Subscribe today to our new newsletter The mPatient Minute. This is a weekly email newsletter that puts our past show and upcoming show into one simple email. Learn about the latest research you may want to support through your participation in a clinical trial. Dr. James R. Berenson, MD Institute for Myeloma & Bone Cancer Research Interview date: September 6, 2013 Summary On this week's show, Dr. James R. Berenson of the Institute for Myeloma & Bone Cancer Research discusses his unique approach to use myeloma therapies in a variety of combinations that looks at dosing, ordering and scheduling to both treat the myeloma while at the same time addressing quality of life issues. He discusses how resistance to one type of myeloma therapy doesn't necessarily mean resistance to others in that same drug class. He also discusses how his Institute and clinic enable him to investigate new targets in a shorter time frame. The live mPatient Myeloma Radio podcast with Dr. Berenson
Jenny: Welcome to another episode of mPatient Myeloma Radio, a show that connects patients to myeloma researchers. We have a few ways for you to hear about mPatient Myeloma Radio upcoming and past interviews. First, you can follow us on Twitter @mpatientmyeloma where we tweet about upcoming and past interviews but we also have a new mPatient Minute Newsletter that organizes the interviews into one weekly post. Just go to www.mpatient.org homepage to subscribe. We have a full schedule with amazing myeloma doctors and you don't want to miss the episodes. Speaking of which, we have an amazing myeloma doctor with us today, James R. Berenson of the Institute for Myeloma and Bone Cancer Research. We also have on the call one of his patients, John Forrester, (also of the IMBCR) who will be giving his introduction. So John, why don't you go ahead.
John: Thank you, Jenny. Dr. Berenson is the founder of the Institute for Myeloma and Bone Cancer Research, more commonly known as IMBCR, and has specialized in research related to myeloma and metastatic bone disease both in the basic and clinical areas for more than 25 years. He has been involved in many of the major breakthroughs that have brought new treatments for patients with these diseases, resulting in both an improvement in the length and quality of their lives. After receiving a Bachelor of Science with Distinction from Stanford University, Dr. Berenson earned his Doctorate in Medicine from the University of California at San Diego. Dr. Berenson completed his internship and residency in internal medicine at the University of Utah Medical Center and fellowships in hematology oncology at the University of California LA (UCLA). He is certified by the American Board of Internal Medicine in both Internal medicine and Medical Oncology. Dr. Berenson has a private practice that specializes in the treatment of patients with myeloma and metastatic bone disease. He is one of a very few myeloma research scientists who is actually on the front lines with patients everyday in a clinical setting. He is also President and CEO of Oncotherapeutics Inc., a corporation that conducts clinical trials related to myeloma and metastatic bone disease as well as other cancers throughout the United States. Born and raised in Portland, Oregon, Dr. Berenson is married to the delightful Debra. They have two children, Shira and Ariana. On a personal note, when I first met Dr. Berenson I was in very bad shape. This was three and a half years ago and I was on life support at Cedars-Sinai Hospital, really in a very near death situation: kidneys failing, no blood, ventilator sepsis, bone marrow almost completely filled with plasma cells. Yuck. Dr. Berenson put me on a custom treatment regimen and that quickly knocked back the myeloma burden on my body and I responded. To the amazement of most doctors there, I got well and walked out of that hospital. I would also like to say the Dr. Berenson was extremely kind to my family and actually gave them his cell phone number so that he could keep in touch with them during the scary weeks. And actually, all patients have his cell phone number, which I think is rare for a doctor. I feel extremely blessed to be working with one of the world's top myeloma scientists and trailblazers, Dr. James Berenson. That care integrated with the best holistic approaches available truly has given me the very best of both worlds. If you saw me today, you would never guess there was a problem. Here to tell you more about his clinic and IMBCR, the research organization dedicated to finding a true and permanent cure for this disease, please welcome Dr. James R. Berenson.
Jenny: Thank you.
Dr. Berenson: Good afternoon.
Jenny: Dr. Berenson. Welcome.
Dr. Berenson: Well, thank you for having me.
Jenny: Would you like to start by sharing a little bit about your institute? When did you start it and what was your purpose in starting it?
