 5,5 mg/L or higher.

How is Multiple Myeloma treated?

The following methods are used:

• Chemotherapy and other drugs
• Bisphosphonates
• Radiotherapy
• Surgery
• Stem cell transplantation
• Plasmapheresis

These methods may vary according to Multiple Myeloma stage.

1. Treatment of solitary plasmacytomas: Usually radiotherapy is used. If the plasma cell tumor is outside bone, it can be removed surgically. Chemotherapy is used only when the disease becomes Multiple Myeloma.
2. Treatment of early myeloma: Patients may not need treatment for years and are generally monitored closely without treatment. Bisphosphonates may be started if bone problems arise.
   Depending on how abnormal plasma cells appear microscopically or antibody levels, some patients at this stage are at risk of active myeloma and should start treatment immediately.
3. Treatment of active (symptomatic) myeloma: Patients at stage 2 or beyond, or with light-chain amyloidosis, generally receive drug treatment.

A chemotherapy combination containing bortezomib (Velcade®), thalidomide or lenalidomide, and dexamethasone is generally used. Thalidomide and lenalidomide are immunomodulatory drugs. Their effects on the immune system are not fully understood, but because they create serious embolism risk, they are used with aspirin or blood thinners. Bortezomib is a proteasome inhibitor. Cells contain proteins important in controlling cell division. In cancer cells, proteasomes degrade these proteins, allowing division to become uncontrolled; proteasome inhibitors prevent this degradation. Combinations with this drug particularly benefit patients with kidney problems and certain chromosome abnormalities in myeloma cells. Dexamethasone is a corticosteroid, structurally similar to cortisol produced in the body. Anti-inflammatory and immunomodulatory effects occur. The United States Food and Drug Administration (FDA) approved a new multiple myeloma treatment on September 26, 2019: the monoclonal antibody daratumumab (Darzalex), combined with bortezomib, thalidomide and dexamethasone for newly diagnosed adults eligible for autologous stem cell transplantation. Darzalex was first approved in 2015 for patients previously receiving proteasome inhibitors and immunomodulators and was the first approved monoclonal antibody for this disease. Many myeloma cells carry abundant CD38, and CD38 has functions including signaling and tissue adhesion. Blocking CD38 through daratumumab binding causes tumor cell breakdown and destruction. Other combinations may include vincristine (Oncovin®), doxorubicin (Adriamycin®) and dexamethasone. Vincristine disrupts microtubules forming the cell skeleton, while doxorubicin disrupts various cell-cycle phases. Bisphosphonates are added to strengthen bones and prevent disease-related fractures. Those used alongside myeloma treatment are pamidronate (Aredia®) and zoledronic acid (Zometa®). The most common radiotherapy , External Beam Radiotherapy, is the most widely used external radiation treatment. Another approach is stem cell transplantation. First, high-dose chemotherapy (sometimes with total-body radiotherapy) kills all marrow cells, including myeloma cells. New healthy blood-forming stem cells are then given, from the patient or another person. Some patients receive additional treatment cycles after transplantation, called consolidation therapy , increasing the chance of all disease signs disappearing. Regardless of transplantation, some patients receive long-term thalidomide, lenalidomide or bortezomib, called maintenance therapy . Although this may delay recurrence, it can cause serious side effects. Many drug combinations can treat Multiple Myeloma. If one drug does not work or stops working, others may be tried. Conclusion Multiple Myeloma is cancer of plasma cells, a type of immune cell. Although difficult to detect initially, it is treatable when found. We will investigate and share Multiple Myeloma treatments in future articles.