Transcription:
New Developments in Myeloma Therapy

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Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast; Conversations About New Developments in Medicine, Cancer Care and Research. I’m your host, Dr. John Leonard and today our topic is New Developments in Myeloma Therapy. I’m very happy today to have as our guest, my colleague Dr. Adriana Rossi, a hematologist and medical oncologist and Associate Director of the Myeloma Center at Weill Cornell Medicine and New York Presbyterian Hospital. Dr. Rossi works to develop clinical and translational research projects focused on patients with relapsed and refractory myeloma, especially around the areas of evaluation of the microenvironment of myeloma cells and a measurement of minimal residual disease. She also has a particular interest in the effects of plasma cell disorders on the kidney. Dr. Rossi, thank you so much for being here today. It’s really great to have you join us on CancerCast.

Adriana Rossi, MD (Guest): Thank you so much for having me.

Host: For those in the audience who are less connected to myeloma; just give us a minute or two on kind of what is myeloma and how do patients present with myeloma and kind of what’s the typical course, historically, before we get to what’s new.

Dr. Rossi: Absolutely. It is definitely a very changing field. Myeloma is considered a blood cancer and just like leukemia, lymphoma; it really resides in the bone marrow. So, that’s one area of confusion and as such, it tends to cause direct damage to the bones and as plasma cells which are the cells that become cancerous in myeloma, are little factories of antibodies; these antibodies float around the blood and can be toxic to kidneys. So, it is a blood disorder, but usually patients will notice some kind of issue with either the kidneys or the bones that will bring them to medical attention and in working those up; we identify the myeloma.

It is definitely not something you find if you are not looking for it, so I think one of the big advances has been educating physicians so that neurologists and nephrologists and other specialists now know to look for it. And so, we are finding it sooner rather than after there’s significant damage. We are also finding it in primary care and screening for surgery, there is some abnormal lab. The primary care is following up and finding them early. So, we now have a significant number of patients who come to medical attention just because they will come to my clinic and say my doctor told me to come, I don’t really know why, but some of them are because of as I mentioned, kidney, bone, sometimes nerve damage, sometimes fatigue and very nonspecific symptoms that end up being attributed to anemia and other such symptoms.

Host: So, like leukemias in particular and to some extent lymphomas which also involve the lymph nodes; myeloma cells reside in the bone marrow, but yet they have all of these affects on the kidneys, the nerves sometimes and the bones, and they are all different situations but maybe in a nutshell, why do cells that live in the bone marrow, the cavity inside the bone either have longer distance affects on these other areas?

Dr. Rossi: They live as you said, the marrow is inside the bone and this is I think you mentioned the microenvironment that is sort of all the other cells that live in the bone marrow. So, a lot of the original focus had been on myeloma cells in studying the cells which are very difficult to isolate. While we can’t seem to make them go away in patients; the minute you do a biopsy or extract them to study them in a test tube; they die off. And so, they are very dependent on their neighborhood and they affect the neighborhood; so in a patient with myeloma, even if they have been in remission where you can’t find the myeloma for ten years; the other components such as the T cells and B cells and the blood vessels and the bone cells are all abnormal.

So, they never really revert back to the same as a patient who has never had myeloma. And one of the affects is the bone. So, bones are constantly being made and broken down and the myeloma cells send the signal say just go ahead and break, done bother making again. So, that’s where the bone damage comes from. And since they are making antibodies at all times; antibody is a protein that gets put into the blood and they mostly tend to clog up the kidneys. If you think of the kidneys as a filtration system; these little proteins sort of get sticky and prevent them from getting the job done. So, that’s mostly of those and the antibodies can also misfold in something called amyloid and, in that instance, they can stick anywhere, most likely it’s the kidneys and the heart, but the GI tract or the nerves are also common targets.

Host: So, before we get to some of the newer treatments; I mean chemotherapy has been a standard treatment for myeloma for many years, I guess going back to the 60s and 70s and then as a follow on to that; higher doses of chemotherapy and stem cell transplant became standard. And it seemed like those kind of made progress, made a difference for some people, but that was limited. Why is it that chemotherapy kind of only goes so far and obviously, I think a lot of the focus has been moving on from there in myeloma?

