Should MRD Guide Myeloma Treatment? A Debate. | Rahul Banerjee, MD and Sridevi Rajeeve, MD |IMS 2024

Hi, everyone. My name is Sridevi Raju. I'm an attending at Memorial Stone Kettering Cancer Center in New York, focusing on multiple myeloma and cell terror. And then my name is Dr. Rahul Banerjee. I'm a sit-up professor at Fred Hutchinson Cancer Center in Seattle, other side of the country, also specializing in multiple myeloma, CAR-T and AL amyloidosis. And so here we're here at the IMS, the International Myeloma Society meeting live in Rio de Janeiro. A little cloudier than usual today, but it was a great session and a lot of things have happened here. We are going to have a fake debate about MRD, measurable residual disease, and whether it should guide decision making or not. So I'll let you go first. Absolutely. So, you know, the whole aspect about MRD, which initially used to be called minimal residual disease, but the court scene is moving towards it being called and an effort led here by Dr. Banerjee to become measurable residual disease is generating a lot of interest among doctors, patients, caregivers into how MRD can be used as an effective tool to advance therapy. So what exactly is MRD and why do we have so much emphasis on it? Right? So MRD is one way of testing how many residual myeloma or any form of disease is there inside the body. It can be tested in many ways. And one of the most reliable ways we tested is by testing a bone marrow sample using a couple of different techniques called next generation flow or next generation sequencing. Now, the difference is that next generation flow has a sensitivity of 10 to the power of minus five, next generation sequencing has a power of 10 to the power of minus six. The difference is that next generation flow might be a little more accessible to almost all institutions and therefore to more patients. However, next generation sequencing is dependent on having access to the third party company that does it for us, which is often not accessible to a lot of institutions and therefore again not to a lot of people. So I'm going to take the side of why we should be doing MRD assessment and you know, Dr. Banerjee here is going to be like, okay, MRD is not quite ready for prime time. So the reason that I'm going to argue that MRD is at prime time at this time is because of this year's FDA's ODAC meeting in which the federal Food and Drug Administration with USA had this big meeting with very prominent doctors all over and we all were discussing whether MRD is ready to be considered as an end point in clinical trials. Why is this important? Because the gold standard of whenever we try to bring a drug to patients is that we try to see if there's a survival benefit. The main survival benefit we look for is something called an overall survival. However, for a trial to report out overall survival, patients have to live that long, we need to collect data and it takes around 8 to 10 years to get that overall survival. So if you imagine you're waiting for 8 to 10 years for one drug to be approved by the FDA, patients may not live that long to get this. So we need to have a surrogate or you know, something that can emulate the benefit that overall survival is doing by having something called a surrogate. So the field had moved towards something called a progression free survival quite a few years back. Progression free survival really cuts short the timeline of how we can bring a drug to a patient from 10 years, let's say 4 to 5 years. Again, is that good enough, especially for diseases like myeloma and other diseases where patients really relapse very quickly, very suddenly and there's an urgent need to change therapies every year or perhaps multiple times a year? No, we need to get these drugs to patients much faster. Here enters MRD. Now MRD is now touted as a surrogate marker for both PFS and overall survival in multiple studies and a large number of analysts did prove that MRD negativity, that is the achievement of no detectable disease inside the bone marrow or peripheral blood can be attributed to a survival advantage in both progression free survival and overall survival. Clinical trials that use MRD are now able to show a response to therapy and we have a basis for actually approving drugs in as small a time as one year which I think is going to be very beneficial for patients especially now we are having patients who are relapsing after multiple diseases, they are waiting for small molecule runs and other runs and if we can get these drugs to them quickly in a matter of like 12 to 18 months, I think that therein lies my argument that we should be considering using. Agreed. So you can see from me nodding that I actually agree Dr. Rajeev entirely that she said, we are supposed to be debating so I will just add one layer of nuance here is that there is a difference between MRD being used in clinical trials as an end