Smoldering multiple myeloma (SMM)

Smoldering multiple myeloma (SMM), also called smoldering myeloma, is a condition in which changed plasma cells build up in the bone marrow. Plasma cells are white blood cells that help fight infection. The changed cells make protein that is not typical. It is called monoclonal protein, or M protein.

SMM is more advanced than the plasma cell condition known as monoclonal gammopathy of undetermined significance (MGUS) but it is not active multiple myeloma. SMM does not cause the organ damage or other changes that define active multiple myeloma.

SMM is sometimes described as a very early form of blood cancer. It also may be described as a condition that comes before active multiple myeloma. Although SMM involves changed plasma cells, it is not active multiple myeloma because it has not caused the damage or other changes that define active disease.

Some people have low-risk SMM that may remain stable for years. Others have high-risk SMM and are more likely to develop active multiple myeloma. Learning that you have SMM can bring worry. Regular testing helps your healthcare team understand your risk and decide whether monitoring or treatment may be right for you.

People with high-risk SMM have a greater chance of developing active multiple myeloma. Some healthcare professionals describe high-risk SMM as an early form of multiple myeloma that has not caused symptoms.

Smoldering multiple myeloma causes no symptoms. There are no recognized early-stage or late-stage SMM symptoms.

Symptoms that appear during monitoring may be due to another condition. But they also may mean that SMM has worsened, also called progressed, to active multiple myeloma. Possible symptoms include:

• New or ongoing bone pain, especially in the back, ribs or hips.
• A broken bone that happens with little or no injury.
• Fatigue, weakness or shortness of breath.
• Frequent or serious infections.
• Nausea, constipation, confusion or thirst that is not usual.
• Passing less urine or having swelling in the legs.
• New numbness, tingling or weakness.

Bone lesions, which are areas of damaged or changed bone, do not occur with SMM. If myeloma causes a bone lesion, the condition may be diagnosed as active multiple myeloma.

A rash is not a typical symptom of SMM. Tell your care team about a new rash, especially if it develops after starting treatment. Neuropathy, which can cause numbness, tingling or burning pain, is not typical of SMM either.

Contact your care team right away if you have a new symptom, even if it seems mild. Symptoms that need medical review include:

• Lasting or worsening bone pain.
• A possible broken bone.
• Increasing fatigue or shortness of breath.
• Frequent infections or a fever.
• Changes in urination or new swelling.
• Numbness, tingling or weakness.
• Confusion, thirst that is not typical, nausea or constipation.

Get emergency care for severe back pain with sudden leg weakness or numbness, trouble walking, or loss of bladder or bowel function. These symptoms may be caused by pressure on the spinal cord.

The exact cause of smoldering multiple myeloma is not known.

SMM develops when one group of plasma cells grows more than expected and produces M protein. Many people first have monoclonal gammopathy of undetermined significance (MGUS), a less advanced plasma cell condition. MGUS may remain stable. Or it may progress to SMM or active multiple myeloma.

Researchers continue to study the genetic and biological changes that allow plasma cells to grow and SMM progress.

The factors that cause a person to develop smoldering multiple myeloma are not fully understood. Factors linked with SMM include:

• MGUS. SMM may develop during follow-up for MGUS.
• Older age. SMM is most often diagnosed in older adults.
• Sex at birth. SMM happens more often in men.

Most people with these factors do not develop SMM. There is no known lifestyle change that reliably prevents it.

Progression to active multiple myeloma

The main complication of smoldering multiple myeloma is that it may worsen, also called progress, to active multiple myeloma. Progression means the plasma cells have increased or changed enough to cause organ damage or other findings that define active disease.

Active multiple myeloma can cause:

• Bone damage or broken bones.
• Anemia, which means having too few red blood cells.
• Kidney damage.
• Hypercalcemia, which means high calcium levels in the blood.
• Frequent or serious infections.

SMM does not always progress. In a systematic review, about 23% of people across all risk groups progressed within 2 years and about 60% progressed within 10 years. Among people classified as high-risk, about 45% progressed within 2 years and about 86% progressed within 10 years. These numbers describe groups of people. They cannot predict whether or when SMM will progress in one person.

Amyloidosis

SMM and amyloidosis are different plasma cell conditions. A diagnosis of SMM requires that there be no evidence of light-chain amyloidosis, also called AL amyloidosis. If testing finds AL amyloidosis, the diagnosis and treatment approach are different.

Myelodysplastic syndromes

SMM and myelodysplastic syndromes are different conditions that affect bone marrow. Current evidence does not show that SMM causes myelodysplastic syndromes. Low blood cell counts can have many causes, so they need medical evaluation.