Dr. Rossi: Absolutely, so just to give a little historic background; we started using melphalan in 1958, 1962 we started upping the dose and we learned that the more you use, the more myeloma you kill; but at a certain point, you start taking down too many other things. It is a fairly nonspecific chemotherapy. In the 80s when we learned how to use stem cells; it allowed us to use such high doses that we could rescue with stem cells and we call that an autologous transplant. And it wasn’t until the 80s, 1980s, that we were able to get a complete remission and so a lot of the excitement over transplant comes from the fact that up until that day, we never got our patients into remission. Myeloma was entirely palliative. We would radiate them and treat their pain and that was about it.

With transplants, we would get a few patients in a complete remission and that was exciting and what has revolutionized the field is that after the turn of the century; some of these novel drugs can get you into a complete remission without having to go through the toxicity of a transplant. So, it’s one of the great debates in the field is now how to position the many, many options that we have. Chemotherapy such as melphalan which is the drug that we use is nonspecific and just attacks all dividing cells and myeloma is just a very worthy opponent who kind of gets smart to anything we do.

The standard of therapy I would say now for a newly diagnosed patient is a three drug regimen because you are hitting it from multiple angles and that seems to give us better success. The whole idea of using a single agent even if it’s melphalan and even if it’s in high doses; sort of puts an evolutionary pressure on the cells that they will then overcome. I certainly have patients in my clinic who got transplants back in the 90s and are still with us and this was before we implemented the concept of maintenance that is now fairly well-established. So, they had a transplant and twenty years later; they are still myeloma free and one of the things that I am most excited about is trying to learn more about again, the disease of the microenvironment.

There is something about those patients that is inherently different from another one who relapses six months into their therapy. And learning about the different myelomas. There are certainly I would say about seven different subtypes that are clinically distinct, right, the ones that are mostly renally affected, the ones that keep relapsing, the ones who get into an MGUS like state, but never relapse and never have end organ damage and the other ones that manage to get into an MRD negative CR but not stay in it. So, in retrospect, you can go back and see, but it would be really nice to have the tools to identify them upfront and be able to design a therapy that is most affective for that patient.

Host: So, before we get to some of the kind of the next generation of treatments after chemotherapy; you alluded to the seven if I had that right, seven different types, more or less and how are these classified? Are they kind of just kind of presumptive clinical definitions or are they genetic definitions? Are these things that someone diagnosed with myeloma would have their doctor send off a test? Kind of where does that stand in the sub-classification of myeloma today in practice?

Dr. Rossi: So, right now, I would say in my mind, it does not exist. We have an increasing number of tools at first that was FISH with the cytogenetics has a risk stratification. We do have a staging system that now incorporates cytogenetics. For a while, certain centers were using gene expression profiling. So, there are different tools that come up, seem to distinguish risk and now we use them. I think it’s a multi-varied analysis that the clinician does, but it mostly comes down to clinical experience. So, physicians who work at myeloma centers, in conferences, in conversation and our anecdotes; we all recognize. We all have these patients and we know it’s a handful. So, I chose seven. But it’s not something that we can test for. It’s not something that fits into boxes, yet. But I fully expect that in the next decade or so we would be able to do that. As you know, there are 60 lymphomas, but that doesn’t necessarily change their management. Myeloma is considered one disease and yet there are patients that need to be managed very, very differently.

Host: So, following chemotherapy  it seems like the two next kind of classes of drugs or type of drugs were the proteasome inhibitors, bortezomib or Velcade being one of those and then the immunomodulatory drugs or thalidomide and lenalidomide and so kind of how did those change things for myeloma patients in the big picture and I know there are now combinations and those combinations have gotten bigger and longer and everything else. But it seems like that was a major step forward.

