Robert Orlowski, MD, PhD
MD Anderson Cancer Center 
Interview Date: January 30, 2020

The new year (and new decade) promises to bring rapid progress in multiple myeloma. In our annual show, Dr. Robert Orlowski of the MD Anderson Cancer Center shares a broad overview of the latest treatments for all stages of disease: smoldering myeloma, newly diagnosed myeloma and relapsed/refractory myeloma. Dr. Orlowski discusses combination therapies, new immunotherapies, new diagnostic technologies and new targeted treatments that are in in the clinic today or in development in myeloma clinical trials. Dr. Orlowski skillfully simplifies the significant work being performed by so many companies for multiple myeloma patients. 

Thanks to our episode sponsor

Jenny: Welcome to Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, GlaxoSmithKline for their support of Myeloma Crowd Radio.

Joining us for today's show is Dr. Robert Orlowski of the MD Anderson Cancer Center. I'm not going to give a lot of intro about our other programs because I want to jump straight into this show, which is one of my absolute favorites of the entire year. So Dr. Orlowski, thank you so much for joining us today.

Dr. Orlowski: Well, Jenny, thanks very much for having me. It's always a pleasure. I wanted to take the opportunity to wish everybody a happy 2020 which hopefully will be even healthier than 2019.

Jenny: We're so hopeful. We look forward to hearing what you are going to share with us today. But before we get started, let me just give a brief intro for you.

Dr. Orlowski is Chairman and Director of the Myeloma Program in the Department and Professor of Medicine, the Department of Lymphoma and Myeloma and Experimental Therapeutics in a Division of Cancer Medicine at MD Anderson Cancer Center. Dr. Orlowski serves as the chair of the Southwest Oncology Group or also called SWOG, which is the institution that puts together many clinical trials in myeloma, and is a member of the NCI Steering Committee, the Multiple Myeloma Tissue Bank Steering Committee, the BMT Committee, and American Society for Biochemistry and Molecular Biology.

Dr. Orlowski is on the editorial board of major journals including Hematology and the Journal of Clinical Oncology as well as others. Dr. Orlowski has received many awards over a number of years including the Leukemia & Lymphoma Society Scholar in Clinical Research, the Leukemia & Lymphoma Society Man of the Year Award, the Emil Frei III Award for Excellence in Translational Research from MD Anderson, and has received many SPORE grants from the NIH. He also has a daily newspaper, if you'd like to subscribe, on a service called Paperli. It is called The Myeloma Daily. Or you can find him on Twitter at @Myeloma_Doc.

Dr. Orlowski, thank you so much again for joining us. I think we have so much to cover that maybe we should just jump right in with precursor conditions.

Dr. Orlowski: Well, thanks again very much, Jenny. Indeed, there's a lot going on in myeloma and a lot of great news. I'm happy that you want to start with precursor conditions because there's a number of new developments. Precursors, in general, are what we call either MGUS, which is monoclonal gammopathy of undetermined significance, or what's called smoldering or, in some cases, asymptomatic multiple myeloma. These are conditions that's sometimes can progress to multiple myeloma. The main difference is that myeloma patients that are symptomatic have one or more of a couple of different findings. One way to remember them is with the mnemonic CRAB where C stands for hypercalcemia, R stands for renal insufficiency, A stands for anemia, and B stands for bone lesions. So any one or more of those means that you probably need to have chemotherapy as opposed to watchful waiting. And then more recently, there were additional criteria introduced including if the bone marrow is 60% or more involved with plasma cells, or if the involved to uninvolved serum-free light chain is 100 or more, or if there are more than one bone lesion on advanced imaging like MRI or PET.

In the smoldering space, there are really two important new developments. One is a publication that came out in the Journal of Clinical Oncology, which was an intergroup trial. It was led by ECOG which, like SWOG, is one of the cooperative groups. This was a trial that compared lenalidomide to observation for patients with intermediate and high-risk smoldering myeloma. What this study found is that people who got lenalidomide by itself had a much longer time to progression to active disease than people who got observation.

So far there has not been a difference in overall survival yet, but the authors of the paper, and I was one of them, did suggest that patients with intermediate or high-risk smoldering disease should be considered for therapy with lenalidomide as a single agent based on that result. There are current trials that are planned by the cooperative group which will compare lenalidomide and dex to lenalidomide and dex with daratumumab and a different trial which will be sponsored by Sanofi, which is one of the companies in the myeloma space which will look at isatuximab, lenalidomide, dex versus lenalidomide and dex.

So if you have smoldering myeloma, you should definitely talk to your physician about whether either lenalidomide by itself or whether enrolling on one of these clinical trials is the right approach for you. It may be that still observation and no treatment is the best approach because not everybody progresses to active myeloma, but you really need a specialist to be able to talk to and hear what your options are.

Jenny: Now, I want to just stress that because it's such a critical point. I have a question too. I've heard some doctors say maybe a lot of these patients are getting misdiagnosed, and they actually have actual myeloma. So do we really need this smoldering myeloma definition, or should we break it into just MGUS and active myeloma? What are your thoughts about that?