point for regulatory approval versus for the patient sitting in front of us in clinic and so I do check MRD pretty routinely as standard of care meaning for my patients in my own clinic outside of a clinical trial. However before we start going down the MRD rabbit hole so to speak, I always have a discussion with my patient first that if you achieve MRD negativity meaning that as Dr. Rajeev said on a bone marrow biopsy no sign of the myeloma, one that doesn't equal cure and two it's not a requirement. There are no data to show that forcing someone to achieve MRD negativity as any benefit to the quality or quantity of life and truly it might actually hurt a patient by trying to push for MRD negativity because again it's not necessarily a measure of, it's not just a measure of the treatment, it's also a measure of the disease biology and everyone with multiple myeloma is different and I have had patients who are MRD positive for many many many years and there's no exception to this and I think how is that possible? If MRD is detected it doesn't necessarily mean that those are cancers, it just means that they're abnormal. They came from the same clone that these cancerous cells came from and some patients may have what's called an MGUS-like phenotype. You may have heard of MGUS before, monoclonal gemopathy of uncertain or undetermined significance which is a precursor to myeloma where the cells are there, they are clonal meaning they're growing a little more than they should but they're not yet causing crab criteria, not yet causing symptoms, don't require treatment. I can't say that some, I mean if you were to check someone with MGUS for example and look at MRD in their bone marrow obviously they will also be MRD positive just like with small during myeloma etc. I can't say that someone has MGUS after they've had cancer because MGUS is pre-cancer but there's an MGUS-like phenotype where some people truly for years after treatment for myeloma may still have some abnormal cells there but no symptoms. And so I think MRD is very nice as a tool to de-escalate therapy and select scenarios but not one to escalate therapy or go up on therapy. As you can tell, we agree on 99% of it but every case is so different so I would say for those of you watching this, talk with your doctor about it and certainly I think if MRD were into blood things would be a lot easier. There are blood-based techniques that are under investigation. Right now the only FDA approved ones are from the bone marrow and so we have work to be done to improve how accessible MRD is but also how useful it is. So obviously talk to your doctor about all these nuances and again don't rush to or don't believe that you have to achieve MRD negativity. The goal of cancer treatment is to live as long and as healthy as possible and we don't quite know how MRD fits into that yet. And to play my own devil's advocate, I completely agree again with Dr Banerjee. Clearly we are not doing a good job debating because we are agreeing with all that we are saying. So we are just standing outside one of the oral abstract sessions in which MRD was the focal point of conversation and I just wanted to highlight one of the oral abstracts that my colleague Dr Korde from Memorial Sloan-Kettering presented in using MRD to de-escalate therapy, maintenance therapy exactly as Dr Banerjee said. So basically it was an investigative trial done at Sloan-Kettering and the high level results of it is that patients who achieved at least two years of MRD negativity were eligible to be de-escalated. Two years of MRD negativity were eligible to be de-escalated and what we really found was that after stopping lenolidamide maintenance therapy, at the 12 month mark almost 89% patients still continue to have MRD negativity and at the two year mark it can drop down to 78% but that's significantly high that's two years of treatment free interval of MRD negativity. Did patients convert during this time? Yes, quite a few patients did. However, very few patients were re-initiated on treatment because they did not meet criteria for what we call true progression and these patients did well. It was found that they do behave, this MRD positivity do behave in a sort of m-gus-like phenotype exactly as Dr Banerjee said and there is a new term that is emerging that we call it as sustained non-progressors. So you have MRD positivity but no other evidence of disease and that is now going to be termed by a lot of experts in the field as a sustained non-progressor and this is a stage we can potentially watch and not really place patients back on treatment and patients can just continue to be closely monitored for evolution of disease. So as you can see MRD continues to be focal point of conversation. We are going to see how the field evolves and how we can really use MRD both as a tool in clinic and both as a tool in clinical trials to try to get drugs to patients as stable.