COMy 2023 | Defining precursor conditions in multiple myeloma & strategies to better predict risk of progression

I’m excited to think about what is really a precursor condition in multiple myeloma. And for many, many years Dr Bob Kyle has really described it as a clinical entity, monoclonal gammopathy of undetermined significance followed by smoldering multiple myeloma. And this has been amazing because for the last 50 years we’ve had really well-defined clinical entities that we can follow patients and detect progression. But if you go back and think when did that clone start? How many people have MGUS walking around? And many of them will never go on to develop myeloma. I think we need more biomarkers to better predict who truly has a malignant transformation that is likely going to go to multiple myeloma in their lifetime versus someone who has what we call normal phenotype. You have mutations in your clones, yet those clones do not have a second factor, an instigator that allows progression. And the potential hypothesis is that it’s a whole tissue that gets affected. It’s not truly only a clone. So even if you have the mutations, even if you have the changes in a cell, it’s not enough to allow progression and you need a whole environment to be affected. And that tells you that yes, you can get a clone potentially even at birth from some of the studies that have been done in MPN and other diseases and those sit in different organs and they can start expanding as we’ve seen with many studies by the Sanger Institute that if I take biopsies from my esophagus or skin, I will have mutations, even p53 mutations but they may never go on to develop cancer. So is this really a precancerous condition? So I think we want to understand better what is an MGUS that causes progression versus what is an MGUS that never will go on to progression, and just have those mutations without anything else. And this is what we’re trying to do, really taking all those factors of the tissue rather than the cells and trying to understand is it the microenvironment, is it the macro environment, is it inflammation, obesity, what we call exposome – what you’re exposed to? What is your own personal risk because you have a genetic variant? If you are born with a gene that increases your chance, what is the immune system doing? What if you get an infection, will that trigger things to happen? All of these pieces are part of the puzzle to understand who truly will progress in their lifetime. And then we can actually say to that person, you are at risk and leave all the other people who may not be at risk of developing myeloma.