Dr. Orlowski: That's a good question. So first of all, you need to make sure that you get a very thorough workup if you have smoldering disease. Some doctors just do a plain X-ray bone survey looking for bone lesions. We know that that isn't enough because either an MRI or a PET scan will be more sensitive and often will detect lesions that are missed by plain X-ray, and those would put you in the category of really active disease that needs treatment. At the same time, if you're in the so-called low-risk smoldering myeloma, those patients often have a risk of progression that is quite low and actually can be similar to MGUS, and those are people that I think we all would agree probably really do not need to be treated. So I do think that still having that smoldering category is a good thing to do. Again, not all of those patients will progress.

One thing to keep in mind, there was a newer risk stratification model that was introduced recently by the Mayo Clinic. They call this the 20-2-20 set of criteria, and that's because there are three factors. One of these is if the bone marrow plasma cells are more than 20%, the second is if the monoclonal protein is more than two grams, and the third is if the involved-uninvolved free light chain ratio is greater than 20. And if you have two or three of those risk factors, then your average time to progression is about 30 months. I think we would all agree that people like that probably should be treated. But if you're in the intermediate or low-risk category, then some watchful waiting would be important.

And then just briefly, the other thing to mention is that there are many of these different criteria that put people into different risk groups. We don't really know for sure which one is the best, which is why again you should go to a specialist to really define it better and hear what your options are.

Jenny: I totally agree with that.

Dr. Orlowski: Moving to newly diagnosed myeloma, for a few years, the standard of care were three-drug regimens for patients that were symptomatic. These were things like predominantly bortezomib, lenalidomide and dex in the US. In Europe, sometimes bortezomib with thalidomide and dex was used. And then another popular three-drug regimen in both areas was bortezomib with cyclophosphamide and dexamethasone. But we now have data for a four-drug regimen which is the VTD or bortez-thal-dex combo with daratumumab. It's now approved as a frontline therapy. It showed an improvement in the response rate, the quality of the response, meaning more complete responders and also in minimal residual disease or MRD negativity.

So that's certainly a good option to keep in mind. There are ongoing studies that are looking at the more popular bortezomib, lenalidomide and dex regimen with daratumumab in the United States and elsewhere. I think many of us feel that the VRd-daratumumab combo will probably be the standard care in the future for newly diagnosed symptomatic patients, especially if they are transplant eligible, which generally means that their organ function is good and that they are relatively fit.

Jenny: Adding dara doesn't seem to add a lot of extra side effects, which is why I think this addition is so popular when you start talking about either transplant eligible patients or even others.

Dr. Orlowski: You're definitely right, that the only really side effect that is increased with the first dose is you can have what's called an infusion reaction, which can be a runny nose or a cough or a little bit of shortness of breath. Usually, there's a four-drug cocktail that's given as a pre-medication to reduce that risk. Typically, that does not happen with the second infusion. By the third infusion, it's usually safe to give the daratumumab as a 90-minute IV, although we all think that sometime this year dara will also be approved as a subcutaneous injection, which will mean that it will be given over an even shorter period of time without the need for an IV in most doses.

Jenny: It will be convenient.

Dr. Orlowski: Moving to the transplant ineligible patient population, one of the newer developments has been the so-called MAIA trial which compared lenalidomide and dex with daratumumab to just lenalidomide and dex. As you can imagine, because daratumumab seems to make every combination to which if added work better, it did look like VRd with dara group was doing better. I think that many folks would agree that for transplant ineligible patients, that's one standard of care and another would be so-called VRd-lite which means bortezomib, lenalidomide and dexamethasone at a reduced dose schedule. Part of that is because the transplant ineligible patients tend to have lower creatinine, or I should say a lower creatinine clearance which means that some of the doses of the drugs, including lenalidomide in particular, have to be reduced.

We also are looking at another antibody called the isatuximab which I briefly mentioned earlier. Isatuximab is an anti-CD38 monoclonal which is similar to daratumumab, which also attaches to CD38. There are some nice trials being done for newly diagnosed patients as well as relapsed refractory patients with isatuximab. So hopefully, soon there will be a choice between using either dara or using isa both in frontline patients as well as in the relapsed and refractory setting.

Jenny: For those who are wondering, is there a difference between them? What do you anticipate when that is approved? In terms of use?

Dr. Orlowski: Yes, definitely. There are some differences between the two in how they attach to the CD38 target protein and in how they work. They've not been compared head to head, so that's tough to say. They do seem pretty similar though in terms of infusion reactions, side effects, and efficacy. I think it will be more a matter of which the practitioner that is working with your patient happens to be more comfortable using, but either one or the other looks like a really good drug.

Now stem cell transplant is still part of the standard of care for multiple myeloma. Typically, it's given after induction therapy and transplant-eligible patients. I would say that one of the more important developments that came out in this area recently was a study that was done at MD Anderson. High-dose melphalan is the drug that is usually used before the stem cell transplant. The folks here at MD Anderson, and this was a study that was put together by Muzaffar  Qazilbash, who's our most senior myeloma transplant doctor, they looked at the combination of melphalan with busulfan. They did find that the two drugs together have a little bit more toxicity which, of course, is always unfortunately something that we tend to see in not just myeloma but in other cancers as well. But the exciting news, especially for higher risk patients, was that the combination seem to keep people in remission substantially longer than if they only got melphalan by itself. High-risk myeloma, by the way, there are different definitions for high-risk myeloma. The one that the International Staging System currently uses is if people have either the ISS stage three according to the old system along with what's called deletion of 17p by FISH, or there also is the translocation (4;14) and also in some cases (14;16) or (14;20) translocations.

