Multiple Myeloma Isn't Just One Disease: Understanding Types and Subtypes

Multiple myeloma is complicated. Two people can both be diagnosed with multiple myeloma and yet have very different versions of the disease.

The word “multiple” doesn't mean that myeloma attacks the body in multiple ways. Historically, it refers to the disease often appearing in multiple areas of the bone or bone marrow.

But there really are many different forms of myeloma, and understanding your particular type can help make all those letters and numbers on your lab reports a little less confusing.

It Starts With Plasma Cells

Multiple myeloma is a cancer of plasma cells, a type of white blood cell found primarily in the bone marrow.

Healthy plasma cells make antibodies, also called immunoglobulins, that help protect us from infection. Each antibody is made from heavy chains and light chains.

The five heavy-chain classes are:

IgG, IgA, IgM, IgD and IgE

The two light-chain types are:

Kappa and Lambda

When one abnormal plasma cell begins multiplying uncontrollably, it creates a clone of myeloma cells. Those cells often produce large amounts of one particular antibody—or just part of one.

That's why someone may hear their myeloma described as IgG kappa, IgG lambda, IgA kappa, IgA lambda, or another combination.

IgG Myeloma

IgG is the most common immunoglobulin type associated with multiple myeloma.

A patient may have either IgG kappa or IgG lambda myeloma, depending on which light chain the abnormal plasma cells produce.

IgA Myeloma

IgA myeloma is another relatively common type.

Just like IgG myeloma, it can be associated with either kappa or lambda light chains.

Light-Chain Myeloma

Some myeloma cells don't produce a complete immunoglobulin at all. Instead, they primarily produce abnormal free light chains.

This is known as light-chain multiple myeloma.

The light chains are either kappa or lambda and historically have also been associated with the term Bence Jones proteins, particularly when abnormal light chains are detected in the urine.

Free light chains are especially important because excessive amounts can damage the kidneys.

IgD and IgE Myeloma

IgD myeloma is uncommon, and IgE myeloma is extremely rare.

Because these forms are seen much less frequently, they can sometimes present differently from the more common IgG and IgA forms.

IgM myeloma also exists but is exceptionally rare and must be distinguished from other blood cancers that more commonly produce an IgM monoclonal protein.

Nonsecretory Myeloma

Most people with multiple myeloma have an abnormal protein that doctors can measure in their blood or urine.

A small percentage do not produce easily measurable monoclonal proteins. This is generally referred to as nonsecretory myeloma.

Modern free-light-chain testing has shown that some patients once considered nonsecretory actually produce small amounts of light chains that older testing couldn't detect.

What About Plasmacytoma?

Plasmacytomas are closely related to multiple myeloma, but they aren't simply another subtype of active MM.

A solitary plasmacytoma of bone is a single localized tumor made of abnormal plasma cells in bone without the widespread bone marrow involvement required for a diagnosis of multiple myeloma.

An extramedullary plasmacytoma develops in soft tissue outside the bone marrow, frequently in areas of the upper respiratory tract.

Some people with a solitary plasmacytoma eventually develop multiple myeloma, which is why continued monitoring is important.

Active, Smoldering and MGUS

Another source of confusion is the difference between MGUS, smoldering multiple myeloma and active multiple myeloma.

MGUS involves a small population of abnormal plasma cells or monoclonal protein without the findings required for myeloma.

Smoldering multiple myeloma involves a greater amount of abnormal plasma cells or monoclonal protein but does not meet the criteria for active disease.

Active multiple myeloma is diagnosed when specific myeloma-defining events are present.

Doctors often use the acronym SLiM-CRAB when evaluating this.

CRAB refers to:

C — Calcium elevation
R — Renal (kidney) problems
A — Anemia
B — Bone lesions

The “SLiM” portion adds specific biomarkers that can identify patients at such a high risk of progression that treatment is recommended even before traditional CRAB organ damage develops.

This distinction is important because active myeloma does not always require existing organ damage before treatment begins.

Then There Is the Genetics of Myeloma

Knowing whether someone has IgG kappa or IgA lambda is only one part of understanding their disease.

Doctors also study the genetics of the myeloma cells themselves.

FISH testing looks for specific chromosomal abnormalities within myeloma cells. Certain abnormalities can help doctors understand the biology and risk characteristics of the disease and may influence treatment decisions.

Cytogenetic testing examines chromosomes for abnormalities, although traditional chromosome analysis and FISH provide somewhat different information.

Gene-expression profiling examines patterns of gene activity within myeloma cells. It has been used in research and some specialized settings to help assess disease biology and risk.

These tests don't tell us that someone inherited myeloma. Instead, many of the abnormalities being examined are acquired changes within the cancer cells themselves.

Why Does Your Type Matter?

Multiple myeloma isn't one identical disease shared by every patient.

One person may have IgG kappa myeloma with standard-risk genetic features. Another may have light-chain disease with kidney involvement. Someone else may have IgA lambda myeloma with a high-risk chromosomal abnormality.

