(Guest Lecture): September 2022 - Diagnosis: A Never-Ending Story

Thanks for the great introduction, Greg. It's always challenging to talk about these people like Dr. Gertz and Dr. McCarthy who are in the business for such a long time and have so much knowledge, not only because of experience, just because their brains are much bigger than mine. So there were great introductions to what I want to talk about and what Greg asked me to talk about diagnosis. And I don't want to, sorry, I walk away from the microphone. I shouldn't do that. It's a never-ending story, which is a good thing in this case. We are in development and you heard the very early steps from Dr. Gertz. You heard the further development from Dr. McCarthy, and I can just piggyback on that. I work with some pharma companies to do our clinical trials and to learn more about the disease because they have the money and they're very supportive. So I'm really grateful for that. The topics that Greg gave me, sorry, I take my mask off. The topics that Greg gave me are three to five years, and I will explain where this is coming from, a changing perception, diagnosis to determine strategies and diagnosis, a continuous process in the area of neuro therapies. Three to five years, that's actually when I started treating myeloma. And I mean that age already, even though I'm a little bit younger than the speakers before me, but when I started treating myeloma, it was 20 years ago. So I do look a little bit younger, people tell me, than I actually am. So I really treat myeloma for almost 20 years now. And at that time, Salt Lake City, which was mentioned where Health Tree is, was where the Winter Olympics took place, if you remember. Most people in this room do, I guess. American Idol aired for the first time, can you imagine? There was a time before American Idol, and Pierce Brosnan was still James Bond. So it's that long ago that I started treating multiple myeloma. I was surprised myself when I Googled it what happened in the year 2002. The standard of care for myeloma back in Germany, and I think to a certain degree, even in the US, was VAD, which is something we don't even use anymore, because we know it's not really good. It's alkylating agents, agents that are destroying DNA. So the things that Dr. Gertz explained earlier, that was the only thing we had. And then these alkylating agents that we mentioned, the melphalan, for patients who could not get a stem cell transplant with a lot of melphalan, they got just less melphalan. And that's what we did. And that's actually the time when I came into multiple myeloma, and the survival was fairly short. I mean, we didn't talk about quality of life. Patients wanted to live a year longer, maybe. So that was the topic that we were talking about at patient meetings at that time. And we waited to treat multiple myeloma patients until they had so-called end-organ damage, meaning they had holes in their bones, they had kidney failure. Unfortunately, that still happens because we don't screen for myeloma, and most of you are diagnosed because you have symptoms. But in patients who have an early stage, we obviously treat earlier nowadays. The reason for that, and those were the criteria, the famous infamous CREB criteria, high calcium, renal insufficiency, anemia, low counts in your blood or bone lesions. So those were the CREB criteria. That was the reason to treat. Why did we not treat earlier? And a lot of people from breast oncology, colon cancer, they say, we don't wait until my patient has metastasis in their bones. I treat them earlier. But they tried that, and they used the drugs that you heard about, this alkylating agents, this telidomide, and it was just not better. The patients had the myeloma later, but they didn't live longer because they just got it later, got symptoms and side effects from the treatments earlier. But their survival, as Dr. McCarthy explained, the overall survival was not better. So we said, let's wait until we really have to treat, and then we treat because then we can kind of justify that we give our patients so many side effects. And this you already saw the time that the patients lived, and it got better over time because that's the area where telidomide was introduced. So it got better, but it was still not really exciting. Today, the diagnosis, and I don't want to go into any details with what's going on with genetics when we look into the tumor cells to look what genes are upregulated, downregulated, what chromosomes are broken or moved from one part to the other. I just want to kind of give you the big picture. Why is it important to know as much as possible about the myeloma? Because we now make our decisions based on that. And the first decision is we added certain prognostic markers for patients who have early stages on top of the CREB criteria. We don't want to wait anymore until the disease progresses or until the disease really has harmed the organism if we know about it, obviously in early stages like smoldering myeloma and MGAS. And now we call it the slim CREB criteria. And you can Google that and find it easily what the slim CREB criteria are. So we treat earlier. That's the first approach, because the treatments that we have are still a lot of side effects, but much less toxic than initially. And they have shown that if we treat earlier, we have a better outcome for our patients. Another thing that was in 2002 when I started treating myeloma, we had not many tools. And you know this saying, and I learned, and Greg is teaching me idioms, American idioms. And I think if one of them is, and Dr. McCarthy uses that a lot, if you only have a hammer, everything looks like a nail. And that's actually what we did. And you can see on the right side, I think those targets are not really suited for a hammer. So that's what we did. We treated every myeloma patient with melphalan because there was nothing else. And so nowadays we have a much better problem because we have many more tools. Now the challenge is to find the right tool for the right patient. That is what we do with our diagnostics. We do the bone marrow biopsies that everyone loves. And Dr. McCarthy and myself just had a few months ago, both one for our research, to learn more, what is the healthy bone marrow. And sorry, that was us. And compare that to our patients and see, okay, what are the differences? Where can we fit a tool that fits to the target that we are treating? And Venetoclax was already mentioned. It's not approved for multiple myeloma yet, but it's one approach that we have to treat patients with something that fits to their disease. And that's something. Then the next question is, when do we do that, right? The sequencing, should we do that right away? Because we know, so this study showed that this Venetoclax, a drug that is used in other cancers, where we