It's also worth noting that there is a so called ultra high-risk myeloma now, or something also called double hit myeloma. That's a term that was adopted from our colleagues in the lymphoma space. And double hit myeloma is defined by one of two things. First of all, we talked about deletion 17p just a moment ago. One of the genes that probably is most important, which is lost when that deletion occurs, is the p53 gene. We normally have two copies of each chromosome, and therefore there is another copy of p53 on the other chromosome 17p, but some people have a deletion on both chromosomes, or they will have a deletion in one and a mutation of p53 on the other. Those are one of the double hit categories. Those people have one of the unfortunately poorest prognoses. And then the second group that are considered ultra-high risk or double hit are if you have four copies or more of the 1q21 region. 1q is the long arm of chromosome one, and it's an area that sometimes have extra copies just in the myeloma cells. If you have two copies, that's normal. If you have three copies, that's intermediate risk. But if you have four or more copies, that's considered high risk.

I think the take-home message from all of that is not that you have to remember all of these. The take-home message is that when you have your bone marrow done, you should definitely have FISH testing because that looks for the deletion 17p and the 1q21 amplification. And also, you should have sequencing done because that will look at the p53 gene and whether it's mutated along with a deletion. So keep that in mind, you should definitely do that at diagnosis. It probably should also be part of what you get done if you're having a bone marrow at relapse, especially after prior stem cell transplant. So that's a lot of stuff to cover, and I wanted to give a break to see it maybe, Jenny, you had a question about any of that before moving onward.

Jenny: This is a really important point. Ten years ago, when I was diagnosed, I went to a seminar and asked patients to raise their hand if they knew what kind of myeloma they had. Probably 5% of the patients raised their hand. At the time, it seemed like, well, if we know the genetics, we may not do anything differently in terms of treating you. But what I hear you saying is that it's much different nowadays. There are different approaches that people can take, like when you're talking about these four-drug combinations with daratumumab, or do you go to transplant, might you consider tandem transplant if you’re ultra high-risk or different types of approaches like how hard you hit it with maintenance afterwards?

You really need to know, if you're going to win this war, who the enemy is for you particularly. As you were mentioning, the 1q gain, those results typically will show up on your FISH test. So you can go back and look at your FISH test and see how many copies you have. But what you mentioned was next generation sequencing test, and that's a separate test from the FISH test. You might have to ask your doctor if they will perform that for you because that gives you, what you were talking about, the deeper dive basically into that particular p53 or other type of mutations like KRAS or BRAF that don't really show up on the FISH test.

So I can't stress your point enough that a diagnosis and relapse when you have active myeloma that you really have to ask your doctor to perform these tests. If you're being seen by a general oncologist, it's not something that they might suggest for you, so you have to kind of drive that process, in my opinion.

Dr. Orlowski: Well, you definitely nailed it. You mentioned correctly that sometimes a tandem transplant is considered for the high-risk patients and that more aggressive maintenance therapy is often considered for the high-risk patients. You mentioned the general oncologist. There are statistics that show that the general private practitioner in the hematology/oncology field sees about one or two new myeloma patients per year and manages a total of about five or six myeloma patients per year, which is a much smaller number than some of the more common cancers like colon, breast, lung, and prostate. So they do their best to keep up with what happens in myeloma, but it is a very specialized field. That's why it helps to have a team that includes your local hem-onc person as well as a specialist even if it means that you have to travel a few hundred miles or a couple of states over to see somebody who specializes in myeloma.

Jenny: Yes, I agree. It's better if you can get treated at a center like that statistically. But if that's not even a possibility for you, at least go get a consult and fly somewhere and get a consult about that. So I think that's really critical. So thank you for covering the genetics because it's really important. As you talk about other things, like the (11;14) translocation as we go along, it really makes a difference in terms of what types of myeloma you have or how your myeloma is genetically changing over time because that does happen with patients.

Dr. Orlowski: Definitely. The myeloma that you have when you're diagnosed is not necessarily at the molecular level, the same myeloma that you may have if you're unlucky enough to relapse in the future.

Jenny: And you need to know every time you relapse, right?

Dr. Orlowski: Definitely. So speaking of relapse, let me transition to some of the new data in the relapsed or refractory category. The main difference, I actually had a patient in clinic yesterday ask me about this. Patients who are considered relapsed are those whose myeloma is growing when they've been off of chemotherapy, and refractory his patients whose myeloma is growing while they are still on chemotherapy. The difference, of course, is usually that people with refractory myeloma, that disease is a little bit more resistant to chemotherapy and can be a little bit tougher to manage than if it has progressed when you are off of treatment for a period of time.

