Dr. Orlowski discusses his research and how faster progress could be made towards a cure if more patients participated in clinical trials. The interview covers four of the latest areas in myeloma research that Dr. Orlowski is pursuing: New treatment approaches where smoldering myeloma is treated earlier, Antibody treatments called PD-1 using a class of drugs already approved for melanoma, Two new immunotherapy approaches where the patient's immune system attacks the myeloma cells including a vaccine approach pre-transplant and also a way of purifying the gene that produces the abnormal protein that is then re-injected to try to stimulate an immune response. Dr. Orlowski also discussed a new class of drugs that prevent myeloma cells from making the protein Stat 3. 

Jenny: Welcome to our first episode of “Innovation in Myeloma.” This is a weekly interview series that connects multiple myeloma patients with experts in myeloma and gives them gives patients insights into their research and clinical trials in an easy-to-understand format. My name is Jenny Ahlstrom and I and other myeloma patients will host this show. I am a multiple myeloma patient who was diagnosed in 2010. I went through three years of treatment and am now in remission. We are very honored to have with us Dr. Robert Orlowski, Director of Myeloma at the University of Texas MD Anderson Cancer Center. He is also my doctor. Thank you Dr. Orlowski for joining us.

Dr. Orlowski: Getting information out to patients is really important, and I want to congratulate you on the effort you are making in that regard. To talk about clinical trials I think it is important to try to look at all of the different areas in multiple myeloma. So let’s start with so-called smoldering multiple myeloma. Many patients with multiple myeloma in the past before they were diagnosed may have had MGUS, or monoclonal gamopathy of undermined significance and some had smoldering myeloma. In the past, we did not treat patients with one of those because the risk of progression was quite low. More recently though, we are able to identify some patients who are especially high risk and there is an increasing trend to think about trying to treat those patients with the thought that perhaps we could reduce the amount of myeloma and therefore delay the time until they develop symptoms and maybe even cure the disease because the earlier you treat, in general, the more sensitive the myeloma. So we have a study coming up with a monoclonal antibody to a target called PD1 and there has been a lot of excitement about this class of drugs which are already approved for melanoma. The thought is that cancer suppresses the patient’s immune system, which is one way it is able to spread. What this antibody actually does is it takes the breaks off the immune system. What we are hoping is that it will help the patient’s own immune system get rid of at least some if not all the myeloma. The other advantage is that because this is an antibody, which is a different class of drugs, it hopefully would not cause any cross-resistance to other drugs that we use if the patient’s disease does later progress.

Jenny: Are you targeting just the smoldering and MGUS patients for that study?

Dr. Orlowski: This study targets the high-risk smoldering patients, but if the study were to show encouraging information, then it could be expanded later to include patients with lower-risk smoldering myeloma and maybe even to MGUS patients, although I think that is a little bit more speculative. Because the risk of MGUS progression is usually so low, only about 1% per year that I think it will be awhile before we use treatment in those cases.

Jenny: Is this an active and open trial?

Dr. Orlowski: This is a trial that we’re finalizing the protocol for and we hope to have it open therefore in the next four months or so at which point we will be active and enrolling.

Jenny: And how many patients could you enroll in that trial?

Dr. Orlowski: Well, the study is designed in such a way that first there is a small trial component to see if we have responses and if there are responses then the trial would be enlarged to allow more patients to enroll. For right now, we’re not 100% sure what the total will be because it depends on how well the strategy works.

Jenny: When I started searching clinicaltrials.gov I found over 540 open myeloma trials so I had a lot of information but no context. I know that you are pioneer in many fields and I know that you were working previously on this antibody therapy – having your own immune system attack the cancer cells. I know you’ve done significant research in the proteasome inhibitors space as well. During my preparation for our discussion I found out that your father discovered the first proteasome inhibitor with a colleage and that you went on to continue that work and ran the first Velcade trial, which I didn’t know as your patient. I thought that was fascinating.