thought, hey, that should work in myeloma as well. And they tried. And you see on the left-hand side, this PFS, the progression-free survival that Dr. McCarthy explained, the time until the disease came back was longer with Venetoclax for the patients who got it, together with the botasimab compared to a placebo. But then they looked at the overall survival and can see the red curve is higher. So not getting Venetoclax was not statistically, but it was better for the patient not to get this new drug. That's not how this works, right? So why is the progression-free survival better, but the overall survival actually worse? And that was the reason we have to think, why do some patients benefit and others don't? And so what they found, there's a change in the cancer cells, in the myeloma cells. One is called a translocation 1114, where when the cells divide, a small piece of the chromosome 11 is transferred to the chromosome 14, I think, to the chromosome 14, I think, or vice versa. So they're on the wrong part, because that happens in cancer patients, they cannot repair themselves so easily. And if you have this translocation as a patient, then those patients who see the blue curve is much higher. And on the right side, there's another genetic change, it's called a BCL2 mutation, or BCL2 is upregulated in those cells, and those patients benefit as well. So we finally come to a point where we can adjust our treatment to patients who don't have these changes. I would not give this treatment, because as you have seen, it's worse. In patients who do have the treatment, these changes, there we can give it. And that's only one example that we adjust. And we are always eager at our meetings when someone is presenting something saying, okay, in this subgroup of patient, it works better. And that's what we are looking for. We don't want to use this one size fits all approach anymore. We still do it in a lot of settings, but we want to be more specific for patient and we identify more targets that can be targeted with a certain treatment. So in the diagnosis, it continues. It's not only at first diagnosis, because what we also know, the myeloma cells mutate. And so they are not, if you do a biopsy at first diagnosis, a bone marrow biopsy, and you do it after the first treatment, after the second treatment, after the third, the cells look a little bit different. Not always, and not all of them, but we know there's something that we call a clonal tiding. So some clones are more susceptible to one treatment combination, and another clone set is more susceptible to another treatment. And unfortunately, we are not that good yet that we know, okay, this will be the best treatment for this patient. So we have to try out, unfortunately. So we see, for example, if these five classes, and there are even more to come, that Dr. Gertz talked about, if you have a certain class or combination of drug classes and give that to a patient, and you see it works well, you can, as a doctor, consider giving something like this, or something similar, maybe another antibody, but combined again with an immunomodulatory drug, or combined with a proteasome inhibitor, later on when the disease comes back, because we kill initially certain subgroup of cells, and then it comes back, it's a more kind of different subgroup of cells, and that's why it's called multiple myeloma. Some people call it even multiple, multiple myeloma, because it's really developing and kind of developing defense strategies against our treatments. And then we treat it with a different combination, and then we treat with a different combination. And that's what we call the novel therapies. We don't use the one-size-fits-all anymore. And what we are also doing, we look for the response. So if we see that a patient has a really good response to a certain treatment, we know that's good. So not a lot of cancer in your body is a good thing, and you might be very surprised to hear that, but that's what I can tell you. Less cancer in your body is better. And that's what we do with the so-called MRD, and you might have heard about it. It's so-called minimal residual disease, and that's something, or measurable residual disease, because we can only measure to a certain level. And unfortunately, even if you're MRD-negative, you're not cured from the myeloma. It's just we cannot measure it anymore. But at least it means it's very, very low. Nowadays, we have technology that can measure one in a million cells, and sometimes even better with that sensitivity in the bone marrow. A challenge is that if we do this, so it's good to have this MRD-negativity. If you're MRD-positive, we can still treat, but there are other things that we have to consider. But one challenge is that we do our bone marrow biopsies, as you know, always here on the pelvis. And if we do a PET CT, for example, you know, it's this way it lights up like a Christmas tree, unfortunately, sometimes. And we can identify areas where the myeloma is growing. If it's growing in the pelvis and you do biopsy there, then we know what's going on. But if it's growing somewhere else, then we have a challenge, right? We know that there's a pretty good correlation, but we also know that you can have all of the above. You can have a PET-positive, MRD-negative patient. You can have a MRD-positive, PET-negative patient, and so on. So you can have all these combinations. That's why we do our diagnostics later on with bone marrow biopsy blood work, obviously, because it's the easiest and imaging. So we combine all these things to get a whole picture of our patient. In summary, our treatments have improved. I hope that's something that you remember from all three talks, and there will be more about that later. They still have to become more individualized, because as I said, some patients respond very well to one set of drugs, while they don't respond very well to another set of drugs. What is even another topic? Which patients develop which side effects to which drug? And we have done back in Germany, we have done a large study where we looked into the myeloma cells and the microenvironment of certain patients and looked, okay, do they develop this polyneuropathy or the peripheral neuropathy that most of you unfortunately know? And we couldn't find anything to identify patients beforehand, because we would not give them treatment like thalidomide or botesimib that can cause this neuropathy. And some patients do great with it, and others have really, really struggles. And then response assessment is becoming more sensitive. Back in the day, we could maybe find one in a hundred cells. Now we can find one in a million cells or even less. And that is something that guides us in our treatment. We know when the patient is in a deep remission, and then we can go on with and adjust our treatment according to that.