They're all living with multiple myeloma, but the biology of their cancers can be very different.

That is one reason myeloma treatment has become increasingly individualized.

Initial treatment today commonly uses combinations of three or four medications from different drug classes, but the exact regimen isn't automatically the same for everyone. Doctors consider factors such as age, overall health, kidney function, transplant eligibility, disease characteristics, genetic risk and previous medical conditions when choosing treatment.

The Most Important Thing to Know

If you've been diagnosed with multiple myeloma, don't be afraid to ask:

What type of myeloma do I have?
Is it kappa or lambda?
What does my FISH testing show?
Do I have any high-risk abnormalities?
How does that information affect my treatment and monitoring?

Multiple myeloma may share one name, but underneath that name are many different biological versions of the disease.

Understanding your myeloma is one of the first steps toward understanding your treatment.

Multiple Myeloma: Evidence of an Ancient Disease That Predates History

 

Prof. Botella López explains: "Both mummies were still wrapped in spectacular shrouds of multi-colored faience beads, which in turn resemble a mask. The body structures of mummies from this period are superbly preserved, and we can discern very clearly what their faces looked like."

The oldest known case of multiple myeloma (and breast cancer) in the world has been found by an international team that includes researchers from the UGR's anthropology group under the direction of Prof. Miguel Cecilio Botella López of the Department of Legal Medicine, Toxicology, and Physical Anthropology.

CT scans of the 3,800-year-old male mummy found in the Egyptian necropolis of Qubbet el-Hawa in Aswan were used to make the findings. The multiple myeloma patient passed away around 1800 B.C. and belonged to the ruling classes of the ruling Egyptian families of Elephantine, or at the very least to the wealthy classes. Since acute infections either result in death or are treated within a brief period of time and, as a result, do not leave any marks on bones, researchers believe that acute infections are the most likely cause of death in this mummy.

Professor Miguel Cecilio Botella López described the remarkable condition of the ancient remains: “Both mummies were still wrapped in spectacular shrouds of multi-colored faience beads, which in turn resemble a mask. The body structures of mummies from this period are superbly preserved, and we can discern very clearly what their faces looked like.”

An international team of researchers, including scientists from the University of Granada’s anthropology group, identified what was reported as the oldest known case of multiple myeloma at the time of the discovery.

Researchers used CT scans to examine the approximately 3,800-year-old male mummy discovered in the ancient Egyptian necropolis of Qubbet el-Hawa, near Aswan. The man lived around 1800 B.C. and is believed to have belonged to the ruling or wealthy classes associated with Elephantine.

The scans revealed numerous small lesions throughout his skeleton. Their pattern and distribution were consistent with multiple myeloma, providing remarkable evidence that this disease affected humans thousands of years before modern medicine had a name for it.

Researchers could identify signs of the disease in his bones, but determining exactly what caused his death is much more difficult. Acute infections, for example, can kill quickly without leaving obvious evidence in skeletal remains. This means we may never know whether multiple myeloma itself, an infection, or another complication ultimately caused his death.

What we do know is fascinating: multiple myeloma is not a modern disease. Its story reaches back nearly 4,000 years.

 

Is Multiple Myeloma Inherited? What Families Should Know

When someone is diagnosed with multiple myeloma, it's natural for family members to wonder: Could I get it too? Did I pass something on to my children?

The simple answer is that multiple myeloma is not considered an inherited cancer in the traditional sense. You don't inherit myeloma directly from a parent, and there isn't one specific "myeloma gene" that determines whether someone will develop the disease.

However, genetics may still play a role.

Family History Can Increase Risk

Research has found that people with a first-degree relative—a parent, sibling, or child—with multiple myeloma have a higher risk of developing myeloma themselves compared with someone without that family history.

That can sound frightening, but it's important to put the increase in perspective.

Multiple myeloma is still a relatively uncommon cancer. Even when a person's relative has myeloma, the absolute chance that they will develop the disease remains low.

In other words, having myeloma in your family does not mean other family members are destined to develop it.

So, What Is Being Inherited?

Scientists have identified a number of inherited genetic variations associated with an increased susceptibility to multiple myeloma and its precursor condition, MGUS (monoclonal gammopathy of undetermined significance).

These genetic differences don't directly cause myeloma. Instead, they may make someone slightly more susceptible to developing the biological changes that can eventually lead to the disease.

Think of genetics as one piece of a much larger puzzle.

Age, ancestry, environmental exposures, changes that occur within plasma cells over a person's lifetime, and other factors that researchers are still trying to understand may all contribute.

What About MGUS?

Nearly all cases of multiple myeloma are preceded by MGUS, although most people with MGUS will never develop multiple myeloma.

That makes MGUS particularly important to researchers.

Instead of waiting until someone develops active myeloma, scientists can study people with MGUS—or those who have a greater likelihood of developing it—to better understand why the condition progresses in some people but remains harmless in many others.

The PROMISE Study

One important research project is the PROMISE Study, which is investigating people who may have a higher risk of developing multiple myeloma.