Dr. Rossi: Absolutely. Those are still known as novel agents and they came out around the turn of the century. And as I had mentioned, we really didn’t have drugs. We had steroids and melphalan until that point and now we had even though I think it’s a misnomer; they are considered targeted therapies. We don’t know what the target is, and I think their success is actually based on the fact that they affect many different things. Like immunomodulators affect angiogenesis and proliferation and apoptosis and sort of whatever item you test, they affect it and that leads to their success. And when they first came on, it was one of the big debates when I was starting as which one should you use first and then the other and in 2019; I would say the standard is to use them together. Because we now have a second generation. The concern back then was like okay if I use this one drug, we know it’s a finite span until the disease relapses and you always want to have something in your pocket to use next. And so, now that we can use them together; we still have something else to use next.

We were having not by themselves, but in combinations with steroids; these drugs had response rates that were comparable to melphalan without all the toxicity. Some of the toxicities we do think about with the immunomodulators is an increased risk of thrombosis and blot clots which we have since learned to mitigate with something as simple as a baby aspirin in the appropriate patient. And the biggest drawback of the first proteasome inhibitor, you mentioned bortezomib, we now have second and third generation, is limiting peripheral neuropathy and so the newer agents really don’t have that as their toxicity profile. So, we have just outgrown it as another measure of success in the field.

Host: So, a patient diagnosed today with myeloma, what are – now it seems like most patients – all patients get combinations and I know there is not one size fits all certainly, and some of this is kind of science and medicine based and some of it is personal preferences. Kind of describe to us a couple of kind of patient profiles and what you think of or what most patients will hear about from their doctor as an in general types of therapies that they might receive.

Dr. Rossi: So, the great situation we are in, where we have so many options and they are all good options; is very frustrating for a lot of the community physicians because that’s one of the most frequent calls that I get is like how do I pick, just tell me which one, just pick one. From someone who only sees myeloma, it’s just such a privilege to be able to then type and select the therapy for the person in the room. So, some variables you take into account is myeloma specific, right, is this someone who was incidentally noted on some preop labs, never even knew they had anything and have no urgency to their care versus someone who came into the emergency room in renal failure and is starting dialysis.

So, the timing and how fast you need to start the therapy and how fast you need a response go into that decision. The cytogenetics as I mentioned before and other factors that we have in risk stratification, so how much of the marrow is involved, like at different centers have different tests. Some of them are very good data, but they are not universally available so, it’s harder to use their utility. So, certain of the cytogenetic things will respond better to a drug class or another so that would inform the decision. Then you can focus on the patient. Some 50 year old professional in Manhattan doesn’t have time to come into the office, I may have an alternative that is entirely oral and doesn’t require as many visits. Or someone who is elderly, and wheelchair bound and has a difficult time coming to the office can be taken into account or someone who is diabetic or has other comorbidities, other medications that might interfere with one of the other and lastly, the toxicity of certain side effects. We have drugs that can be cardiotoxic so you will avoid that in someone who has a cardiac history versus avoiding neuropathy causing drug in someone who already has diabetic neuropathy. So, you can put all of that into one giant bundle and pick just the right triplet.

Host: So, it sounds like for someone who focuses in myeloma; it’s not a one size fits all issue by any stretch, and you could easily see ten new patients in a row and treat all ten, different ways based on their features, based on their myeloma, their tumors and so on. So, it’s a lot to keep track of as well. So, I want to – before we move on to some of the newer treatments and what you are excited about. There seems to have been a lot happening in the areas of MGUS or monoclonal gammopathy of uncertain significance and smoldering myeloma. These are kind of early conditions or pre-myeloma in some people, types of conditions. First of all, what are those because there are obviously a lot of people that have those that either will or won’t get myeloma and may or may not need an intervention? But it seems like a lot of people and if the approach to that changes, it seems like that could be something that has a big impact for a large number of patients.

Dr. Rossi: Agreed and that’s another huge point. So, I would say we have tremendous success in the newly diagnosed patients. So, a newly diagnosed patient with myeloma has a certain amount of plasma cells that are abnormal in their bone marrow. They are producing an abnormal antibody in their blood and there is some end-organ damage. That was the classic definition of myeloma. They require treatment.