Dr. Berenson: The institute just celebrated its 10th anniversary and the idea was to develop new therapeutics from laboratory-based work from fresh tumor samples from our patients as well as already-established cell lines. This work has led to the development of many new treatments as well as identification of new pathways to target new treatment for. We've been very excited to be able to translate the work in the laboratory of the Institute for Myeloma and Bone Cancer Research directly into the clinic through the conduct of clinical trials that are done not only by our own group with many of our own patients participating really on both ends. That is, giving us bone marrow to test as well as being a patients or participants in the clinical trials but as well at many sites throughout the United States through our clinical trials group called Oncotherapeutics. So we kind of do everything from nuts to bolts, that is, very basic research, all the way to taking care of patients and not only taking care of their needs for myeloma but their overall needs. So we like to say that it's really about our patients having a complete life not, not necessarily only a complete response, meaning the myeloma can't be found.
Jenny: Well, that's wonderful. It seems like with the institute and Oncotherapeutics it appears that you're kind of working towards this all-in-one approach. What advantage do you feel that that's giving you?
Dr. Berenson: Well, the advantages I can tell you are from several points. One is the rapidity with which things could get done within this private institution are literally about ten-fold faster than in the university setting or large institutional setting. Second, from seeing things happen in the clinic on our own individual patients we can go back in the laboratory and try to see if these new combinations will actually prove useful in animal models, optimize them, and then bring them back from anecdotes, or specific patient examples, into large clinical trials. We've actually done that in multiple occasions and just in the last several months we've identified two potential new drugs that can be used in novel combinations and they're proving worthwhile both in the clinic and the lab. We've also been able to develop a new serum marker through samples that have been banked on nearly 500 of our own patients over the last several years, and that seems to be a very useful marker now to follow myeloma. Perhaps it will be useful to follow a lot of other cancers as well. We're working on that.
Jenny: Wonderful. Would you like to give us an overview of your research in general and then we can kind of drill down into specifics?
Dr. Berenson: Sure. Well, our goal is to find treatment that will only impact the tumor and leave the rest of the body alone and I like to quote my wife, who John mentioned earlier, Debra -- who's an actress and one of our board members, she used to produce a lot of theater that she was in -- and he used to say to her, "It's about being more specific, not just about being more." So more action isn't necessarily more better. We want more specific action on the cancer and we take that to task in everything we do from the lab to the clinic. So we are trying desperately to develop therapies that leave the rest of your body alone and just attack the cancer. In that regard we have been working both on gene therapeutic approaches and antibody conjugate approaches, which are proving useful at this point in the lab, can't tell you yet in the clinic. We're very excited about the data on that. We've also tried to find new targets, and those are specific proteins or factors that drive the myeloma or make it survive or make it resistant to other treatments, and trying to see if we can develop therapies to overcome that and we're actually doing that now as well in the laboratory. Hope to be able to translate that in the clinic in the future as well.
Jenny: In terms of genetics, can you describe exactly what you're targeting? Are there specific genes that you're looking for? Are you breaking things down into myeloma subtypes or genetic profiles?
Dr. Berenson: Well, our attempt is to be able to develop therapies that target a genetic marker that is common to all the cancer calls in a given patient. Based on work I did 30 years ago as a fellow at Caltech in LA that's the antibody genes, the genes that make the abnormal antibody, and by targeting those we're able to develop therapies that only will be released in cells that harbor that specific genetic marker, and that's only the myeloma cells. On the antibody level there are certain proteins that are very common to myeloma cells and by targeting those with a toxin or an effective drug hooked onto the, antibody which is bound to the cancer cell, the concentration of the drug can be thousands of folds higher than that are released. It's released within the cancer cell compared to the rest of the body and thus those toxins, which are highly effective at killing the myeloma, leave the remainder of the body alone. So there is a protein-based approach specific and then a genetic-based specific approach.
Jenny: Are these considered immunotherapy approaches?
Dr. Berenson: Well, one is. One is immunotherapeutic. It's an antibody-based conjugate. The other is more of a genetic approach. We certainly are interested in other immunomodulatory effects of many of the drugs, such as the drugs like Revlimid, Thalidomide, Pomalyst. These drugs are immunomodulatory as well as seem to make perhaps other antibody therapies work better. We're seeing evidence with some of the new therapies that are in development that Revlimid can make them look better.
