What is the aim of this review?
To find out whether early treatment helps people with high-risk smoldering multiple myeloma compared to simply 'watching and waiting' (observation) until the disease becomes active.
Key messages
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Early treatment with a newer targeted medicine, daratumumab, may help people with high-risk smoldering myeloma live longer and may delay the disease from becoming active. The medicine might have unwanted effects, including serious unwanted effects, but the evidence for these safety outcomes is very uncertain.
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Another type of medicine, lenalidomide, might have little to no effect on delaying disease progression, helping people live longer, or improving their quality of life. Lenalidomide might also have unwanted effects, including serious unwanted effects. However, the evidence for all outcomes is very uncertain.
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For older cancer medicines or other targeted therapies, there is not enough evidence to know if they help or cause harm.
What is high-risk smoldering multiple myeloma?
Smoldering multiple myeloma is an early, non-cancerous condition of the blood plasma cells that does not cause symptoms, but can develop into active multiple myeloma. People with high-risk smoldering myeloma have a higher chance of this happening. The different types of early treatments available for this condition include:
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newer targeted medicines called monoclonal antibodies, which help the immune system find and attack cancer cells;
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medicines that work with the immune system in other ways, called immunomodulatory agents;
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traditional cancer medicines called alkylating agents; and
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other targeted medicines called cytokine inhibitors, which block specific proteins.
What did we want to find out?
We wanted to find out whether early treatment:
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delays the development of smoldering multiple myeloma into active disease;
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helps people live longer;
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has any unwanted effects, including serious unwanted effects; and
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affects people's quality of life.
What did we do?
We searched for studies that compared early treatment to simply "watching and waiting" (observation) or dummy treatment (placebo) in adults with high-risk smoldering multiple myeloma. We summarized the results of the studies and rated our confidence in the evidence based on factors such as study size and methods.
What did we find?
We found seven studies that involved 1096 adults with high-risk smoldering myeloma. The biggest study included 390 adults and the smallest study included 50 adults. The studies were conducted in countries around the world, but most were in Europe and North America. The study follow-up times varied greatly, from around 29 months to over 12 years. Pharmaceutical companies funded or were involved in five studies.
Main results
Early treatment with daratumumab (a monoclonal antibody) may reduce the risk of the disease progressing and may reduce the risk of death. It might have unwanted effects, including serious unwanted effects, but the evidence for these safety outcomes is very uncertain.
Lenalidomide, (an immunomodulatory agent) might have little to no effect on delaying disease progression, helping people live longer, or improving their quality of life. Lenalidomide might also have unwanted effects, including serious unwanted effects. However, the evidence for all outcomes is very uncertain.
We are unsure if alkylating agents or cytokine inhibitors have an effect on the disease.
What are the limitations of the evidence?
We are not confident in the findings for most treatments. This is because most studies were small and used methods that could introduce errors in their results. The way doctors identify high-risk disease has also changed over time, making it hard to compare studies. Furthermore, it is possible that some studies with negative results have not been made public, which could affect our conclusions.
How up-to-date is this review?
We searched for studies up to October 2025. Several studies testing other new treatments are still ongoing.
Leer el resumen científico
Objetivos
To evaluate the benefits and harms of different early interventions compared to observation alone or placebo in people with high-risk smoldering multiple myeloma.
Métodos de búsqueda
We searched MEDLINE, Embase, CENTRAL, two clinical trial registries, and conference proceedings up to 1 October 2025.
Conclusiones de los autores
Early intervention with daratumumab may reduce the risk of disease progression and mortality in people with high-risk SMM. The evidence on the risk of adverse events with daratumumab is very uncertain. For immunomodulatory agents, the available evidence is of very low certainty, partly due to conflicting results, so we are unable to draw conclusions about their effects. There is insufficient evidence to support the use of older agents like alkylating agents or cytokine inhibitors. The decision to initiate early treatment in high-risk SMM requires a careful, individualized risk-benefit assessment and shared decision-making.
Financiación
This Cochrane review was supported by the Tri-Service General Hospital (TSGH-D-114168).
Registro
Protocol (2023) DOI: 10.1002/14651858.CD015494
