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A new study has shown that small genetic changes in a key protein can determine whether myeloma cells resist or respond to treatment – findings that could help clinicians choose more effective therapies for patients with this type of blood cancer.
Researchers at The Institute of Cancer Research, London, examined how subtle mutations in CRBN gene, which codes for the protein cereblon, affect a major class of myeloma drugs.
The study, published in the journal Blood, revealed that not all mutations in CRBN are equal and that some patients could benefit from newer generations of drugs even after older ones stop working. This work was primarily funded by a Cancer Research UK Clinician Scientist Fellowship grant and supported by additional funding from the Cancer Research Innovation in Science Cancer Foundation and The Institute of Cancer Research (ICR), which is both a research institute and a charity.
Why drug resistance matters
Immunomodulatory drugs (IMiDs) are a cornerstone of myeloma treatment, acting as ‘molecular glues’ to bind to the CRBN protein and trigger the destruction of cancer-promoting proteins inside cells.
However, resistance to IMiDs is a growing challenge. Over time, myeloma cells can adapt by altering or reducing the CRBN protein – the target these drugs rely on. Up to one-third of patients who stop responding to these drugs acquire mutations in the CRBN gene, which encodes the protein that IMiD-type drugs bind to in order to trigger cancer-killing effects. Until now, it has been unclear whether all such mutations block drug action or if some are less harmful.
The research team recreated 12 CRBN genetic mutations previously detected in patients by introducing each change into laboratory myeloma cell models. They then tested how the altered cells responded to both established IMiDs and newer cereblon E3 ligase modulators (CELMoDs).
Lead author Dr Yakinthi Chrisochoidou, who was a Postdoctoral Research Fellow in the Myeloma Biology and Therapeutics Group at the ICR at the time of the study, conducted much of the experimental work, using the models to test how mutations influenced drug response and mapping structural changes at their atomic level. Her work provides one of the most detailed views yet of how the CRBN protein interacts with these therapies.
Three clear patterns emerged. Some mutations completely disabled the CRBN gene, stopping all drug activity. Others had no measurable impact, leaving the drugs fully effective. A third group had drug-specific effects – blocking older IMiDs but allowing newer CELMoDs to keep working.
Structural modelling, supported by a newly generated high-resolution 3D structure of cereblon produced by the research team, helped explain why this is the case. CELMoDs are designed to bind more tightly and make additional molecular contacts with the CRBN protein, which may let them overcome certain mutations that defeat the older drugs.
More personalised myeloma treatment
The findings could help refine how clinicians interpret genetic test results for myeloma patients. Until now, a mutation in the CRBN gene might have been assumed to signal resistance to all IMiD-type drugs. This new research suggests a more nuanced approach – one where the specific mutation matters.
Senior Author Dr Charlotte Pawlyn, Group Leader of the Myeloma Biology and Therapeutics Group at the ICR, said: “As access to myeloma cell sequencing for patients increases, we need to think carefully about what those results mean. It’s not as simple as saying, ‘You have a mutation, so this drug won’t work.’ Understanding the biology behind each change helps us tailor treatment choices more accurately.”
Broader significance
These insights could also inform the design of future molecular glue drugs – a fast-growing class of precision medicines now being explored beyond myeloma. By showing which parts of the CRBN protein are most critical for drug binding, the research highlights how small chemical modifications could make future compounds more resilient to resistance.
For patients, the ultimate goal is to keep each line of therapy working for longer. Dr Chrisochoidou said: “This kind of study helps ensure that we interpret genetic results correctly. Rather than ruling out an entire drug class, we can identify which treatments still have a chance of working – and that’s a big step forward.”
The ICR has been instrumental in driving progress in myeloma, find out more about how we have led the way in myeloma research over the decades.