One of the big developments was the presentation of the so-called CANDOR study data. This was a trial that looked at carfilzomib and dexamethasone with the addition in one arm of daratumumab. A I mentioned earlier, with daratumumab, which seems to add to the benefit of a lot of different regimens hereto addition of dara to carfilzomib-dex made the car-dex regimen better in terms of response rate, the complete response rate, and the MRD negativity.

One of the reasons that this could be a very useful regimen is that many patients are on lenalidomide maintenance therapy either after transplant or after just chemotherapy alone. And then if they progress on the lenalidomide, the disease may be, as we just mentioned, refractory to len. So coming back with the lenalidomide containing combination may be less effective, and then using something like bortezomib with dara and dex or carfilzomib with dara and dex may be a better approach because the more new drugs that you use, probably the better the outcome will be. So I think that was an important development.

Jenny: Yes, and other combination strategies may be. Quads are probably in there too, right?

Dr. Orlowski: Well, quads are probably coming in the relapsed and refractory setting as well. None of them are yet FDA approved because the trials are still ongoing. I think the challenge, of course, is always, as I mentioned earlier, when you add more drugs, you're going to have a little bit of a greater risk of toxicity even though many of the drugs that we're adding now like dara and others have relatively minimal added risk, but there always is some. We have to measure the potential benefit versus the potential risk. In many cases, those have not yet been fully defined.

But the good news in the relapsed and refractory setting is that we have a lot of new options. One of them is a drug called Selinexor which probably about six months ago or so was approved by the FDA in combination with dexamethasone. This is an all-oral combination, has about 25% response rate. It worked even in people whose myeloma progressed after prior bortezomib, carfilzomib, lenalidomide, pomalidomide and daratumumab. Those are patients whose myeloma really is tough to treat. There are some side effects with the drug, which can include fatigue, drop in platelets, and a change in appetite, which sometimes can require intravenous fluids and anti-nausea medications. But it definitely is a good option to keep in mind. Other combinations are being studied now as well, including especially with bortezomib and with other drugs

Jenny: Can I ask your question about Selinexor before we move on?

Dr. Orlowski: Sure.

Jenny: I know it was used in the setting where people had relapsed many, many times and was approved. I can't remember how many prior lines of therapy it was approved for. But do you see Selinexor being used closer or more up front at earlier relapses? Is that where it's headed?

Dr. Orlowski: It's a great question. There are ongoing studies in earlier patient populations. The hope always is that when a drug works in very advanced disease that it will work even better in earlier lines of therapy and hopefully have less toxicity because the patients are a little bit less beaten up by having had fewer chemotherapy regimens. It does look like in small studies that giving it earlier does result in better outcomes, but we still need the large phase three trials to be sure about that.

Jenny: Okay, great. Thanks.

Dr. Orlowski: You also mentioned earlier the (11;14) translocation which is present in about 10% to 15% of patients with myeloma. It is also present in a higher proportion of patients with light-chain amyloidosis as well as in plasma cell leukemia. There is a drug called Venetoclax which is approved for leukemia in a number of settings, but this drug targets a protein called BCL2. This protein is expressed at higher levels in patients that have that (11;14) translocation, again another reason for you to know your official results because the (11;14) is detected by FISH. If you have that abnormality, Venetoclax combinations can have up to 80% response rates. The drug by itself actually has about a 30% to 40% response rate. It's kind of like a designer drug that works best for the (11;14) translocated patients. If you've got that translocation, it should definitely be high on your list of things to try either on a clinical trial, or it may be possible for you to get the drug on a compassionate use basis or even to purchase it out of pocket because it is FDA approved for leukemia as I mentioned earlier.

 

Jenny: And when do you see FDA approval coming for myeloma patients? Because, to me, this is the first time really that a myeloma drug is specifically targeted for a particular translocation or gene deletion or things like that. When do you think that will happen?

Dr. Orlowski: We're certainly hopeful that it will happen soon. The trials that are needed to get that approval are already underway. So let's keep our fingers crossed. Again, there are quite a few of these studies. So if you have that (11;14) and can't afford to pay for it out of pocket, then that would be an option for you to avail yourself of.

Jenny: Great.

Dr. Orlowski: I mentioned the compassionate use approach. Another drug to consider is belantamab mafodotin. This is an anti-BCMA antibody. It's called an antibody drug conjugate. What that means is that it's an antibody with a drug attached to it. It binds B cell maturation antigen, which is expressed on almost all myeloma cells. Once it binds, the antibody is taken up inside the myeloma cell, and the drug is released causing the myeloma cell to die. So it's kind of like a Trojan horse, if you remember back to Greek mythology. This drug in daratumumab refractory patients has about a 30% to 40% response rate, and it's up to 60 to 70% in patients who do not have daratumumab refractory disease.

It's also a very easy drug to give because it's once IV every three weeks with minimal to no steroids. The main side effects to keep in mind are a drop in the platelet count. Some people can have a little bit of blurry vision because of a corneal side effect. So you do need to be seeing an ophthalmologist before you go on that and also during treatment. We hope this drug will be approved soon. But in the meantime, it is available on a compassionate use basis. You can talk to your physician about getting access to it if you're looking for new options.

