Leukemia & Lymphoma

Myeloma Risk Factors, Diagnosis, and Treatment

An Overview of Myeloma

Myeloma and multiple myeloma are different names for the same cancer. The word multiple is optional and it refers to the numerous tumors that develop in the bones of people with this disease.

Myeloma, leukemia, and lymphoma are the three main kinds of blood cancer or hematologic malignancy. Of the three, myeloma is the least common. The chances of developing myeloma increase with age and most people who are diagnosed are in their 60s or older.

Although it can occur in younger adults, less than one percent of cases are in those under the age of 35.

What Is Myeloma?

Myeloma is a cancer that begins in the bone marrow. In healthy adults, bone marrow is the living tissue packed into the spongy inner hollows of certain bones. There, it continually makes and releases new red blood cells and white blood cells of all types, ensuring you have a steady supply in your blood.

However, myeloma is a cancer specifically of the plasma cells—a very specialized type of white blood cell. The main job of plasma cells is to make antibodies, the microscopic proteins that tag foreign invaders for immune destruction.

A healthy population of plasma cells secretes an entire portfolio of different antibodies to attack a single germ. In myeloma, there is a ‘clone’ of troublesome plasma cells—many copies of the same plasma cell in the bone marrow produce an identical protein (a monoclonal protein or M protein) which is abnormal. This malignant clone of plasma cells does not wait for a germ to invade; it produces M protein continually and in excess.

 

Precisely how a healthy plasma cell becomes a cancerous one is still not fully known, but scientists are gaining ground. Importantly, it’s now understood that myeloma belongs to a family of different plasma cell diseases. Many people with certain precursor plasma cell diseases eventually develop multiple myeloma.

Symptoms

Not everyone with myeloma has symptoms at first, so catching myeloma early in its course is challenging. Symptoms to look out for include the following:

  • Bone pain, especially in the backbone or chest
  • Fatigue
  • Unintentional weight loss
  • Frequent infections
  • Nausea, constipation, and/or lack of appetite
  • Feeling excessively thirsty
  • Confusion or brain fog
  • Numbness or weakness in the legs

Often the symptoms of myeloma are linked with the particular effects of the malignant clone and/or the antibody-proteins they produce. For example:

  • As abnormal cells within the bones build up, bone pain, weakness of the bones and fractures are possible, potentially with nerve damage.
  • When myeloma cells start crowding out the body’s blood-forming cells, people can develop low cell counts. ​A reduced number of red blood cells, or anemia, can contribute to symptoms like weakness and dizziness. A shortage of white blood cells can make you more infection-prone. And platelet shortages can lead to bleeding problems from injuries that would ordinarily be less serious.
  • Myeloma cells can signal other cells to break down bone, releasing calcium that may reach dangerously high levels in the blood. Known as hypercalcemia, this excess in blood calcium comes with its own set of symptoms, including extreme thirst/excessive urination, confusion, severe constipation, belly pain, and loss of appetite.
  • Sometimes myeloma cells produce proteins that are harmful to the kidneys and nerves. This can produce kidney disease or, in the case of affected nerves, numbness, tingling or weakness. Such tingling and pain in the hands, arms, feet, and legs is known as peripheral neuropathy.
  • The build-up of myeloma protein can also result in a thickening of the blood—almost like adding too much flour to pancake batter. This thickening is called hyperviscosity. It can slow blood flow to the brain and cause confusion, dizziness, and other symptoms.

Is There a Pre-Myeloma?

Early diagnosis of myeloma is challenging as symptoms may not emerge until advanced stages. Sometimes, there may be vague symptoms that are at first attributed to other diseases.

However, scientists have identified a family of different plasma cell diseases, some of which can eventually progress to myeloma, such as the following:

  • Monoclonal Gammopathy of Undetermined Significance (MGUS)
  • Plasmacytoma, or solitary plasmacytoma.

MGUS

When you have too many copies of the same antibody, this is known as a monoclonal gammopathy or MG. People with myeloma may have MG, but not everyone with MG has myeloma. In fact, there is a long list of diseases associated with the presence of MG and many of them are not cancers.

When a person has MG but there are no clues as to what’s causing it, it’s known as an MG of undetermined significance or MGUS. Not everyone with MGUS will go on to develop myeloma, but some may, which is why annual monitoring is necessary.

Although it is a benign condition, MGUS carries a risk of becoming myeloma at a rate of about 1.5 percent per year. The odds go up with higher numbers of abnormal plasma cells in the bone marrow and also with higher levels of M protein in the blood.

MGUS is usually monitored but not treated.

