Smoldering multiple myeloma: What it is, how it progresses and the latest research

By Jessica Saenz

Multiple myeloma is a type of blood cancer caused by a buildup of abnormal plasma cells in the bone marrow. As the abnormal plasma cells accumulate, they crowd out healthy cells and cause symptoms such as bone pain and tiredness.

In 1980, Drs. Robert Kyle and Philip Greipp, Mayo Clinic hematologists, coined the term "smoldering multiple myeloma" to describe an accumulation of abnormal plasma cells in the bone marrow without any symptoms. Hematologists now know this condition usually has all the biological features of cancer and is associated with a high risk of progression to multiple myeloma.

Cancer researchers have since been investigating how, why and when smoldering multiple myeloma (SMM) progresses to active multiple myeloma and what can be done to delay progression.

S. Vincent Rajkumar, M.D., and Rafael Fonseca, M.D., Mayo Clinic Comprehensive Cancer Center hematologists, explain what SMM is and how treating it could delay or prevent multiple myeloma.

What is smoldering multiple myeloma?

The first phase of abnormal plasma cells building up in the bone marrow without causing symptoms or complications is a benign (noncancerous) condition called monoclonal gammopathy of undetermined significance (MGUS). Approximately 10% of people diagnosed with MGUS will develop multiple myeloma in their lifetime.

If abnormal plasma cells continue to accumulate and acquire additional biological abnormalities, MGUS evolves into SMM.

"Multiple myeloma is a malignancy (cancer) often associated with symptoms such as anemia, hypercalcemia and renal (kidney) failure. Smoldering multiple myeloma has many features of malignancy, but it is asymptomatic, so people don't know they have it," says Dr. Rajkumar, the Edward W. and Betty Knight Scripps-Edward C. Rosenow III, M.D., Professor of Medicine.

These conditions are more alike than not. "Through careful genetic analysis, we have learned that we cannot differentiate SMM from the active form of the disease," says Dr. Fonseca, the Getz Family Professor of Cancer.

When does smoldering multiple myeloma progress to multiple myeloma?

Dr. Rajkumar says researchers are trying to understand better when SMM progresses to multiple myeloma. "Some patients have low-risk smoldering multiple myeloma, which can stay dormant for a period of time but has a higher risk of progression than the precancerous MGUS stage, while other patients have high-risk smoldering multiple myeloma, which is more like full-blown multiple myeloma that is asymptomatic," he says.

High-risk SMM is more likely to progress to multiple myeloma than low-risk SMM.

"We expect disease progression in the first two years in about 50% of patients with high-risk SMM. After that, the rate of progression goes down, but we have followed patients from older clinical trials and found that the vast majority of people with high-risk SMM will eventually develop multiple myeloma," he says.

Dr. Rajkumar recommends that people diagnosed with MGUS or SMM seek care at a healthcare institution that specializes in myeloma and other blood disorders. "Patients need to be carefully evaluated to find out whether they have SMM, MGUS or active multiple myeloma. If they do have SMM, they need to know if it is low or high risk."

These questions sometimes require a second opinion. "Many of the referrals I get are from physicians and patients struggling with the question: 'Should we treat or not treat?' Even in high-risk SMM, the numbers and the condition's features matter. So, we are careful when counseling patients," says Dr. Rajkumar.

Is there screening for smoldering multiple myeloma?

There are no screening recommendations for SMM, so it is usually diagnosed by accident. As abnormal plasma cells accumulate, they release monoclonal proteins, or M proteins, into the blood. MGUS and SMM are sometimes discovered because a blood test conducted for another reason indicates the presence of these M proteins.

Dr. Rajkumar and other researchers are still weighing the risks and benefits of screening more people for SMM. Until they learn more, he does not recommend screening people with average risk.

"There might be some populations with high risk who should be considered for screening," says Dr. Rajkumar. "That includes people with two or more relatives with a history of multiple myeloma or people with African ancestry who have a relative with myeloma."

Hope for slowing multiple myeloma development.

Active surveillance is currently the standard of care for SMM. However, Dr. Rajkumar recently led a clinical trial to investigate whether treating patients with high-risk SMM could slow its progression.

"In this trial, we found that by the six-year mark after SMM diagnosis, 80% to 90% of patients in the observation arm of the trial had enough progression that many physicians would begin myeloma treatment," says Dr. Rajkumar.

Study results published in December 2024 showed promise toward a path to treat SMM. "The trial involved 390 patients with high-risk SMM. Half of the patients had careful active monitoring. The other half received daratumumab, a drug used to treat active multiple myeloma. The trial found that early intervention using daratumumab, which was given for three years, delayed progression to active myeloma and prolonged overall survival," says Dr. Rajkumar.

Dr. Rajkumar says multiple myeloma treatment often involves three to four drugs, bone marrow transplant and continuous therapy, which affect patients' quality of life. Slowing SMM's progression to active multiple myeloma also delayed the need for treatment. "The trial accomplished this with reasonable safety and without adversely affecting quality of life," he says. "This is a major finding."

"While there is still some debate about how to select these patients, I have no doubt this will be the future of timely intervention. Ideally, we'll be able to treat patients before they have to suffer from complications of the disease," says Dr. Fonseca. "It is because of rigorous clinical trials like Dr. Rajkumar's that we can start envisioning a brighter future for people with myeloma."

Learn more

Learn more about multiple myeloma and find a clinical trial at Mayo Clinic.

Join the Blood Cancers and Disorders Support Group on Mayo Clinic Connect, an online community moderated by Mayo Clinic for patients and caregivers.

Also, read these articles:

• Research shows new treatment could delay cancer progression in patients with high-risk smoldering multiple myeloma
• Multiple myeloma: Its evolution, treatment and the quest to catch it early
• CAR-T cell researchers at Mayo Clinic optimistic about future of treating blood cancers
• Advances in multiple myeloma treatment