Jenny: These antibody drug conjugates, they started in other diseases like leukemia and things, didn't they, and now they're coming to myeloma?

Dr. Orlowski: They did and there are other antibody drug conjugates, for example, in breast cancer and others. I think this is a very interesting concept using an antibody essentially as a drug delivery tool because, of course, the antibodies are very specific and that helps you to avoid getting the drug into normal cells and limit some of the side effects. So I think this is an area that will definitely be growing. We're actually even doing some research in my laboratory with new antibody drug conjugates as well because the price of making these has dropped so much that it's within the reach of really every laboratory and institution.

Jenny: Fantastic. That's great.

Dr. Orlowski: People also are very excited about bispecific antibodies as well as car T cells. Let me start with the bispecifics which sometimes are called BiTEs. The main difference is that the bispecific is an antibody, kind of like daratumumab or isatuximab or belantamab, but those antibodies have two binding sites against the same protein. In the example of belantamab, both of the binding sites target BCMA. The bispecific though has two different binding sites. Usually, one attaches to a protein on the cancer cell, and the second attaches to a protein on a T cell. So what it does is it brings the patient's own T cell next to the cancer cell, it activates the T cell to make it angry, and the T cell then attacks the cancer cell and kills it.

The advantage here is that unlike many of the car T cell products, which has to be made individually, the bispecific antibody is off the shelf. You don't have to remove the patient's T cells and engineer them in a laboratory before you reinfuse them. Many companies have these bispecifics now in clinical trials. Most of them are targeting BCMA. The results so far look in terms of response rates, very similar to what we're seeing in the car T cell space, meaning 70%, 80% and 90% response rates. What we don't yet know is whether the durability of those response rates will be the same as with the car T cell therapies because the follow up on those studies is not quite as long yet. In terms of side effects, you can see cytokine release syndrome which is also seen in patients getting car T cells. That essentially is the result of the activation of the T cell. When the T cell becomes activated and angry, it releases proteins like interleukin 6, among others, and you can get fever as well as some inflammatory symptoms. But usually those are pretty well tolerated and easily managed with a little bit of steroid premedication, or we have other approaches including antibodies to IL-6 or the IL-6 receptor.

Jenny: Oh, before you move on --

Dr. Orlowski: Oh, sure.

Jenny: -- Let me ask a couple questions. Also, the BiTEs are typically, like you said, are off the shelf. They're mostly like regular infusions as opposed to the CAR T that you're going to talk about. I was blown away by the number of BiTEs that are being developed in myeloma. There are like seven or eight or something. I was just blown away by that.

Dr. Orlowski: Well, there's probably even more than that by now. But you're right, there are quite a lot. It's tough to know yet which one is going to be the best. It may be that they all will be great which would be a nice problem to have. But definitely look for clinical trials of these bispecifics or BiTEs. The structure of the BiTE is a little bit different than of the bispecific antibody, but the concept is the same. You're bringing the patient's own T cell, activating it, and putting it right next to a cancer cell. So this is really exciting technology where you're utilizing the patient's own immune system to be able to fight off the myeloma.

Jenny: And this might be an approach for patients who can't wait, like their myeloma is progressing and they may not be able to necessarily wait for

CAR T cell production or something like that. So they could jump right into a BiTE clinical trial.

Dr. Orlowski: Correct, you're right, because the whole process of making the car T cell, if it's an autologous CAR T, can take a while. You have to get what's called apheresis to collect your own T cells. They get usually shipped off to a laboratory at the pharma company where they put the chimeric antigen receptor inside. They grow the T cells, make sure that they're pure and clean. And that whole process can take up to two to three weeks or more. You can, in most of the trials, get some kind of chemotherapy while you're waiting, but you're right that there are some people whose myeloma is progressing too quickly to wait that long. And then a BiTE or a bispecific where you don't necessarily have to wait would be a good option in that regard.

Jenny: Great. Do you want to talk about CAR T's? I know there's been so much development in CAR T, but people are really working on extending the duration of response for CAR T and other strategies.

Dr. Orlowski: Definitely. I think probably everybody knows that the BCMA-targeted car T's look very good. The response rates again are usually 80% to 90% or 95%. The duration of the responses usually run 12 to 18 months or more. But it does look like not everybody is achieving a complete remission and not everybody is staying in complete remission. They do relapse.

So there's a few things that people are doing, some of which were presented at ASH. One thing that's interesting is -- and this is mostly from the group in Seattle -- they presented data on a study where they were adding what's called a gamma secretase inhibitor to the BCMA car T approach. What that does is gamma secretase is a protein that is sort of like a pair of scissors and cuts BCMA off the surface of the myeloma cell. Then the myeloma cell can look invisible to the CAR T, plus you've got all this free BCMA floating around that may block the CAR T from getting to the myeloma cell. But if you inhibit those pair of scissors, then the myeloma cell has more BCMA on its surface, and it's more sensitive to this car T approach. And although their study didn't yet show greater sensitivity because it was too early, they did show that the inhibitor increased the amount of BCMA on the myeloma cells, which I think is a great first step and really should show that there would be greater sensitivity.