Plasmacytoma

Sometimes there is only evidence of one single plasma cell tumor. When this happens, it’s called a plasmacytoma or isolated plasmacytoma of bone, rather than a myeloma.

A lone plasmacytoma may also develop outside the bone marrow in another organ. In this case it’s called an extramedullary plasmacytoma. Many people with a solitary plasmacytoma will go on to develop multiple myeloma, so close monitoring for signs of myeloma is important.

What Happens in Myeloma?

Think of your bone marrow as a football stadium packed with fans. Each fan is a cell and there are many different cell types. In this stadium, plasma cells are the fans that were given a flag to wave at the halftime show. And each plasma cell/fan has a different colored flag, representing the unique antibody it makes.

In healthy bone marrow, other cell types outnumber plasma cells. So, in our stadium, most fans don’t have colored flags. Still, there are enough fans and colored flags to fill the stadium with virtually every shade of every color—a spectacular diversity of antibodies.

Now imagine that a single plasma cell holding a gray flag mutates and manages to clone itself, becoming two identical fans, each holding a gray flag. Then two become four, four become eight, and so on—all holding their gray flags. Eventually, there are way more gray flags than expected. The gray flags represent multiple copies of the same protein—a monoclonal protein or an M proteinbecause it comes from the single troublesome clone of cells. This excessive amount of monoclonal protein in the blood or urine is something that can be detected in lab tests.

Now suppose one cell from the malignant clone gets up to buy a drink, but then returns to the wrong section of seating, still continuing to clone itself. The clone starts in a new section, and again two become four, four become eight, and so on.

These malignant plasma cell clones can start to take over the stadium. They crowd out rows and sections of seating that used to belong to healthy marrow cells, like ones that make your supply of red cells, white cells,  platelets, and even other plasma cells holding colored flags. So, as the number of gray flags increases, the number of normal, polyclonal colorful flags can decrease.

And malignant clones can also affect other nearby cells in the stadium. Plasma cell clones can release chemical messengers that cause nearby "fans" to behave inappropriately. Some of them (osteoclasts) will start to drill into the cement of the stadium (bone resorption), releasing clouds of dust (calcium) that spread throughout the stadium and beyond (the bloodstream).

Types of Myeloma

When myeloma develops, it can emerge and unfold differently in different people. Some of the terms used to classify myeloma include:

  • Asymptomatic Myeloma
  • Smoldering Myeloma
  • Symptomatic or Active Myeloma
  • Light Chain Myeloma
  • Nonsecretory Myeloma
  • Myelomas of distinct genetic sub-types

Asymptomatic vs. Smoldering vs. Active/Symptomatic Myeloma

In some people, there is an “in between” phase of disease—a condition in between MGUS and active myeloma, that is. When this happens, it’s called ​asymptomatic ​myeloma and, in such cases, there are few signs of active disease or the myeloma is stable.

In ​smoldering myeloma, the bone marrow becomes filled with extra plasma cells. Some 10 percent or more of the marrow cells may be from the myeloma clone and/or M protein levels become greater than 30 g/L. However, in smoldering myeloma, there is still no anemia, no kidney failure, no elevated calcium levels in the bloodstream, and no damaged soft areas of bone. Smoldering myeloma is usually observed but not treated; however, researchers are looking into the possible benefits of early treatment in some situations.

Symptomatic or active myeloma needs to be treated. There are M proteins in the blood or urine and an increased number of plasma cells in the bone marrow. Soft spots can appear in parts of the bone, weakening the bone, causing pain, and increasing the risk of fractures. And, those items absent in the description of smoldering myeloma from above may come to fruition in active myeloma.

Proteins Help Classify Myeloma

The kind of protein the myeloma cells produce also helps determine what kind of myeloma one has. Antibodies are huge proteins that have different parts or chains. Heavy parts, or heavy chains, and light parts, or light chains, all come together to form a single whole antibody.

In the naming of an antibody or immunoglobulin, the heavy chains determine what letter comes after the immunoglobulin (Ig). So, for instance, the most common heavy part found in myeloma M proteins is IgG, which accounts for about 60 to 70 percent of myeloma cases. Next is IgA. Rarely, IgD or IgE may be involved.

In some cases, myeloma cells may produce only incomplete antibodies or they may secrete only light chains. These are called Bence-Jones proteins and are so small that they often pass from the kidneys into the urine. Almost 20 percent of all cases of myeloma secrete only light chains.

Roughly one percent of all cases of myeloma do not secrete ​enough M proteins or light chains to be detectable at all. In these cases, more sensitive tests are used or the symptoms of myeloma plus the finding of abnormal plasma cells in the marrow lead to a diagnosis.