There is no routine screening recommendation for people at average risk of smoldering multiple myeloma. The condition typically is found when a blood test done for another reason shows M protein. It also may be found during follow-up for MGUS. The goals of testing are to:

• Confirm that a plasma cell condition is present.
• Distinguish SMM from MGUS and active multiple myeloma.
• Check for organ damage.
• Estimate the risk of progression.

Diagnostic criteria

SMM is diagnosed when testing finds one or both of the following:

• M protein level in the blood of at least 3 grams per deciliter, or M protein level in the urine of at least 500 milligrams in 24 hours.
• Changed plasma cells making up 10% to less than 60% of the cells in the bone marrow.

For a diagnosis of SMM, you also mush not have light-chain amyloidosis or a myeloma-defining event. Light-chain amyloidosis, also called AL amyloidosis, is a different plasma cell condition. A myeloma-defining event is a sign that plasma cells are causing organ damage or that test results meet the criteria for active multiple myeloma.

Myeloma-defining events include organ damage sometimes grouped under the term CRAB:

• C — High calcium. A blood calcium level above the diagnostic threshold.
• R — Kidney, also called renal, issues. Kidney function below the diagnostic threshold.
• A — Anemia. A hemoglobin level below the diagnostic threshold because of myeloma.
• B — Bone damage. One or more bone lesions caused by myeloma.

Other test results that may mean SMM has become active multiple myeloma include:

• Plasma cells make up 60% or more of the bone marrow.
• A blood test shows a free light-chain ratio of 100 or higher, and the involved light-chain level is at least 100 milligrams per liter.
• An MRI shows more than one area of changed bone marrow, with each area measuring at least 5 millimeters.

Your care team interprets these results together. One result alone may not provide enough information to make a diagnosis.

Differences between MGUS, SMM and active multiple myeloma

A myeloma-defining event is a sign that plasma cells are causing organ damage or have reached a level that meets the definition of active multiple myeloma.

The main differences are:

• MGUS: The M protein level is below 3 grams per deciliter, plasma cells make up less than 10% of the bone marrow, and there are no myeloma-defining events.
• Smoldering multiple myeloma: The M protein level or the number of plasma cells in the bone marrow meets the definition of SMM, but there are no myeloma-defining events or light-chain amyloidosis.
• Active multiple myeloma: Testing finds a myeloma-defining event, such as organ damage caused by myeloma or certain high-risk test results.

Tests

Your care team may use the following tests:

• Blood tests. A complete blood count measures blood cells. Other tests measure calcium, kidney function, M protein, immunoglobulins and serum free light chains.
• Urine tests. A 24-hour urinalysis may measure M protein and show how the plasma cell condition is affecting the kidneys.
• Bone marrow testing. A bone marrow biopsy measures plasma cells and allows testing of their chromosomes and genes. The procedure may cause short-term soreness, bruising or bleeding.
• Imaging. A whole-body low-dose CT scan, MRI or positron emission tomography (PET) scan may look for bone lesions or areas of changed bone marrow.
• Repeat testing. Blood, urine and imaging tests are repeated over time. Changes in results may be as important as a single measurement.

Risk level

Your healthcare team uses a risk assessment to estimate how likely SMM is to change to active multiple myeloma. This is called progression. The risk is different for each person and may change as test results differ over time.

How the 20/2/20 model works

The 20/2/20 model, also called the 2/20/20 model, uses three test results:

• Plasma cells make up more than 20% of the bone marrow.
• The M protein level in the blood is more than 2 grams per deciliter.
• The ratio of involved to not involved serum free light chains is more than 20. Free light chains are parts of antibodies made by plasma cells.

The number of these findings determines the risk group:

• Low risk: No findings. The estimated risk of progression within 2 years is 6%.
• Intermediate risk: One finding. The estimated risk of progression within 2 years is 18%.
• High risk: Two or three findings. The estimated risk of progression within 2 years is 44%.

High risk does not mean that SMM will become active multiple myeloma. These percentages are estimates based on groups of people. Genetic changes in plasma cells and changes over time in M protein, light chains, hemoglobin and kidney function can help your care team understand your risk estimate.

Treatment depends on the risk of progression, test results, age, overall health and personal preferences. Active monitoring and early treatment may both be reasonable options for some people with high-risk SMM.

Active monitoring

Active monitoring means having regular visits and tests without starting medicine right away. It also is called active surveillance or observation.

Monitoring may include:

• A physical exam and review of symptoms.
• Blood and urine tests.
• Imaging when needed.
• A repeat bone marrow biopsy in some situations.
• Reassessment of the risk category.

Visits often occur every few months at first. Your care team decides the schedule based on your results and risk level.

Active monitoring avoids treatment side effects when treatment may not yet be needed. It is important to keep every follow-up appointment because SMM can progress without obvious symptoms.