Before they get to that, there is – you may have the proteins and the cells, but no damage. That is categorized under smoldering myeloma. And MGUS is the very, very beginning where you just have some abnormal cells and some low level protein. Interestingly, everyone’s first question is how did this happen, where does this come from and we don’t really know. But there is a clear association with age. So, the average patient with myeloma is diagnosed at age 69. If we were to take an entire population of the United States and send SPEPS looking for this abnormal antibody in all Americans; 5-10% of the population at that age would have an abnormal protein. So, before everyone runs off and asks to have it looked at; the reason we don’t recommend doing that is that 99 of them will never become clinically significant. So, the diagnosis of MGUS ends in undetermined significance. The protein is there. We don’t really know if it will ever bother you. The reason we don’t ignore it is that one percent of them will go onto develop something clinically significant.

So, I think MGUS is good and myeloma is good. The smoldering myeloma is a much more heterogeneous group. So, by definition, in the bone marrow anywhere from 10-60%, so you can imagine it’s a very different patient with 10% versus 60% involvement. So, there was a category known as ultra-high risk, smoldering that is now a disease biomarker and we do recommend treatment for those patients. So, if you were at risk; we do now treat and that line is moving earlier and earlier so there were a number of clinical trials presented at the last ASH meeting actually using these three drug combinations, so a full therapeutic endeavor in smoldering myeloma to try to prevent the patients from ever having end organ damage. Long-term results are still pending on that. The most exciting part about those studies is the VAS correlatives so hopefully we will be able to identify which patients again, separate the bins and treat only those who really need it.

Host: So, this kind of fits the classic screening challenge paradigm where you find people with earlier precursor disease, maybe, maybe that’s a big question mark there; you could treat them aggressively or differently and prevent that disease from getting bad or causing big problems. On the other hand, you are treating a lot of people who aren’t going to get the bad disease and the toxicity, expense, anxiety is a big part of it. So, it sounds like in myeloma, you have your own version of that scenario here.

Dr. Rossi: Exactly.

Host: So, one area of treatment for cancers and being a lymphoma doctor myself, we’ve had antibody treatments for over twenty years and now myeloma has an antibody treatment. Tell us about that a little bit and how that’s changed things.

Dr. Rossi: Yes, we definitely had a lot of lymphoma envy for those many decades. Our first monoclonal antibody and second were both approved in 2015, so it’s fairly recent to us, but very game changing. I think monoclonal antibodies can be combined with other therapies in ways that you can’t necessarily cumulative just put drugs together for the overlapping toxicity. So, daratumumab I think is the one that has most excitement. It’s a monoclonal antibody that targets CD38 and it had single agent activity upwards of 30% which is pretty much unheard of. Nothing else in myeloma had done that. And this was in the relapsed refractory setting. So, very encouraging monotherapy and it has now had four other approvals with different combinations in the relapse setting and most recently in the upfront setting.

Host: And so that is really I guess improved response rates, duration of response? What’s been the big – are people living longer? What’s kind of the big impact of that?

Dr. Rossi: So, it’s very hard to tease apart because there were four drugs approved in 2015. Again, the field continues to change. Survival is doubling. In 2000, you would have been quoted a three year survival. Side note, on the internet, there’s a lot of things that are still from back then that have these erroneous numbers. Now for the average patient; if I had to pick a number, I would say ten to twelve but again, there is a big confidence interval on the high risk versus low risk patient and all these different variables that go into this. But a lot of times when we try to generate that number; we are talking about a median survival from a clinical trial and there’s a line on the graph that is just never reached. Our patients continue to live on longer and longer and so, each year that goes by, the survival is one year longer which is a really good problem to have.

Host: So, are stem cell transplants going away in myeloma or not or maybe or time will tell?