Genetic Sub-Types

There are a variety of genetic abnormalities associated with myeloma. Sequences of DNA have been studied so that it is known, for instance, that having one of these genetic abnormalities may affect or predict how your disease will respond to treatment. Researchers hope that such genetic profiling will continue to help lead to advances in myeloma treatments.

Causes

In most cases, scientists don’t know precisely how myeloma begins. Rates differ by race—African-Americans greater than Caucasian-Americans and Caucasian-Americans greater than Asian-Americans—yet the reasons are unknown. Certain genetic changes in the plasma cells have been identified, but what causes these changes in the first place is not always clear.

Genes are encoded in DNA, which is packaged into 23 pairs of chromosomes. In some people’s myeloma cells, parts of chromosome number 13 are missing, known as a deletion. These deletions appear to make the myeloma more treatment-resistant.

In roughly 50 percent of people with myeloma, the malignant clone has a chromosome with what’s called a translocation—part of one chromosome has switched with part of another chromosome in the myeloma cells. When such rearrangements turn critical genes on or off, it can promote malignancy.

Researchers also believe that abnormalities in other cells in the bone marrow may also play a role in myeloma. For instance, certain immune cells called dendritic cells can make chemical signals that cause healthy plasma cells to grow. So, excessive signaling by dendritic cells might contribute to the development of myeloma.

Diagnosis

If symptoms are suggestive of myeloma, lab tests on blood and/or urine, imaging of the bones, and a bone marrow biopsy are usually done.

Blood Tests

  • Complete Blood Count (CBC): This involves automated counting of blood cells of different types to determine whether your numbers fall in a normal or abnormal range. When myeloma cells spread out in the bone marrow, some of the blood cell counts will be low. Low red blood cell count is a common finding.
  • Immunoglobulins (Ig) Quantification: Ig quantification is done to see which, if any, of the five different types of antibodies are at increased levels—IgA, IgD, IgE, IgG, and IgM. In myeloma, one of these may be high and the others may be lower than normal. Other patterns are possible.
  • SPEP and UPEP: This refers to serum protein electrophoresis and urine protein electrophoresis. These tests can identify whether there is a monoclonal protein buildup or spike involved.
  • Free Light Chains: This test measures the amount of light chains in the blood. This might be done, for instance, in a patient with myeloma for whom no M protein is found by SPEP.

Bone Marrow Tests and Biopsies

People with myeloma have too many plasma cells in their bone marrow. So, a bone marrow biopsy and aspiration is done to assess the counts and obtain samples. It can be done either at the doctor’s office or at the hospital. Biopsy specimens are then examined by a pathologist and undergo further laboratory testing.

Genetic Testing of Cancerous Cells

Genetic tests are often done on the abnormal cells as part of the diagnosis and evaluation of the myeloma. Cytogenic analysis refers to tests that examine changes in the chromosomes of the myeloma cells.

Certain mutations and genetic rearrangements also help doctors predict how a malignancy might behave. A variety of different tests are available and in use to evaluate a person’s cancer genetically once the cells are obtained.

Amyloid Biopsy

High levels of abnormal antibody proteins put myeloma patients at risk for developing amyloidosis. Amyloid is a substance that can build up in any tissue and a biopsy helps diagnose this disease. Most often, this biopsy involves using a needle to remove some belly fat.

Scans and Imaging

Myeloma cells are known for their ability to make so-called lytic lesions in bones. They may recruit other cells called osteoclasts to destroy bone or cause soft spots in discrete areas of bone.

Often a series of x-rays that includes most of the bones is done. When this kind of imaging is performed, it’s known as a bone survey or skeletal survey. Other kinds of imaging may be especially helpful in certain cases, such as finding plasmacytomas that can’t be seen on x-rays.

When to See a Doctor

Consider making an appointment with your doctor if you have any persisting signs or symptoms that worry you. Symptoms of myeloma can be vague and nonspecific.

If you have been diagnosed with MGUS or solitary plasmacytoma, it is important that you and your doctor keep an eye on things as these plasma cell diseases can progress to myeloma. Always ask your doctor any questions you may have about your particular condition.

A Word From Verywell

If you or a loved one were recently diagnosed with myeloma, it is very normal to feel confused, angry, overwhelmed, or all of the above. A cancer diagnosis is life-changing in many different ways.​ It may help to hear other people's stories. Survivorship workshops, conferences, and even social media are excellent ways to connect with others who may share your struggles or have similar experiences and insights.

Sources:

Hengeveld PJ, Kersten MJ. B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy? Blood Cancer Journal. 2015;5(2):e282-.

Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma. Haematologica. 2016;101(4):396-406.

Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046–1060.

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