And then the other thing that people are doing to try to enhance response rates and durabilities. First of all, people are looking at targeting different combinations of antigens. For example, there's another target called GPRC5D which is highly selective for myeloma cells and also SLAMF7. So we think that if you combine a car T against BCMA and a car T against one of these other targets that it's kind of like combination chemotherapy, two chemotherapy drugs, if you pick the right ones, will work better together. We think also that two car T cells against two targets will work better together.

And then the other approach that people are taking, which is just starting now, including trials at MD Anderson, among other places, are what are called allogeneic CAR T. One of the reasons we think why sometimes patients that get their own T cells reinfused may not have an optimal response is, first of all, their T cells may be not as healthy as could be because, of course, they've been through lots of prior therapies and their myeloma cells may be very drug resistant. But if you use an allogeneic, a donor CAR T, then that patient, of course, first of all, would not have had prior chemotherapy, and that means that hopefully their T cells will be healthier and may be more active against the myeloma.

For those of you that maybe have had an allogeneic transplant and you know that there can be what's called graft versus host disease, these donor T cells are usually engineered to knock out portions of their immune function so that they cannot cause graft versus host disease but they can still attack the myeloma cell. So those are still in early phases, but I think that there is a lot of excitement about that. Those also would be off the shelf because one donor can give enough T cells to make car T doses for, in some cases, several hundred patients. So you would have that waiting period that you do now with autologous car T. Hopefully, that would also bring down the price of the therapy.

Jenny: Yes, that's fantastic. I love that approach. It's great. Greater availability and faster development.

Dr. Orlowski: Yes. There also are new drugs out there. I think one of the interesting ones is a drug that doesn't yet have a name, but it's called CLR 131. This is a small molecule that actually binds to a phospholipid. So this is a fatty molecule, if you will, on the surface of cancer cells. The CLR 131 have radioactive iodine attached to it. We know that myeloma cells are very sensitive to radiation. We don't use a lot of radiation in myeloma because we can't radiate the whole body, although if people have a solitary plasmacytoma or if they have one particularly problematic spot, we do use radiation. But this molecule may be a way to deliver radiation right to the myeloma cells while sparing relatively normal cells. There are some really early very good data with that molecule. So that may be another interesting approach to bring back radiation to treatment of multiple myeloma, not just localized myeloma.

Jenny: So much is happening. It's amazing.

Dr. Orlowski: In terms of other diseases, I mentioned earlier a little bit about plasma cell leukemia. Because a lot of patients with that disease have the (11;14) translocation, there is interest in using Venetoclax there as well as CAR T cells. For AL amyloidosis, we also have interest in using Venetoclax as well as daratumumab. There may be some applicability of these drugs to Waldenstrom as well which is sort of half a myeloma and half a lymphoma but often is treated by myeloma specialists as well.

Jenny: Yes, great. In terms of maintenance, what are the new strategies? And especially for immunotherapies like CAR T, if it's not that durable, are they looking at different approaches to extend the durability using maintenance for CAR T?

Dr. Orlowski: That's a great question. There are trials that are looking at adding, for example, an immunomodulatory drug like either lenalidomide or pomalidomide after the CAR T is infused or adding other antibodies to try to keep the T cells from becoming exhausted. Those are still very early on, but I think that there will be an applicability for that. Also, a lot of the studies are using what I referred to earlier called minimal residual disease or MRD testing. This can be done, right now it's usually from a bone marrow where either by flow or by next generation sequencing, you can more sensitively detect even teeny tiny amounts of myeloma.

What we know is that people who are MRD negative have a longer remission duration. Not surprising because less cancer is always better than more cancer. But if somebody turns from MRD negative to MRD positive, we do know that that patient eventually will have a clinical relapse as well. So I think that the MRD testing should be important for a number of reasons. Number one, prognostically, you'll have a better idea of how long you'll be in remission. Number two, in the future, I think that people who convert to MRD positivity, we should think about not waiting until they have a clinical relapse but treating sooner. Most importantly, I think the FDA is very close to using MRD as an endpoint for drug approval. The advantage of that is that we'll be able to hopefully get drugs approved more quickly and not have to wait as long for some of the clinical outcomes because people with myeloma still need new therapeutic options in newly diagnosed relapsed and refractory disease.

Jenny: Right. So if you're using MRD as an endpoint on your clinical trial, we can get results faster. A lot of times now, patients are living so much longer that a trial may take eight or 10 years or more for you to get the results. If you use MRD as an earlier marker, then you could say, okay, we passed that part of the test. Let's move forward with this different treatment combination and then see what happens over a longer period of time, but then we don't need to wait eight or 10 years for that realization.

Dr. Orlowski: Yes, you're exactly right. For example, we just recently started a SWOG maintenance study where you get either lenalidomide or lenalidomide with daratumumab. And after two years, if you're MRD negative, you get randomized to either continue maintenance or stop maintenance so that we know if MRD negativity means that you could even be off of therapy for many years. But we expect that the results of that trial may, as you exactly mentioned, take eight to 10 years to get. That's, of course, great because it means people are doing so much better, but it also can be a little bit frustrating because we'd like to know the answers as soon as possible so that we can help people as soon as we can.