Dr. Rossi: I think it will be a long time. I would very much like to see a day where I didn’t have to put patients through transplants because I do do those very personally. Every time we try to compare it, it is hard to make the transplant go away. The biggest study that was supposed to answer that question for us was an RVD followed by transplant versus continuous RVD with a delayed transplant and again, the divided field, there was a great progression free survival benefit, but no overall survival benefit so, depending on which way you wanted to read the data; you quote one number versus the other. So, it is still a very effective way of getting patients into a deep and durable remission. It’s just not changing the overall survival. So, I think it has its place and again, there are certain patients that are very alkylator sensitive and definitely will benefit from it and others that don’t get to that place.

As a general rule, for a newly diagnosed patient if I can; I would like to get them to what we call an MRD negative state which is the deepest remission I am able to detect in 2019. And the other data that came out of that clinical trial was that patients who reached that MRD negative state did have a survival benefit and so, I don’t know that I can recommend it. it is not ready for prime time. It’s definitely advised to be used in every clinical trial so that we learn about this minimal residual detection as we have new tools; that depth of response keeps getting deeper and deeper and it’s a moving target. So, while myeloma is consider incurable; it is highly treatable and it’s treatable to a deeper and deeper state every time we have a tool to find it at that one and a million, one in ten million state.

Host: So, this concept of MRD or minimal residual disease is one that’s very common in blood cancers and hematologic malignancies, making its way a little bit into some other areas as well in cancer; but this concept that we have these sophisticated tools whether they are flow cytometry, whether they are molecular testing, whether they are combinations and getting the patient’s amount of disease to a level that we can’t see anything or that it is below the threshold of detection; it seems like in every disease we can think of, the group of people that are MRD negative meaning don’t have detectable disease or have low levels of disease do better than those that are MRD positive or do have detectable disease. And that’s intuitive. I guess the question is do we change treatment on that basis? And I think in many different blood cancers, the idea of well you are an MRD negative patient, which is good; can we give you less therapy or different therapy? If you are an MRD positive patient, do we give you more therapy, which therapy? Is that basically the state of where you are in myeloma? Are there any other nuances there that are kind of a big myeloma question in the field?

Dr. Rossi: Yeah, so I don’t know that myeloma is different from any other disease. One of the big arguments is are you MRD negative because you had a nicer disease to begin with and you were going to get there no matter what? So, once you get there, can we leave you alone? And the counter argument is like no the person who can get there is the one who could potentially be cured, and you should continue to treat. So, for now, there is not a clear idea of what to do with that information. In general, I just try to get them there so it is my personal practice to change therapy if I can’t get them there. And for example, in the timing of transplant, if an autologous transplant is going to be part of the therapy; should it be used upfront or later. I think if you attain an MRD negative CR with an induction; you may not need the stem cells.

Host: So, in the rest of our time, I want to focus on kind of new drugs and new agents and I know a big focus of you and your group is research and clinical trials. What are the two or three or four kind of exciting new drugs or categories of drugs that patients with myeloma or interested in the field should be paying attention to because it’s possible that in the near term or medium term; they could be entering standards of practice or at least have the possibility of making a difference for patients?

Dr. Rossi: Yeah, so there are so many things happening in the field as has been the case in the last decade. If I had to pick a couple, I think the two drugs that are sort of next in line for approval. One would be selinexor which again is a completely novel mechanism of action that we haven’t gotten to see in myeloma. It is a nuclear transport inhibitor. And so, it’s completely different and it is being tested in a number of different diseases. The biggest important thing is that the patients who were studied in the mono therapy were what we call penta-refractory so, these are the patients that you would say you’ve had all of the drugs that we have as standard of care and there is nothing else. There is still a response rate with selinexor. So, something that can salvage patients who have had everything else with the caveat that there does seem to be quite a bit of toxicity and we are still learning how to mitigate that. So, tempered enthusiasm.

And the next one is venetoclax which is approved for other disease states and lymphomas but in myeloma, not there yet. As I mentioned, we have the cytogenetics to help classify the patients. The most interesting thing with venetoclax is an exceedingly high response rate specifically in the group who have a translocation 11;14. So, it kind of moves us towards this field of tailoring treatment to a patient’s specific disease state. So, move us into that field and both of these drugs do seem to combine fairly well with others. So, it would most likely continue to be used in combination.

