Myeloma is different from many other cancers. It almost always gives off smoke before it catches fire.

That smoke usually comes from a specific ‘precancerous’ condition called smouldering myeloma. When doctors spot it in the blood, they know they’ve found someone with a much higher risk of developing myeloma than normal – someone who might benefit from treatments to stop the disease before it starts.

And yet, today, the standard approach is to watch and wait.

The problem is that, in this case at least, smoke doesn’t always mean fire. Smouldering myeloma bears many of the hallmarks of myeloma, but it can be clearly visible in the blood for years without causing symptoms, and many people with the condition will never develop active cancer at all. Offering all of them preventative treatment could stop some cases of myeloma, but for as many as 1 in 2 people, it could mean facing difficult and ultimately unnecessary side effects.

If researchers are going to find a way past this impasse, our understanding of smouldering myeloma needs to get much more precise.

That’s what makes a new Cancer Research UK-funded project at University College London (UCL) so important. The team are investigating whether some of the genes we inherit from our parents could help predict which people with smouldering myeloma have the highest myeloma risk.

A new approach to smouldering myeloma

Myeloma affects blood cells called plasma cells in the bone marrow. Around 6,500 people are diagnosed with it in the UK each year, usually in their 60s or later. There’s been a lot of progress recently, and almost 6 in 10 people diagnosed with myeloma will survive it for at least five years. Currently, though, it’s still considered incurable.

In that context, prevention becomes even more important.

Encouragingly, scientists have uncovered enough about smouldering myeloma cells to define some high-risk features and begin testing treatments that might stop them progressing. But the central problem hasn’t changed. For all the work they’ve done, researchers still can’t reliably explain why smouldering myeloma becomes myeloma in some people and not others.

Dr Elise Rees and her team at UCL are taking a much wider view. Instead of looking for more answers inside smouldering myeloma cells, they’re investigating the way people’s bodies respond to them. And the work Rees has done so far has raised an intriguing possibility: inherited differences in the immune system might create a blind spot that stops it from seeing smouldering myeloma as a problem.

Natural killers and inherited genes

Specifically, Rees’s team are investigating the role of genes linked to immune cells known as natural killer (NK) cells, which are a crucial part of the body’s early anti-cancer defences. Their “natural”, or innate, ability to kill potentially dangerous cells is almost entirely down to the genes we inherit from our parents. 

If you want an idea of how NK cells work, you might want to picture them as bouncers. They’re the only immune cells able to identify when cells aren’t carrying “self” ID that proves they’re meant to be part of the body. That’s useful for spotting and dealing with many types of potential cancer, but smouldering myeloma cells are unusually good at producing fake documents. 

Even so, this doesn’t seem to be an issue for everyone’s NK cells. We all inherit different numbers and combinations of genes for checking cell IDs from our parents. Each NK cell has its own selection, along with a host of other tools for protecting us. That diversity helps the immune system deal with different types of intruders and threats.

This is where things get a bit counterintuitive. While having a wide variety of NK cells with lots of different ID-checking systems sounds like a good thing, Rees’s work so far suggests it might actually make it harder for the immune system to control smouldering myeloma.

Her theory is that, when NK cells have access to lots of different ID checks, they can become so focused on using them that they miss other signs of danger. It’s as if, once they’ve thoroughly checked smouldering myeloma cells’ forged documents, they stop paying attention to what the cells are actually doing – no matter how damaging their behaviour might become.

Exploring the COSMOS 

The new project will test Rees’s hypothesis using cutting-edge technology to investigate samples and data from Cancer Research UK’s COSMOS study. COSMOS has already recruited a diverse group of more than 600 people with smouldering myeloma, and it’s steadily improving our understanding of the condition by tracking those people over time.

Now, Rees and her researchers will zoom in on the behaviour of NK cells across this group and look for any evidence that inherited genetic differences might impact myeloma risk. NK cells aren’t usually studied in this much detail, so the work could help scientists better understand how to treat and prevent other cancers too.

Beyond prevention, the project could also help answer another major question around myeloma: why people of African ancestry are more likely to develop it than other groups. Focusing on NK cells won’t solve the mystery on its own, but it could help reveal whether differences in the immune system are part of the explanation.

“In the long term, our work will inform more personalised approaches to monitoring and treating people with precancerous conditions like smouldering myeloma,” Rees explains.

“We want to uncover why the immune system sometimes fails to stop cancer developing and how this knowledge can be used to intervene earlier.”

Smouldering myeloma: from precancer to cancer prevention

This new study is part of a much wider research effort to find ways of predicting and preventing myeloma. Alongside COSMOS, Rees is also working on the MODIFY study, which is testing whether a combination of immunotherapies can help prevent or delay myeloma in people whose smouldering myeloma cells are considered high risk.

That could be a big step forwards, but it’s still limited by the fact it’s only focusing on the appearance and genetics of smouldering myeloma cells themselves. For Rees, that’s like only looking at one half of a picture.

“The current risk stratifications that we use aren’t necessarily precise, and they don’t take the individual into account,” she explains.

MODIFY is using some of the best prediction tools available, but even those can only identify when someone has a 1 in 2 chance of developing myeloma within the next two years. That’s still comparable to a coin flip.

“How do you respond to that?” asks Rees. “Some of these treatments might be quite intensive, and many people with myeloma are older, so it can be a difficult conversation.”

This is still the beginning, but discoveries from Rees’s study could add more precision to MODIFY and other similar trials, and eventually begin to change standard care. “We want to give more information and ultimately more options for individuals to decide what may suit them the best,” she says.

Crucially, it’s people who are facing smouldering myeloma today who are making that possible. As Rees herself makes clear, “without patients volunteering to be in any of these trials and agreeing to share their samples, we wouldn’t be able to do any of this.”

Thanks to their generosity, doctors may one day be able to look at patients’ immune genetics alongside their smouldering myeloma cells. That full picture could make the condition much easier to understand and predict. Then, people diagnosed with smouldering myeloma wouldn’t face the same uncertainty, and the doctors caring for them would know when they need to act to stop myeloma before it starts.

Liz and Tim