What Drives Smoldering Myeloma to Active Myeloma?

Smoldering multiple myeloma is a slow-growing precursor stage to multiple myeloma. A person with smoldering myeloma has signs of myeloma, such as abnormal plasma cells and/or protein in the blood and urine, but no symptoms. 

Predicting the risk of smoldering myeloma progressing to active myeloma is important, and research is ongoing to better understand what factors can influence this risk. At the 2025 International Myeloma Society annual meeting in Toronto, experts shared a wide variety of factors such as genetics, weight, environmental exposures and immune system function that can all increase the risk of progression. 

Are there genetic factors that cause smoldering myeloma to progress?

Mehmet Samur, MD of the Dana Farber Cancer Institute focused on genetic factors. Genetic changes in smoldering myeloma patients are detectable even at the smoldering stage. He shared that 82% of people with smoldering myeloma already have clonal mutations. Of those, 67% have mutations that are unchanging, 18% have clones that start to grow, and 15% have clones that are starting to change. 

There are specific mutations that are known to advance smoldering myeloma to active myeloma. Mutations that predict higher progression include: 

• APOBEC, which plays a role in DNA and RNA editing.
• GSS, which is an antioxidant.
• NRAS mutations, which can promote cell survival and cause resistance to cell death.

Gene losses or gene additions can also influence disease progression.

Dr. Samur proposed that genetics be combined with the standard 20/2/20 smoldering risk model. According to this model, smoldering myeloma with more than 20% of bone marrow plasma cells, an m-protein over 2 g/dL, and a free light chain ratio over 20 is considered high risk. 

When he added genetics to the 20/2/20 model, Dr. Samur said that patients who would progress to active myeloma could be identified quickly. Patients that weren’t considered high risk according to the combined models were going beyond 5 years without disease progression. 

What role does the immune system play in smoldering myeloma progression?

The immune system can also play a role, according to immunotherapy expert Madhav Dhodapkar, MD of the Fred Hutchinson Cancer Center. He noted that age impacts immune function and so does the status of the microbiome. Having good gut diversity matters for a healthy microbiome. 

What is important when monitoring smoldering myeloma?

Sigurður Kristinsson, MD of the University of Iceland has significant experience in precursor conditions, leading a countrywide screening effort to detect the earlier precursor to smoldering myeloma, called MGUS, in the entire population of Iceland. He noted that smoldering myeloma is common and progression from smoldering myeloma to active myeloma is on the rise. 

He noted that what matters are trends over time. Each clinic visit you have with your physician should be about evaluating the change, not looking back at your baseline value. He stressed that each patient needs to be evaluated individually. 

What do we know about the causes of smoldering myeloma progression?

Natalie Callander, MD of the University of Wisconsin added to the list of potential causes of progression. She shared well-known causes of environmental risk factors like asbestos, paint, fertilizer, agent orange, being a 911 responder, radiation, and air pollution. Other risk factors that more than doubled progression included:

• Age
• Race, with Black patients having a higher incidence
• Autoimmune disorders like rheumatoid arthritis, pernicious anemia, and Sjorgren’s syndrome
• Chronic infections and chronic immunosuppression for transplant recipients
• Body mass index (BMI) over 30. 

Dr. Callander suggested that Black patients and those who were family members of myeloma patients join the PROMISE study being run at Dana Farber Cancer Institute to help identify additional reasons for disease progression. 

Dr. Callendar noted that it was becoming more common to break the disease into two types of smoldering myeloma—one is more like MGUS, with a low risk of progression, while the other is more like actual myeloma. 

Smoldering myeloma can be a stressful condition for patients. Finding better methods to determine which patients will progress and which won’t will help both patient and provider better manage the condition both clinically and psychologically.  

Read the latest myeloma research on HealthTree.

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