The study has included individuals with a first-degree relative who has multiple myeloma or another blood cancer, as well as Black/African American individuals, because multiple myeloma and MGUS occur more frequently in this population.

Researchers hope that identifying MGUS and studying people at increased risk will eventually help us better understand who develops myeloma, why progression occurs, and whether earlier intervention could someday prevent active disease.

Should Family Members Be Tested?

At this time, routine genetic testing or screening for every relative of someone with multiple myeloma is not generally recommended simply because myeloma runs in the family.

However, people with a strong family history may want to discuss it with their healthcare provider. Research programs such as PROMISE may also provide screening opportunities for people who meet their eligibility requirements.

The Bottom Line

Multiple myeloma isn't directly inherited, but susceptibility to developing it can run in families.

Having a parent, sibling, or child with myeloma may increase your risk compared with the general population, but the overall likelihood of developing the disease remains relatively small.

Research into inherited risk, MGUS, and the earliest biological changes leading to myeloma continues to grow. What scientists learn may eventually allow us to identify people at greater risk much earlier—and perhaps one day stop myeloma before it ever becomes active disease.

https://www.enroll.promisestudy.org/

What's in Your Blood—and What Does It Have to Do With Myeloma?

 

Before we can really understand multiple myeloma, it helps to understand what is happening inside our blood and bone marrow.

Blood may look like one simple red liquid, but it is actually made up of several different components, each with an important job.

What's in Blood?

Blood contains four major components:

Red blood cells carry oxygen from the lungs throughout the body and bring carbon dioxide back to the lungs. When myeloma interferes with the production of red blood cells, anemia can develop, causing fatigue, weakness, and shortness of breath.

White blood cells are part of the immune system and help protect the body against infections.

Platelets help the blood clot and control bleeding.

Plasma is the pale yellow liquid portion of blood. It makes up more than half of our blood and carries blood cells, proteins, nutrients, hormones, antibodies, electrolytes, and waste products throughout the body.

But here's where myeloma can get a little confusing.

Plasma Isn't the Same as a Plasma Cell

Despite their similar names, plasma and plasma cells are two different things.

Plasma is the liquid part of your blood.

Plasma cells are specialized white blood cells that develop from B lymphocytes and are found primarily in the bone marrow. Their job is to produce antibodies—also called immunoglobulins—that help protect us from infection.

And plasma cells are where multiple myeloma begins.

Antibodies and Myeloma

Healthy plasma cells make antibodies that recognize and help fight bacteria, viruses, and other threats.

Antibodies contain heavy chains and light chains. The five major heavy-chain classes are IgG, IgA, IgM, IgD, and IgE. The two types of light chains are kappa and lambda.

Normally, many different plasma cells produce many different antibodies to protect us against a wide variety of infections.

With multiple myeloma, however, one abnormal plasma cell begins multiplying, creating a large group—or clone—of abnormal plasma cells.

These myeloma cells may produce large amounts of one abnormal immunoglobulin or part of an immunoglobulin.

You may hear this abnormal protein called an M-protein, monoclonal protein, paraprotein, or M-spike. Some forms of myeloma primarily produce abnormal free light chains rather than a complete immunoglobulin, and a small percentage produce little or no measurable monoclonal protein.

When Abnormal Plasma Cells Take Over

The problem isn't simply having an abnormal protein.

As myeloma cells multiply inside the bone marrow, they can interfere with the body's ability to produce healthy blood cells. This can contribute to anemia, weakened immunity, and sometimes low platelet counts.

Myeloma cells also interact with the surrounding bone marrow environment in ways that can damage bones. The abnormal proteins produced by myeloma cells can contribute to kidney damage in some patients.

This is why multiple myeloma can affect much more than the blood.

It can affect the bone marrow, bones, kidneys, immune system, and other parts of the body.

What About MGUS?

Finding a monoclonal protein does not automatically mean someone has multiple myeloma.

Some people have a condition called MGUS—monoclonal gammopathy of undetermined significance. MGUS involves a monoclonal protein or abnormal plasma-cell population but does not meet the criteria for active multiple myeloma.

Most people with MGUS will never develop multiple myeloma, although doctors generally monitor it because a small percentage of people progress each year.

There is also an intermediate condition called smoldering multiple myeloma, in which there are more abnormal plasma cells or monoclonal protein than with MGUS but no myeloma-defining event requiring treatment.

Understanding the Blood Helps Us Understand Myeloma

Multiple myeloma is often called a blood cancer, but much of the disease begins deep inside the bone marrow, where our blood cells are made.

Understanding the difference between blood plasma and plasma cells—and knowing what red cells, white cells, platelets, antibodies, and bone marrow actually do—makes it much easier to understand why myeloma can cause such a wide variety of symptoms and complications.

The more we understand what is supposed to happen inside healthy blood and bone marrow, the easier it becomes to understand what changes when myeloma enters the picture. As of February 2023, it is impossible to cure this cancer.