Jenny: Can we subtype myeloma at this point?
Dr. Berenson: Well, we can subtype it based on genetic markers. You can argue what that means clinically right now because most myelomas these days is actually able to respond regardless of what we formally called high-risk disease, and the small numbers that are -- those that harbor what's called p53 or 17p minus, that is, our missing part of chromosome 17 -- we really can't tell patients what to get to make them do better. That's the problem.
Jenny: Do you think we'll be able to get to that point?
Dr. Berenson: Yeah, I think so. I think with time we will. The problems with therapies changing so rapidly is that prognostic factors that may have been relevant even several years ago may no longer be relevant as we develop new treatments. That is the problem.
Jenny: A question on that, I guess there seems to be a blast of new therapies coming out. It looks like there are HDAC inhibitors and immunotherapy types and it just seems like there's a whole slew of new therapies. This question relates to any new therapy -- without long-term data on new therapies, how do you know if the new ones will ultimately have better results than an existing therapy over time? How do you balance that as a researcher?
Dr. Berenson: Well, it is a balancing act. You're absolutely right. So we don't unfortunately know long-term outcomes in a lot of new drugs such as Carfilzomib or Pomalyst and we have to guess based on drugs that are similar. In the case of Carflizomib it's Velcade; in the case of Pomalyst it's Revlimid, but we don't really know that something untoward may happen in a good or bad way with these drugs. So we're also learning that resistance to one drug doesn't mean you're resistant to a drug in a similar drug class, and that was the one we were taught back in medical school because these drugs have a lot of off-targeted benefits that make them work in situations where, say, another drug in the same class does not.
Jenny: Do you want to go into any detail in any research studies that you're currently working on?
Dr. Berenson: Well, sure. In the laboratory we're working on a factor called traf-6 and we're showing you can make a lot of other drugs work better. It's involved in the same pathway that Velcade and some of the other drugs work, and it's astounding how much better the drugs work in the face of blocking this factor. We are also working on a new serum marker, called the B cell maturation antigen, which should shut off the myeloma cells into the blood and it could be used to follow the disease, and we now have recent data that suggests it may contribute to the immunodeficiency, which is the hallmark of myeloma as well. We also have very good data on several other new targets in myeloma as well, some of those I can't mention because I'm limited by what our agreements are with the companies but it's pretty exciting. The antibody conjugate or some other combination therapies that we're doing in the lab looks very exciting. We're actually able to, for the first time, cure myeloma completely in our animals with some of the antibody conjugates. We've never seen that before.
Jenny: Well, that's stunning and I'd like to talk about that. If you think a cure is coming then where do you think it's coming from?
Dr. Berenson: I don't want to say with certainly that a cure is coming immediately. I think that we're moving in that direction. People's live are certainly being extended but I can't tell you with good certainty when we're going to have, quote, a cure. I think we certainly are offering patients a lot more options than ever before. I think that's really good news, really good news.
Jenny: Yes. It's great news for all of us. Now, I saw that you are working on stem cell research, kind of how the myeloma begins. Can you talk a little bit about that - about how it starts and then what you're doing to target it at its inception?
Dr. Berenson: We are trying to identify -- I like to call it the Eveready Battery Cell -- the cell that keeps giving the disease and see if we can develop therapies that will eliminate that. We have been working on that for some time, trying to subset cells from the myeloma clone from some of our patients, and see which types of markers identify a small group of cells within the whole clone of myeloma that a patient harbors, that keep on growing in the mice. This is really an important clone in order to eventually try to cure the myeloma because you got to get rid of those Eveready Battery Cells.
Jenny: Right, they keep generating. Let's see, do you want to talk about any of those studies in particular?