Dr. Orlowski: Well, that’s true. Some people get the family business when they grow up and other people get the family research field as an inheritance. So I was in the second category.

Jenny: We are very lucky that you were. For the patients that are listening, can you help us categorize these different areas of research? Can you help us categorize these into buckets that we can understand?

Dr. Orlowski: Well before we leave immunotherapies, I thought I would let you know about a couple of other studies that are going on at MD Anderson because we are really excited about immunotherapies. One study that is open right now and you know a lot about transplant having gone through that getting the high doses of melphalan and melphalan is good because it kills myeloma cells but also can cause some damage to normal cells. Usually the transplant is not enough because you need some treatment afterwards, as you received. One of the things we are trying to do now in stimulating the immune system is that we are actually taking blood from patients with myeloma before the transplant, isolating the myeloma protein, or what’s also called the M-protein or monoclonal spike. We are then giving that to patients before the transplant as a vaccine to try to increase the number of T-cells, which are a type of immune cell that react against that protein. Then we collect those T-cells and expand them in the laboratory and after patients get the high dose melphalan we give them back these expanded T-cells – basically their own cells that they are getting back with additional vaccines with this myeloma protein and this is actually supported by a large grant from the National Cancer Institute called a SPORE grant. What we are again trying to do is boost the patient’s own immune system to get rid of even more myeloma than would be possible with just the melphalan alone. That’s a trial that’s open right now and again we are excited about it because as you pointed out there are a lot of different drugs – small molecules like proteasome inhibitors and immunomodulatory drugs and steroids and alkalating agents that are used in myeloma, but one of the things that we haven’t done enough of is to use the immune system to help with the battle. So hopefully, this will be a good step. And briefly I’ll mention one other study, which is very similar, but targeting patients with something called Waldenstrom macroglobulin anemia. This is a less common condition than myeloma but it is a related cancer where you can detect an abnormal protein in the blood and some of the same complications as in myeloma can occur including anemia, and fatigue and infections and kidney damage. What we are doing in this study is we are taking the cancer cells themselves from the patient. We’re purifying the gene that leads to production of the abnormal protein and then that gene is going to be injected back into the patient with some modification to try to stimulate an immune response. And again the goal is to try to stimulate the patient’s own immune system to do a better job of getting rid of their disease. That study is going to be open later this year as well for patients who don’t yet have symptoms with the goal of maybe preventing the disease from growing or maybe curing it all together. I think looking towards the future, this combination approach is going to be the way that we start to cure more and more patients with myeloma and related diseases, meaning that we will do a combination of chemotherapy, stem cell transplant and some kind of immunotherapy.

Jenny: With these two coming up, could you tell us how patients can enroll and how they know if they are qualified? Sometimes trying to find out if you are qualified can be pretty difficult.

Dr. Orlowski: That’s a great question. One of the best web sites is clinicaltrials.gov. This is a web site sponsored by the National Cancer Institute and virtually every clinical trial for every disease, not just myeloma, that is being run not just in the United States but many that are being run in other countries is listed. There’s a very good search engine. All you do is put in “myeloma” and you can add more parts to the search, like if you want to look at trials in Texas or trials within a certain distance of your own location, you can put that in there and it will give you a list of all of the trials with a particular disease or with a particular drug and the listings provide important information because they have inclusion and exclusion criteria. These are the things that determine whether a patient can or cannot be eligible and also there usually should be information about the physicians and nurses that are running the studies which include phone numbers and in some cases email addresses. That way if you are not sure based on what is on the web site you can call the site which is running the trial nearest to you. In terms of MD Anderson, I can give you my email address rorlowsk@mdanderson.org or we also have a referral line which is 855-myeloma – not that difficult to remember. Patients can just call in directly or contact me via email.

Jenny: Let me go back just a bit to the SPORE study. When I did a search on clinicaltrials.gov on your name I found 10 open clinical trials additionally more that are in progress. Is this SPORE trial considered one of the open trials, or one of those in process right now?