Treatment for high-risk SMM

A medicine containing daratumumab may be given to adults with high-risk SMM. The medicine is given by shot, also called injected, under the skin. Daratumumab is a monoclonal antibody that attaches to a protein called CD38 on plasma cells.

In a study of 390 people with high-risk SMM, daratumumab reduced the risk of progression or death by 51% compared with active monitoring. At 5 years, 63.1% of people who received daratumumab did not die or have disease progression, compared with 40.8% of those receiving active monitoring.

Possible risks include:

• Reactions during or after an injection.
• Infections.
• Low levels of certain white blood cells.
• Thrombocytopenia, which is a low platelet count.
• High blood pressure (hypertension), also called hypertension.
• Effects on blood-matching tests before a transfusion.

This treatment is approved for adults with high-risk SMM. It is not approved for other SMM risk groups. Talk with your care team about the possible benefits and side effects, as well as how treatment may affect your daily life.

Can smoldering multiple myeloma be cured?

SMM may remain stable for many years, but it does not usually go away on its own. Treatment for high-risk SMM aims to delay or prevent progression to active multiple myeloma. Researchers are studying whether early treatment can provide long-term control or cure SMM in some people.

No diet, supplement or lifestyle change has been shown to cure SMM or reliably keep it from progressing. Healthy habits can support your overall health and help you stay as healthy as possible if you need treatment.

Consider these steps:

• Go to all monitoring and imaging appointments.
• Tell your care team about new symptoms.
• Stay physically active at a level your care team says is safe.
• Eat a varied, balanced diet unless your care team recommends specific restrictions. Dietary approaches are being studied, but none has been proven to prevent SMM progression.
• Ask how to protect your bones and reduce your risk of falls.
• Review vitamins, herbs and other supplements with your care team before taking them.
• Ask which vaccinations are appropriate for you.

Avoid making major diet changes or taking supplements based on claims that they can eliminate M protein. Evidence does not support these claims.

Living with a condition that may or may not get worse can cause worry. Understanding your monitoring plan may make the worry easier to manage.

It may help to:

• Ask your care team to explain your risk category in plain language.
• Find out which changes in test results would lead to more testing or treatment.
• Keep copies of your laboratory and imaging reports.
• Write down questions that you have between visits.
• Talk with a mental health professional if worry affects sleep or daily activities.
• Connect with a support group for people with plasma cell conditions.
• Invite someone you trust to go with you to appointments when you want help taking notes.

You may first talk with your primary healthcare professional about test results outside of the standard range. You may then be referred to a doctor who specializes in blood conditions. This doctor is called a hematologist.

What you can do

Before the appointment:

• Ask whether you need to fast or prepare for any tests.
• Gather previous blood and urine test, imaging, and bone marrow biopsy results.
• Make a list of your medicines, vitamins and supplements.
• Write down symptoms and when they began.
• Note any family history of blood cancers or plasma cell conditions.
• Gather your insurance information and appointment schedule.
• Consider asking someone you trust to go with you or join by phone.

Questions to ask include:

• Do my results show MGUS, SMM or active multiple myeloma?
• Which findings confirm the diagnosis?
• What is my current risk category?
• Which risk model do you use?
• How often will I need blood tests, urine tests or imaging?
• Which symptoms should I report right away?
• Should I consider treatment or a clinical trial?
• What are the possible benefits and risks of daratumumab?
• Could another condition be the reason for my test results?
• How will we know if SMM has progressed?

What to expect from your doctor

Your healthcare professional may ask:

• Why were the first tests ordered?
• Have you had bone pain, fatigue or frequent infections?
• Have you noticed changes in urination, thirst or bowel habits?
• Have you had numbness, tingling or weakness?
• Have you had broken bones you can't explain?
• Do you have kidney disease, anemia or osteoporosis?
• Does anyone in your family have a plasma cell condition or blood cancer?
• Which medicines and supplements do you take?

Smoldering multiple myeloma does not use numbered stages such as stage 1, stage 2 or stage 3. Instead, it is classified by the risk of progression.

If a myeloma-defining event occurs, the diagnosis changes to active multiple myeloma. The care team then stages the active myeloma and creates a treatment plan.

There is no single 5-year or 10-year survival rate for everyone with SMM. Survival depends on factors such as age, overall health, risk level, treatment and whether SMM progresses to active multiple myeloma.

In a phase 3 study of people with high-risk SMM:

• 93% of people who received daratumumab were alive after 5 years.
• 86.9% of people who had active monitoring were alive after 5 years.

These results apply only to people who met the study’s requirements. They cannot predict what will happen to one person.

A separate review looked at how often SMM progressed to active multiple myeloma. By 10 years, about 60% of people across all risk groups had progression. Among people with high-risk SMM, about 86% had progression.

If SMM progresses, it becomes active multiple myeloma. Then, a person's outlook depends on factors such as age, overall health and treatment.