Dr. Berenson: Well we are doing a lot of work with both Pomalyst and then also the Carfilzomib. Both in the clinic and the lab we're able to show something I think very important with these drugs and that is that you can overcome resistance in one drug class with another. So we've had a lot of people think of, for example Carfilzomib and Velcade is both proteasome inhibitors so if you're resistant to one you're resistant to the other and clearly that's not true in the clinic or in the lab. So we're able to really increase the number of offsets for patients as we begin to say, "Nope, just because you're resistant to drug in one class doesn't mean you won't be very responsive to the other." The other thing we're beginning to look at, the sequencing of drugs and what order drugs should be given in and whether in fact adding drugs in -- it's commonplace after you fail something to add more drugs together, is that really the right approach or should you withdraw one drug? We just don't know.
Jenny: So you're saying you're trying to figure out which combinations work the best and in what order to --
Dr. Berenson: In what order to give them.
Jenny: And then how many to give at one time.
Dr. Berenson: Right.
Jenny: Because it seems like a lot of the research is, "Let's give three or four at one time," and you're thinking that that might not be the right approach?
Dr. Berenson: I don't necessarily think that we are doing a service to a patient by pummeling him with more drugs. We just don't know. Now, we may be better off by using less drugs than giving lots and lots of drugs together and we don't do that. You see, what we do is we figure that if one is good, three must be better and three at maximum dose is better, and all of that may be a short-term gain. In the long-term that may do a disservice of the patient as their bone marrow begins to have problems and other things come up. You’ve got to be very careful.
Jenny: Well, can you speak to that, the combination and how it affects the bone marrow over time?
Dr. Berenson: I mean, you probably damage the bone marrow and therefore patients -- my assistant is running a marathon tomorrow and I like people to run marathons and actually finish the race. So that means running 10 minute miles maybe better than 5 minute miles because you'll actually finish all 26. We have to think about the long-term view now in myeloma. This is no longer a sprint race. People are no longer hanging off the cliff and falling off like they were back in the 90s. They have a lot of time to think about what they're going to do and they don't necessarily have to be in big rushes that we put them in.
Jenny: Yes. Well, I know myeloma patient Gary Petersen has created a website with survival statistics and I encourage patients to take a look at that at www.myelomasurvival.com. Your five-year results are excellent. So how are you able to achieve these results compared to others using maybe the same combinations of therapies?
Dr. Berenson: I think what we try and do is not have a myopic view of this disease. We try to have a more expansive view and look at the big picture and try to recognize that there are lots of options. I saw a patient today in-clinic, literally he has had myeloma 30 years and we've been taking it slow with him over 30 years. He's had active disease. He just hasn't indolent myeloma. We have many other examples like that of patients who are 20, 25 years out and we've gotten multitudes of different regimens that we have patients who had up to 25 different prior treatments. So it's very depressing when I read reports usually outside of the US where patients are given no second options, let alone third, fourth and fifth options. There was a recent paper appearing from a large study suggesting that patients who are refractory to a Velcade which meant they were really stable, not necessarily actually refractory in my view which means progressing, and had seen Revlimid would die within a short period of time and I think that's based on the fact they're not given options. You have to have options. I recently have been dealing with a Canadian patient who's very sad because the number of options up there is so limited this patient cannot even receive Carfilzomib and can't even get Lenalidomide or Pomalyst. I mean, it's very frustrating. So the survival is related to the creativity and the persistent ability of the oncologist to persevere with trying new things, and a lot of people aren't willing to do that. I am. I don't care. I like to say, keep your eye on the ball and the ball's the patient. It really should be.
Jenny: If there's a specific list of medicines that are available for myeloma patients, how do you give them more options?
Dr. Berenson: Is there a specific list?
Jenny: Well, I don't know. Velcade, Pomalyst and Carfilzomib and the immunomodulatory drugs.
Dr. Berenson: Right.
Jenny: I mean, there are standard myeloma drugs I guess is what I'm saying.
Dr. Berenson: Well I would tell you standard dose and standard schedule is not necessarily our standard. Because I would tell you, many of these doses are way too high, way too toxic and do not allow patients to stay on therapy, and certainly do not allow them a future so that they can tolerate more regimens down the line which they will need. They will not be cured in most cases today but that doesn't necessarily mean that they're not going to have a good, long life and that something else isn't going to work.
Jenny: Then once a patient who comes in with a slower-growing myeloma versus a more active or more high-risk I guess you consider it myeloma, how does your approach differ between those two?