Jenny: Right. I mean, there's so much development being done. It's just so amazing, and I'm so grateful for it. We have several questions. So I want to jump into those, if you don't mind.

Dr. Orlowski: Definitely.

Jenny: If you have a question for Dr. Orlowski, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Perfect. Thank you. Hi, Dr. Orlowski. First, just thank you for everything you've shared thus far. It's been very helpful. You mentioned the deletion 17 and p53 as high-risk myeloma. Are there any specific therapies that are looking to be effective for these?

Dr. Orlowski: Well, thanks for that great question, also because I know I think we only have until the top of the hour. I did want to give people my email address. If you have questions, please feel free to email me. It's rorlowski@mdanderson.org.

We are working on a number of therapies that we think will be especially good for p53 either deletion or mutation. There are some data that suggest that maybe pomalidomide could be one of those. There are also some data that suggest that Selinexor could be good. And then we have a drug that we've been working with in the laboratory which should be available hopefully by the middle of the year in clinical trials from a small company called Heidelberg Pharma. This is an antibody drug conjugate which has a drug attached, which is especially good at deletion 17p myeloma. So look for that one, if possible. Again, consult with a myeloma expert because these are folks that need special attention to try to get the optimal outcome.

Caller: Perfect. Okay, thank you so much. I'll do that.

Jenny: Okay, great.  Next caller, go ahead with your question.

Caller: Hi, Dr. Orlowski. Thank you for coming on today. How is melflufen different from melphalan? Are the toxicities really not different? Will it replace melphalan for transplant or be administered in some other way?

Dr. Orlowski: Yes, great question. Thank you very much. So melflufen is what's called a peptidase-activated drug. It's sort of a prodrug, if you will, but becomes converted to an alkylating agent. So it has a mechanism of action that, in some ways, is similar to melphalan. It also right now is showing good activity in relapsed and refractory myeloma. So if you're looking for new options, you might definitely look to that and whether there would be a trial available. I think it's still a little bit too early to know whether it will replace melphalan in the setting of stem cell transplant. That would take a large trial that would need to be randomized. I think as I mentioned earlier, I would argue that the combination of melphalan and busulfan should now be the standard of care and that therefore may be the right study to do would be melphalan and busulfan versus melflufen and busulfan. But we'll see how things develop. I definitely think it's an interesting drug.

Jenny: Okay, great. Thanks for your question and great answer. Next caller, go ahead with your question.

Caller: Hi. Thank you so much, Dr. Orlowski, I wondered if you could give us a definition of intermediate risk smoldering myeloma. I know that we're looking at the various definitions, including the 20-2-20, but oftentimes I hear intermediate risk and wonder what determines intermediate versus low risk.

Dr. Orlowski: Yeah, so if you go by the 20-2-20 method, high risk is if you have two or three of those factors, again one being bone marrow plasma cells greater than 20%, the second being M protein more than two, the third being involved to uninvolved free light-chain ratio of greater than 20. If you have one of those factors, you're intermediate risk, and if you have no factors of those three, you're at low risk. Just to give you an overview, if you're intermediate risk, the estimated time to progression is about six and a half years whereas if you're a low risk, the median time to progression is about nine to 10 years. So it does make a big difference in deciding whether to get treatment or not. Again, we are not 100% sure which though of these risk stratification methods is the best one.

Caller: Okay, thank you.

Dr. Orlowski: Thank you.

Jenny: Thank you for the question. Great question and great answer. Next caller, go ahead your question.

Caller: Hi, Dr. Orlowski and Jenny. This is Dana Holmes. I always look forward to your annual show with Jenny, Dr. Orlowski. You have such a great way to explain so much in a short time in such a patient-friendly way. So I thank you for that. I also want to say I agree with both you and Jenny about the importance of myeloma patients becoming informed about their flavor of their disease. But I also want to add that I believe, as a smoldering patient, it's just as important for my fellow smoldering patients to understand that as well because the more we can learn now while we're smoldering, the better off we'll be when it comes time to face treatment.

Dr. Orlowski, Dr. Don Benson's group at Ohio State University has a paper in the Biology of Blood and Marrow Transplantation Journal about the outcomes of auto stem cell transplants in (11;14) patients. I know your center also did something similar. OSU found no significant difference in outcomes following an auto SCT in (11;14) patients and high-risk patients. They actually compared (11;14) to the high-risk patients, and they make note of how (11;14) myeloma is predicted to be BCL-2 dependent as you mentioned. So the use of the BCL-2 inhibitors in induction or possibly post-stem cell transplant would be an attractive option to improve outcomes. So are we going to be seeing clinical trials studying these as Venetoclax or other BCL-2 inhibitors in the newly diagnosed myeloma patient population soon?

