Genetic Changes Can Predict Smoldering Myeloma Progression

Smoldering multiple myeloma (SMM) is a slow-growing precursor stage to multiple myeloma. For some people, this disease progresses to multiple myeloma, but for others it does not. For patients diagnosed with smoldering multiple myeloma, they often have a single, stressful question top of mind: “Will my disease progress?” The standard “watch and wait” approach, while safe for many, can produce anxiety and feel like waiting for bad news. 

Mehmet Samur, MD of Dana Farber Cancer Institute presented groundbreaking research at the International Myeloma Society 2025 conference in Toronto showing how scientists are delving into the genetic code of smoldering myeloma cells to create a forecast that could change how we manage this precursor disease forever.

The study aimed to map the genomic journey from smoldering myeloma to active multiple myeloma, identifying the key genetic events that drive this transition. By sequencing the entire genome of hundreds of smoldering myeloma patients, researchers are beginning to understand not just what changes but when. This provides crucial clues for predicting a patient’s future risk.

Key drivers of disease progression are present from the start

One of the most profound findings from the study is that the fundamental genetic drivers of myeloma are established very early, often long before the disease becomes symptomatic. 

When researchers compared samples from the same patients, one taken at their smoldering myeloma diagnosis and another after they progressed to active myeloma, they found remarkable stability. The vast majority of the driver mutations and major genetic abnormalities that define a patient’s myeloma were already present in the SMM cells.

It is like an architecture blueprint for a building. The core design that defines the final structure (active myeloma) is already laid out when only the foundation (smoldering myeloma) is visible.

This was further confirmed by studying the “clones,” or distinct families, of cancer cells. The analysis revealed that 82% of patients who progress to myeloma do so with a dominant clone that was already present and detectable at their initial smoldering myeloma diagnosis. The foundational genetic landscape, it seems, is set in stone from the beginning. 

An unstable foundation: How the genome evolves over time

If the main drivers don’t change, what pushes the disease from smoldering myeloma to multiple myeloma? The answer lies in genomic instability. 

While the primary blueprint remains the same, the entire genome becomes more chaotic and fragile as time goes on. Dr. Samur’s research showed that as smoldering myeloma progresses, the cells accumulate a host of smaller, widespread DNA alterations. These aren’t specific driver mutations, but rather a sign of general damage. These “genomic scars” build up, increasing the likelihood that the disease will advance.

What separates progressors from non-progressors?

The most critical goal of this research was to identify the specific genetic red flags that distinguish people with smoldering myeloma who will likely progress from those who will remain stable. To conduct this kind of deep genetic analysis, scientists must first isolate the myeloma cells from a patient’s bone marrow. This is often done using advanced lab techniques like flow cytometry, which can identify and sort a specific cell population based on protein markers.

By comparing the genomes of these isolated cells from the two groups, several key differences emerged. The smoldering myeloma patients who progressed to active myeloma were significantly more likely to have: 

• Gain of chromosome 1q (gain(1q)) and alterations on chromosome 8. 
• Mutations in a specific driver gene called ANP32E. 
• A higher frequency of mutations in the critical tumor suppressor gene TP53.
• Alterations in the cancer-driving MYC gene.
• Higher overall genomic instability, including more total mutations, deletions, and “genomic scar” scores. 

These markers act as a genetic signature, providing the first clear, biological distinction between a stable smoldering myeloma and one on the verge of becoming active myeloma. 

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