Findings from the major study iStopMM has been used to redefine monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma.
We spoke with Þórir Einarsson Long, one of the authors of Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study, published in Blood Cancer Journal, about the purpose of the study, and how it can help in cancer screening.
So, what is the purpose of the iStopMM study, and how does it relate to individuals with chronic kidney disease?
“The study itself is called the Iceland Screens, Treats or Prevents multiple myeloma (iStopMM). We screen for various cancers, such as breast cancer, and cervical cancer. The question we want to ask is whether it is good to screen for MGUS or monoclonal gammopathy of undetermined significance, which is the premalignant state of multiple myeloma. In the study, more than half of the Icelandic population over 40 years of age participated, which lead to us screening 75,000 individuals for MGUS. As a result, around five per cent of those screened have MGUS, which is what we expected based on previous studies.”
“There is an in-between state when you don’t have any symptoms, but you still have myeloma, and that’s the group of individuals we want to target to see if we can start the treating them early and prevent them from developing a symptomatic incurable disease.”
“These individuals were then randomized into three groups. The first group is where we don’t do anything. We don’t contact them at all, they don’t know whether they have MGUS, and we don’t know that they have it. It’s as if they were never screened in the first place. The second group is followed up based on the current guidelines that are recommended for following up MGUS, which is often diagnosed by accident, where you can be looking for something else, but you find MGUS. You determine what you should do with the diagnosis, and then follow up regularly, according to these guidelines.
“Then we have the third group, with more intensive follow-ups. We meet them more often and do more testing. Because with this premalignant state of MGUS, there’s only a small subsection of individuals that will develop a cancer or multiple myeloma. There is an in-between state when you don’t have any symptoms, but you still have myeloma, and that’s the group of individuals we want to target to see if we can start the treating them early and prevent them from developing a symptomatic incurable disease.”
With Iceland having a relatively small, homogenous population, you can learn a lot, specifically about the Icelandic population. Is there an issue that the study may not be replicable in other places?
“A part of it is a strength, because we have this small nation; we have a lot of information on all Icelanders. We have good records of individuals and their diseases, and it is easy to follow up with these individuals. There is also a lot of genetic data.”
“But it’s also a limitation that that we have this small population, as it’s mostly Caucasian and very genetically homogeneous. That is maybe the largest limitation to this study, whether it could be replicated in other populations.”
So how did the study determine new reference intervals for serum-free light chains in the individuals?
“We screened these 75,000 individuals for these monoclonal gammopathies, these abnormal proteins in their blood. And one of those tests is this free light chain assay where we can measure these small proteins called light chains. Kidney function affects the concentration of light chains because they are partly excreted with the urine. We took all of those that had been screened, we excluded those that had heavy chain MGUS, that is not light chain dependent, and then we had information on the kidney function, through the measuring of the creatinine levels, which estimates their kidney function.”
“Then we looked at how these results, the levels, were distributed through this particular group of individuals. We saw that, as expected, with deteriorating kidney functions, there are higher concentrations of light chains. It’s a little bit different in the two proteins that we measure, kappa or lambda.”
“We saw that, as expected, with deteriorating kidney functions, there are higher concentrations of light chains.”
“We also looked at the ratio between them as there are differences in how kidney function affects these two proteins. When you are determining a reference point, the classical method is you take a normal population, or presumably healthy population, and then you determine an interval which is normal. In most cases, either 95% or 99% central limit reference intervals are used, and in our study, we decided to use 99% intervals mainly to limit the risk of false diagnosis of these premalignant states, as this is problematic for patients to get a false diagnosis.”
What are the potential clinical implications of these new reference intervals and diagnosis and management of chronic kidney disease?
“The clinical implications of this are quite large. As you get older you are more likely to have both MGUS, and myeloma, and other related diseases and you’re also more likely to have kidney disease. The number of people with chronic kidney disease and possibly some pre-malignant or malignant state of monoclonal gammopathies is quite large group. It’s been very unclear until now, how to interpret the results of this important test in individuals with kidney disease. What is normal? What is abnormal?”
“It’s been very unclear until now, how to interpret the results of this important test in individuals with kidney disease. What is normal? What is abnormal?”
“The spectrum of kidney function from having a mildly impaired kidney function to having dialysis is very wide, but the same interval was being used for all these patients previously, and it was based on a small group of patients. So, it was very unclear what these measurements meant, so this was always in the back of our minds. Is this a monoclonal disorder or is it just the abnormal kidney function that is causing these abnormal measurements?”
How does the study contribute to our understanding between chronic kidney function and serum -free light chains?
“We have an image in our paper that shows how the levels change with decreasing kidney function, both the kappa and the lambda, and then the ratio, and both kappa and lambda rise with decreasing kidney function, and you can clearly see it. It kind of skyrockets when you have severely impaired kidney function, but when you take a look at the ratio you see it rises with decreasing kidney function but then you reach a certain plateau. You can’t get an extremely high ratio just through abnormal kidney function. Then it’s something else that’s causing it.”
How does the study compare with other studies in the field of chronic kidney disease and serum-free light chains?
“There had been studies previously published with reference intervals for those with chronic kidney disease. That was a single interval for all patients with kidney disease but also a very wide interval, , and this was based on only six or seven hundred patients who were measured clinically. In our case we have a screened population, meaning there’s no selection or no bias in who is measured and who is not measured.”
“This study is more precise than those previously done and gives more information on the subgroups of individuals with different stages of kidney disease.”
“So, our study was unbiased, and the group is almost 10 times larger than the previous studies. This gives us the opportunity to determine reference intervals that are stratified by kidney function. If you want to stratify the reference intervals by groups, you need to have a large group to be able to do that, and that’s what we were able to do. This study is more precise than those previously done and gives more information on the subgroups of individuals with different stages of kidney disease.”
What future studies could be done within this specific area to give us more information between the relationship with chronic kidney disease and serum free light chains?
“That’s something that needs to be done and will be done. With this study, we are just describing how these levels change with kidney disease and suggesting what is a normal reference interval. We have no information about outcomes for these patients. What does it mean that you’re outside the reference interval or inside the representative interval? Does it mean that you’re free from developing a monoclonal gammopathy or not? That is something that we will see in the future when we follow up these individuals and see who develops a real monoclonal disease and who doesn’t. Which is exactly what the iStopMM study is doing. From that information, we can then see what the sensitivity and specificity of these reference intervals are, and that information is needed.”
And is that something that you will be working on?
“Yes, when we have collected all the data, but we will need to wait some time until people develop the outcomes that we are looking for.”
Photo of Þórir Einarsson Long: University of Iceland/iStopMM