Dr. Orlowski: The study that is being done right now with the vaccination and then the T-cell approach are currently open. Part of the search engine allows you to search on who is the principal investigator, but do keep in mind that in a larger place like ours we have six physicians who specialize in seeing myeloma patients and some of these studies are being done by different physicians so just looking up one physician’s name may not give you the whole spectrum of what is going on at that institution.

Jenny: Can you tell us a little more about the myeloma practice at MD Anderson?

Dr. Orlowski: We have a large practice as you can imagine. There are six physicians and we are recruiting for an additional new physician. Most of the time we can get patients in within 3 or 4 days for an appointment if they call for a consultation. We have a number of clinical trials which span the globe in terms of covering patients who are newly diagnosed myeloma, myeloma that has relapsed and also myeloma that has become refractory. We also have a lot of new drugs trials for people who are looking for new possibilities for therapy and unfortunately we still need more drugs to try and get to the point where we are trying to cure the myeloma. There are a couple of drugs that we are particularly excited about. There’s a trial with a drug called ARRY-520, it doesn’t yet have a name, but it’s shown a response rate up to 30% in patients with myeloma that have stopped responding to other drugs like Velcade, Revlamid, and Decadron. We also have some upcoming studies with new classes of molecules. We will be site for Deratumumab,which is an exciting new antibody that looks like it works by itself against myeloma and we talked about the benefits of antibodies earlier. Probably at the beginning of 2014 we will have a study with what is called antisense oligonucleotides against stat 3. Stat 3 is an important protein for myeloma survival. What these do is to prevent the myeloma cells from being able to make this protein. That’s a totally different class of drugs – one that we are excited about and hope they will help in myeloma therapy.

Jenny: As a general question, I know that about less than 5% of patients with all cancers and in myeloma participate in clinical trials. But the CancerNetwork did a study where they found that over 70% of patients said they would be willing to participate in a clinical trial. So from your perspective and because you have run many clinical trials, and have many patients, what do you see as the challenge in enrolling patients and how can we overcome that?

Dr. Orlowski: Those are great questions. One of the great advantages of clinical trials are that first of all you may get access to new drugs that have already been shown to be active against myeloma but may not have yet gotten FDA approval. The other benefit of course is the more patients that go on clinical trials, the more quickly drug development will go and the more rapidly therefore drugs will be approved. I think the reasons people don’t go on studies is usually fall into a couple of categories.First of all, not all patients are being treated in a place where clinical trials are available. And so you have to be able to have the ability to look around and in some cases travel beyond where you are being treated and that can be sometimes expensive and not very convenient, so that’s often one barrier. A second barrier is that sometimes patients may be worried that they will be placed on a placebo but most of the studies that are done for myeloma, most of them do not have placebos and the patients are placed on the fully active drug. It’s usually a good question to ask, but there is usually no placebo involved. Another reason may be the patients do not know about the availability of trials even in the places they are being treated. That’s why some of these web sites like clinicaltrials.gov would be very important because the more patients know about what treatment options are available, the more options they will have and therefore the better they will do.

Jenny: Where you have multiple open studies like the SPORE and antisense, how would a patient go about selecting which approach they would want to take?

Dr. Orlowski: That’s another good question. One of the reasons we have multiple studies open is that first of all they are targeting multiple types of patients and they may have different criteria. We try in a place like MD Anderson at least one study that fits everybody that walks in the door. If patients have more than one option, which would be a good thing as far as I’m concerned, the best way to decide is to discuss the options with their families and caregivers with the physicians and nurses that are involved. Sometimes if you have a choice between two different drugs and one of them has a longer track record and has shown activity, it may be more appropriate to pick that one because if the other drug is still relatively unknown, most people like to go with the one that has the longer track record. Other considerations could be convenience. Some of the drugs are given orally, some are given by injection, which can be very quick, or by IV which can take a long time. If they don’t have the ability to stay in a location for a long time, lets say the trial is out of town, then it makes more sense to pick the one that is given orally, because that’s going to be much more convenient. Usually those are some of the factors that come into play. Other issues are what are the known side effects of the drugs. As one example, if a patient has neuropathy, either because of the myeloma or because of the previous drug treatment and one of the options they have is another drug that may cause neuropathy, they may want to avoid that drug and participate in another study that doesn’t have any neuropathy associated with it.