The more exciting field is obviously immunotherapy. I think the number of patients who bring me a New York Times articles and other news clippings kind of points to the attention that it is getting. And just like with so many other things, myeloma is a little bit behind. We have got a little lymphoma envy on the CAR-T program. Because it took us a while to find a target that will treat the myeloma and not take down other cells or have undo toxicity; I think BCMA provides us that target. It is definitely the one that’s moving ahead the fastest.

We have monoclonal antibodies targeting BCMA, the BiTES and the CAR-Ts. So different mechanisms targeting what may be will our new target. We also have CAR-Ts targeting other things such as CD38 and the other antigen is sort of much further down. The BCMA CAR-T I think will be up and coming in the next year or two which is very exciting. Again, nearly 100% response rate was very exciting as we start to get time away from the original studies, we see they are not as durable as we would have liked. It is great, because it is kind of a one and done at the moment. We used to sell transplants as do this and then you can be off therapy now you require maintenance. Right now, we do CAR-T cells without maintenance. But we are still learning how to use them so there may be different targets, there may be different constructs that allow us to modulate the toxicities, learning to mitigate the cytokine release syndrome and all of these things. I think with experience, they will become a less prominent part of the therapy.

And I briefly mentioned the BiTES which are bispecific antibodies, and these are small molecules. So, whereas the CAR-T as the name implies is an actual cell with a receptor on it; the BiTE is just a small floating receptor that will put the tumor and T cell together. So, the theory is similar in activating your own immune system to attack the cancer. And the toxicities happen to be similar as well.

Host: So, I want to end with just your thoughts on – you work in a myeloma center where there are people that have different expertise that they bring to bare on the many different problems and challenges and complications that myeloma patients can have. That seems to me to be particularly important in myeloma given the complexity and maybe if you could just take a second and why is that so important for patients with myeloma in particular, and kind of what some of the expertise that the center here and elsewhere brings to bare when you have such a critical mass of people who are so focused on treatment and management of patients with myeloma?

Dr. Rossi: So, as patients live longer and longer, just the population of patients with myeloma is exceedingly large. I think one of my patients said it best when she says I have shared custody with her local oncologist and most patients with myeloma would benefit. If they are not near a myeloma center and are being treated locally to at least have an expert at a myeloma center give an opinion, consult, get to know their case to help tweak these small details.

Unfortunately, with these new drugs coming out; I have community physicians who are either very reluctant to take on a new drug or on the other hand who are very excited to use it and don’t necessarily get familiar with the preventable toxicities. And so, knowing which reagents, what schedule to use them on and what prophylactic to use is very useful. At our center, our nurses, our secretaries, our medical technicians; all they do is myeloma and extrapolate that to our pathologists and our nuclear medicine partners. So, it’s very nice to have the finesse to pick up on very small variations and to focus on the supportive care.

I think I mentioned at the beginning, one of the biggest things is the quality of life of patients has really remarkably transformed in the past decade. With things like bisphosphonates and now RANK ligand to keep their bones strong, aggressive use of growth factors which again, if you treat other diseases maybe it’s contraindicated; in myeloma, we are very liberal with giving growth factor and chemo at the same time and other small nuances. Avoiding things like Advil which most patients with pain would like to take some can be very toxic to our patients’ kidneys.

Host: So, it sounds like there’s not only a lot changing and a lot happening; but really patients with myeloma and the complexities of this disease really require people that can be attentive to all of these details and obviously, also know the new things that are coming along and can apply them the best. So, this has been a great discussion. I want to thank you for joining us today. I want to also thank our audience for listening in and I would like to invite you to download, subscribe, rate and review CancerCast on Apple Podcasts, Google Play Music or online at www.weillcornell.org. We also encourage you to write to us at CancerCast@med.cornell.edu with questions, comments and topics you’d like to see us cover more in depth in the future. That’s it for CancerCast, Conversations About New Developments in Medicine, Cancer Care and Research. I’m Dr. John Leonard. Thanks for tuning in.