Dr. Orlowski: Well, Dana, first of all, thanks for your very kind words, and thanks for everything that you do to help promote education of myeloma patients, both with smoldering and with active disease. The (11;14) space does have a variety of data out there. I can tell you, for example, I know Don Benson's paper here at MD Anderson. We put our experience together a couple of years ago. Although certainly the (11;14) patients did not look like the high-risk patients, their outcomes in our experience were a little bit worse than the "good risk" or standard risk patients. So I think the jury is still out. The more information that people publish about this, the better because again these are 10% to 15% of the population. So no one center has everything to say about this population.

I do think it makes a lot of sense to look at adding Venetoclax to newly diagnosed patients with (11;14). I think you mentioned maintenance as an approach. Definitely, if you still have residual disease after transplant, that's (11;14) positive, it would be rational to do. I think it might even be interesting to add it to melphalan when you're getting a stem cell transplant because it should add to the sensitivity of those myeloma cells to the melphalan --

Caller: Oh, so do you mean prior to actually putting those cells back in, you would give Venetoclax with melphalan? That's interesting.

Dr. Orlowski: Well, we know that even the high-dose melphalan does not 100% kill off every myeloma cell in the patient. Especially, let's say, if you do a bone marrow, before you collect your stem cells and it turns out that there are still myeloma cells left and they're (11;14) positive, would I be in favor of a trial that would look at adding melphalan with Venetoclax? I think that would be very interesting to do. Of course, don't do this at home without a clinical trial because we don't know the toxicity yet, but I think from a molecular and biological perspective, there would be a lot of rationale to do that.

Caller: Yeah, that's really interesting because quite honestly, when I was first diagnosed, my (11;14) presented itself. I'm still smoldering. I actually just hit my eighth year. Initially, when I was diagnosed through the Mayo Clinic's progression risk model, I was high risk. Fast forward to the 2020, I'm now intermediate risk, but here I am, eight years later, still plugging along. So I'm grateful for that because it really truly has given me the time to educate myself as best as I can about my flavor of this disease. I think from what I'm seeing and reading over the last few years is that we're really moving away from that standard risk label for (11;14), not necessarily high risk but certainly not standard risk. Do we see maybe somebody coming up and saying, hey, it's really intermediate risk, and we really need to relabel, or keep it a standard risk and let's hope that Venetoclax will be our ticket?

Dr. Orlowski: I wouldn't want to go as far as to say that it's intermediate risk quite yet. But whether you want to create an even intermediate category between standard and intermediate, I think every patient is going to be a little bit different. But of course, by the way, in your case, you know that once you get past five years from your diagnosis of smoldering, the risk of progression goes down dramatically. So you are in a good position as far as that because probably your risk of progression right now is the same as if you were diagnosed with MGUS.

Caller: Yeah, even though you tell me that and I read that all the time, it doesn't make me any less anxious about this disease. So I'm not hanging up my research skills or my shoes just yet.

Dr. Orlowski: No, no, definitely not.

Caller: I'd really love to stick my head in the sand for a while and walk away and think that I'm fine, but I know better not to. So I just really plug along with it. I think that's another important message for smoldering patients is just don't become complacent. Continue what you're monitoring. It's really important to be under the care, in my opinion, the direct care of a myeloma specialist because there are just so many benefits to that, including potential clinical trials and just all of the stuff that's developing that local oncologists may not have their fingers on the pulse with. Dr. Orlowski, concerning MRD testing, is there any sample bias to MRD testing?

Dr. Orlowski: Well, there is sample bias from the perspective that the flow cytometry is probably a test that's a little bit easier to do. You don't need a baseline sample. You can do that even if you hadn't, for example, had that tested by next generation sequencing whereas if you're in complete remission and you haven't had a baseline sample, then that can be an issue. The way that you obtain the sample is important as well because usually when you have a bone marrow aspirate, it's the first pull that has the most plasma cells. If you're sending a later pull, then you're going to be less able to really determine whether plasma cells are there or not. So the sampling is important. Of course, myeloma, especially if it's at low levels, can be quite patchy. One spot may be more involved than another.

Caller: Right. Okay. One last question, because I know that the hour is over, concerning BCMA-targeted therapies. Is BCMA found exclusively on myeloma cells, or is it also found on healthy normal B cells? Therefore, these drugs target those as well? Does that make sense?

Dr. Orlowski: It's a good question. It does make sense. BCMA is also found on normal plasma cells. There are a few precursors to plasma cells that have some B cell characteristics that also have BCMA expression. But compared to, for example, CD19, which is the target used for many lymphoma car T cells, BCMA has a much more restricted expression pattern. But you do hit a small population of normal cells when you target BCMA.

Caller: Okay, great. Well, Dr. Orlowski, thank you so much for your time. It's always such a pleasure chatting with you. Jenny, thank you for this platform. Much appreciated.

Jenny: Thanks, Dana. Great questions.

Well, Dr. Orlowski, thank you so much for joining us today. We're sorry to go over a little bit, but we're just so grateful of your generosity with your time, and sharing your incredible expertise is just unbelievable.

Dr. Orlowski: My pleasure. Again, happy and healthy 2020 for everybody listening and for their friends and family.

Jenny: Okay, thank you so much. Thank you to all who tuned in to today's show. Thank you for listening to Myeloma Crowd Radio. Join us next time as we continue to connect patients with these incredibly talented researchers.