Dr. Berenson: I think we over-treat today about 80% of myeloma. I think perhaps we could pummel it for a few months and then back off. We don't generally do that. We just keep pummeling away. I do believe there shouldn't be really drug holidays and patients should stay on therapy to control disease. I am a believer in that but I'm a believer that you should give therapy that allows people to live their life. Patient just was in clinic today on a Carfilzomib interesting trial to try and see if we slow it down, will it actually be better tolerated? He's doing quite fine, fine enough the day after, two weeks ago he went to 14,000 feet in the Sierras and in about two weeks he's going off to Himalayas to try to get to 18,000 or 20,000. So we like those stories. We like people to be able to have their lives.
Jenny: Patients want to be able to do that and sometimes, I know. I had both combination therapies and transplant and there are pros and cons of both. So sometimes it's tough being in those combination therapies.
Dr. Berenson: Right. That is right and I think sometimes you may not necessarily need all of the drugs or certainly all of the dose or schedules. For example, we showed several years ago that Doxil is a very active drug used probably by less than 10% of oncologists to treat myeloma and because side effects in the past were fairly dismal. By just changing the schedule around a little bit and giving less drug on a more often basis. makes it an extremely well-tolerated drug.
Jenny: So when someone comes in, how do you choose upfront therapy, trying to figure out what the best mix might be for them?
Dr. Berenson: Well I think it's not -- I don't want to tell you today. We unfortunately in myeloma have done studies like in childhood leukemia and to do risk-based therapies with long-term outcome. People talk about how this is a very logical thing that's done. That just is not the case. It's not really based on clinical trials. There aren’t a lot of clinical trials done in the upfront setting that tell us how intense you should go and even trials that suggest survival advantages are based largely on data generated outside the US where the patient didn't really get a second chance or certainly not much of one. It's pretty easy to show an advantage of one trial in combination over another when you go over Niagara Falls when you're done. Whether that's relevant at all to a US group of patients, you can really argue.
Jenny: Going back to what you said about your Canadian patients or patients that live out of the country, what do you recommend to them? What would you recommend?
Dr. Berenson: Oh, man. I mean, it's very frustrating. They have to be very persistent with their attending physicians but that doesn't necessarily make them be able to give drugs that are not approved in that country and totally unavailable in that country.
Jenny: Is it similar with patients around the globe that you've seen or is this is a Canadian issue?
Dr. Berenson: Oh, yeah. That's why I find it's a folly to suggest the data from some country with lesser medical resources is relevant to patients in highly-sophisticated LA or Beverly Hills. Those results may not be at all relevant to my group of patients. I mean the bottom line is, is how long the patients live and with what quality and I think we do a very poor job of putting together data that looks at that. Of course people would argue that people who live in more affluent parts of the world get better care and I would say, "So be it." It just shows better care gets better outcome. They may also argue that people who live in more affluent parts of the world can afford to get that care. They may argue also that we select for what we call lead time bias because we see a wealthier population -- we see the disease in an earlier time point, we call that lead time bias -- and therefore maybe they're just living longer because we've identified the disease earlier. I don't actually believe that. I believe there may be a little of that but not much.
Jenny: Now with your own data, because you have samples and you have a data pool to pull from, what kind of advantage does that give you when it comes to looking at (I want to keep saying sub-typing but I don't really mean that.) What I mean is just taking a look at your data and making conclusions based on that data?
Dr. Berenson: Well, I think that you're right. That's what we need to do but the problem is we haven't really done studies to say, "You're going to get four drugs at full dose and you're going to get one drug and we're going to add in drugs at lower dose." Nobody's been willing to make that giant leap across the Grand Canyon because we have all these great new drugs. People go, "We'll just throw more of them at the patient," and I'm not necessarily thinking that's right. I would say, "Take your time. Take a breath. Don't just run around. You can stand there a lot of times."
Jenny: And try to delay it?
Dr. Berenson: So that's something we need to think about a lot more these days. I also think the disease is often treated for relapses that are imaginary. They're a laboratory phenomenon. Perfect example is a patient in today day, Mary Kay, who came in having had lapsed two weeks ago. It suggested her protein had returned. Well, the labs were repeated and guess what? There was no return. It was a lab error. So if you don't like your labs, just repeat them. I tell my patients often, "You'll like them better a second time." Much better off you are by waiting than jumping into something new. Very often that's the case.