Jenny: If a study is offered at multiple locations, how can a patient know that?

Dr. Orlowski: Usually if you go to clinicaltrials.gov and look up a particular study you are interested in, it will list at the bottom of the page usually, all of the institutions that are participating and you can see if they are actively recruiting or not. As you are pointing out, some trials are open at only one institution or two, some of them are open at 30 or 40 and that web site will have list of those that are open. It’s always a good idea to call ahead just to be sure because a trial, even if it is active, may be temporarily closed because some of the data are being analyzed. So before you make plans to go to University XYZ to get onto a study, it’s always a good idea to call ahead and make sure the trials is open and available.

Jenny: You’ve been involved in research for many, many years. In your opinion, if there was one thing that could help speed up the progress to find a cure, what would it be?

Dr. Orlowski: I think what you’ve mentioned earlier is the most important thing, which is to have more patients be involved in clinical trials. Because if we could increase the number to double what we currently have we could evaluate drugs twice as quickly. In order to get a drug approved by the Food and Drug Administration, the pharmaceutical companies usually have to run large studies which can be 200 all the way up to 600 or 700 patients and in addition to enrolling the patients they have to be treated and then the data – how well the myeloma responds, for example- have to be collected and analyzed. If we could cut the time needed to enrollment in half, then we could get the drugs that work approved much more quickly and out to patients much more quickly.

Jenny: That’s what we are trying to do. That would be great. I’d like to go back to your antisense study and learn a little more about that.

Dr. Orlowski: The advantage of some of the antisense technologies gets back to the differences between the drugs that are small molecules and drugs that are big molecules. Small molecules (and this would include things like melphalan, Velcade, Revlamid, Kyprolis, Pomalyst) they are so small that they can get into every cell in the body and they have effects on multiple targets, and some of those effects can lead to side effects. Drugs like antibodies or antisense molecules, which are much larger, are much more specific. The antibodies, for example, will often attach, predominantly only to myeloma cells. The antisense molecules only effect certain genes inside cells and leave all the other genes untouched. What we hope is that we get a much more specific effect with fewer side effects. When you have fewer side effects, patients feel better, they have a better quality of life and they are better able to tolerate treatment. We want to kill the myeloma cells, but we want to do so while preserving the patient’s ability to do their daily activities and continue their other pursuits.

Caller question: My husband has had myeloma for the last four years. Most recently he has been on Carfizomib for 2 cycles. There is a possibility that he now has systemic lymphoma.

Dr. Orlowski: There are patients that have myeloma and another cancer. Part of that is because the immune system in patients with myeloma is not as strong and also some of the therapies may increase the risk of other cancers. For example, the melphalan at the time of transplant. If he has cutaneous t-cell lymphoma or anaplastic lymphoma that of course needs to be diagnosed and we need to make sure that we know what he has. There are treatments available for these diseases and in some cases the treatments available may be curative so although the situation is never good when you have more than one cancer, it may be that he may be still cured. I suggest you go to a place where they have the level of expertise needed because clearly he is not your average patient.

Caller: Is it possible to get primary treatment at MD Anderson and then get the protocol followed at a local facility?

Dr. Orlowski: Definitely. A lot depends on what the recommended treatment is and how much experience the local doctor has with that treatment. We do this very commonly that we make a recommendation and either all the treatment is done locally or you can do the first cycle here, then go home and continue to get additional treatment at home. That is very common.

Jenny: Thank you so much Dr. Orlowski for participating. We have a companion doctor directory where we would like to invite myeloma specialists to join so patients can find myeloma doctors near them. We look forward do doing this again and thank you again for your time.