MGUS & Smoldering Myeloma in 2025: iStopMM Screening and Risk Updates
The iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) study in Iceland—the world’s first population-wide screening effort for multiple myeloma (MM) and its precursors—continues to shape how doctors understand and manage conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).
According to Principal Investigator Sigurður Yngvi Kristinsson, MD, PhD (Professor of Hematology, University of Iceland — Reykjavik, Iceland),“the iStopMM trial has one mail goal, and that is to evaluate the impact of screening for the multiple myeloma precursor, which is called MGUS. To do that, we asked all Icelanders eight years ago aged 40 years and older at that time to participate in the study — we got more than 54% of the whole Icelandic population to join. Since then, we have gathered more than 75,000 samples and screened them for the precursor. And it turns out that almost 5% of the Icelandic population has the precursor MGUS."
“The iStopMM study is the largest nationwide clinical trial of any cancer precursor ever performed in the world,” with the goal of “diagnosing the individual at the MGUS phase to be able to treat them at the smoldering myeloma phase and prevent them from ever developing myeloma,” added Dr. Kristinsson.
In 2025, several high-profile iStopMM publications offered new insights that could directly impact patient care and diagnosis. Here are the key takeaways.
Hypercalcemia in MGUS: Not Always a Red Flag
According to this publication in the journal Blood, the iStopMM study observed if high calcium levels in the blood (hypercalcemia) signal a higher risk of progression to multiple myeloma. Of 2,546 people that were followed closely, 7.5% had high calcium at least once, and about half of those cases were temporary. Multiple myeloma was found in only 3 people, and all had other symptoms such as bone damage, not just high calcium alone. Most cases of high calcium were caused by unrelated conditions like primary hyperparathyroidism or other cancers.
What this means
For people with MGUS, hypercalcemia rarely indicates myeloma progression and never on its own. Doctors should evaluate hypercalcemia in MGUS patients the same way they would in the general population, looking for common causes first.
Why this matters
Many patients with MGUS worry that every lab result could mean their condition is turning into multiple myeloma. This study offers reassurance: hypercalcemia by itself is not a red flag for progression. Understanding this can reduce unnecessary fear, help guide appropriate testing, and ensure patients get care focused on the most likely causes of their symptoms.
Thrombosis Risk in MGUS
Another iStopMM publication in the British Journal of Haematology discusses how researchers followed 3,668 people with MGUS for about 4 years. They found that people with MGUS had a 43% higher risk of venous thrombosis (blood clots in the veins) compared to those without MGUS. However, there was no increased risk of arterial thrombosis (such as heart attacks or strokes). The amount of M protein in the blood did not affect clot risk.
What this means
MGUS increases the risk of venous blood clots, but not arterial clots. This means that people with MGUS may need closer monitoring for clot-related problems, even if their condition has not progressed to multiple myeloma.
Why this matters
For patients living with MGUS, the risk of blood clots adds another layer of concern beyond the possibility of myeloma progression. Knowing that MGUS can raise the chance of venous clots—but not heart attacks or strokes—helps patients and doctors focus on preventive steps, like recognizing clot symptoms early and managing other risk factors. This research also points to a possible subgroup of patients with “monoclonal gammopathy of thrombotic significance,” where clotting risk itself may require attention.
New Definition of Light Chain MGUS Could Prevent Misdiagnoses of Myeloma
This JAMA Oncology study published by the iStopMM team examines light chain monoclonal gammopathy of undetermined significance (LC-MGUS). This condition is diagnosed using a blood test that measures free light chains (FLC). But current “normal ranges” for this test are not accurate, leading to many false-positive results.
In the iStopMM study, researchers created new age-specific reference ranges for FLC. Using these new cutoffs reduced the number of LC-MGUS diagnoses by 82%. Importantly, none of the people who were reclassified as not having LC-MGUS went on to develop blood cancers during nearly 5 years of follow-up
What this means
The study shows that current testing can overdiagnose LC-MGUS, causing unnecessary worry and follow-up. By using new age-based definitions, doctors can diagnose more accurately and avoid labeling thousands of people with a condition that isn’t truly there.
Why this matters
For patients, a diagnosis of MGUS can bring lifelong anxiety about the possibility of progression to multiple myeloma. This research shows that many LC-MGUS diagnoses may not be correct, and those patients are not at increased risk of developing cancer. A more accurate definition means fewer false alarms, less unnecessary monitoring, and care focused only on those truly at risk.
New Free Light Chain Test Ranges Sharpen MGUS Risk Predictions
Adding weight to the redefinition, a Blood Cancer Journal paper examined a Danish MGUS cohort of the iStopMM study. The free light chain (FLC) ratio is an important blood test used to predict whether monoclonal gammopathy of undetermined significance (MGUS) might progress to multiple myeloma. Older reference ranges for the test often flagged too many people as “abnormal,” leading to worry and higher-risk labels.
In this Danish cohort of the iStopMM study, nearly 7,000 people with MGUS were reclassified. About one-third of “abnormal” cases were reclassified as normal when using newly revised age- and kidney-adjusted FLC ranges. These reclassified individuals had no higher risk of progression than those already considered normal. At the same time, those who still showed an abnormal result under the new cutoffs were clearly at higher risk
What this means
The new test ranges improve accuracy, helping doctors better identify who is truly at risk for progression and who is not. This research helps by ensuring overstating risk for many people is avoided, while still flagging those who need closer monitoring.
Why this matters
For patients, being told they are “high risk” can create years of anxiety and extra medical follow-up. These results confirm that many people previously labeled high risk are actually at low risk. Using the revised test ranges means fewer false alarms and more focus on patients who truly need it.
Hidden Infection Risks Found in Smoldering Myeloma
Finally, the iStopMM project published this study in Nature, finding that infections are one of the most serious health challenges for people with multiple myeloma. Yet, less is known about infection risks earlier in the disease. Using iStopMM data, researchers looked at people with smoldering multiple myeloma (SMM) and compared them to people with MGUS and to healthy peers. They found that people with SMM had more infections and needed more antibiotics than both groups. The higher infection risk was partly explained by “immunoparesis,” a condition where normal antibody levels are suppressed.
What this means
Even before myeloma develops, people with SMM are at higher risk for infections. Doctors may need to monitor infections more closely in these patients and consider preventive strategies.
Why this matters
SMM is often thought of as a “watch and wait” condition, but this study shows that infections are already a significant problem during this stage. Recognizing this risk could help reduce illness and improve quality of life for people with SMM.
What iStopMM Means for the Future of Myeloma Prevention
Together, these 2025 iStopMM findings show how much progress is being made in understanding myeloma precursors. From reducing false alarms in MGUS testing to uncovering hidden infection risks in SMM, the research reshapes both diagnosis and patient care. Most importantly, it offers patients clearer answers, fewer unnecessary worries, and more targeted monitoring. With each discovery, the IMF’s iStopMM project brings us closer to truly personalized care in myeloma prevention.