Jenny: With that let's talk about minimal residual disease for a minute because I know a lot of people are talking about that and what that means. In the work that you're doing, can you talk to us about what your view is?
Dr. Berenson: We did all the early studies on that. In fact, in the early 90s what we did is -- my identical twin brother invented a device called the CellPro or Ceprate device which took stem cell product and was able to select for healthy stem cells and then let all the myeloma cells go away -- and we had to measure the amount of tumor contamination. It was an FDA-based study so we had to go by what they wanted us to do, which meant we had to identify the tumors down to one in a million normal cells, which was pretty tight. It was very laborious, very expensive. Unfortunately, most of what's called MRD today is not MRD. It's not minimal residual disease. It's actually minimally effective residual disease because they don't really measure the minimal residual disease very accurately. So I have a hard time with assays that try to tell me they can measure it the same in each patient when there's no data to support that, and some of the funnier studies are ones in which they can measure the protein but they can't find any of the myeloma using MRD-based assay, which shows you how lousy their MRD assay is.
Jenny: So as a patient, how do you know if you're getting a good MRD assay or good baseline of testing? We did an interview with Dr. Landgren and he was saying that there was 100 times variance in some of the testing that's done, and so especially in cytogenetics testing. So how does a patient know if the lab results…
Dr. Berenson: They cannot know. They're not going to know unfortunately. This is very sophisticated stuff. I don't think it means very much right now. I really don't. I mean, unlike my sister with APL (acute promyelocytic leukemia) -- cured with arsenic by the way, which works for myeloma, and vitamin A -- and my cousin Ken, one of Bryan Druker's first Gleevec patients 10 years ago, who truly are in PCR and negative CRs. I don't think we really see that in myeloma today. If you really get down to brass tacks and can measure it, remember this is also a spotty disease. So the attainment of a CR from bone marrow in the left hip doesn't mean in the right rib it also would be gone. It's a spotty disease.
Jenny: So what do you recommend to patients in terms of getting tested?
Dr. Berenson: I don't recommend they do MRD outside of a clinical trial today. I don't think it tells you anything that's useful. First of all, even if it told you something that was there, they couldn't tell you what to do about it that would mean something either way.
Jenny: How about other testing? Like either gene array sampling or is the MRD testing cytogenetics testing? Is that what that is?
Dr. Berenson: No. Cytogenetics is an attempt to identify specific chromosome abnormalities that either predict responsiveness to drugs or predict your overall outcome. That is, either how long you're going to respond to that agent or how long you're going to live, and the problem is this is a quickly changing atmosphere right now -- environment, if you will -- because of the rapidity with which combinations and new treatments are being made. Things that were prognostic several years ago no longer are and I suspect that's the same now in the Carfilzomib, Pomalyst era and we don't even know what those are. I would tell you, if you are missing part of chromosome 17 that's not good but that's probably about 10% of myeloma today, and the problem with that is even if you're missing it, these people are told they should have high-dose therapy. But the outcome in that group is awful.
Jenny: I know that's not a good marker. So there's cytogenetic testing. There's MRD testing, which you don't recommend unless it's in a trial setting.
Dr. Berenson: Right.
Jenny: There's imaging testing. Is there any other kind of testing that you recommend that you look at?
Dr. Berenson: Well, we're trying to develop new markers like our own. But outside of a clinical trial I would tell you at this point garden-variety following the usual protein electrophoretic testing, the quantitative immunoglobulin, the free light 24-hour urine, that certainly is the way to monitor the disease. In terms of predicting what you should get as a therapeutic, nobody has done a study looking at low or high-risk patients with different treatments. So even though people have tried to develop risk-adapted therapeutic guidelines, there's no outcome data to support that one way of doing it is better than the other. We propose those kinds of trials but most companies are not very interested in those and it's too expensive to do those without corporate support.
Jenny: Now I was having another interview and we were discussing federal funding for research. They were saying it's been anemic and had dropping and it's significantly impacting our ability to do medical research. Do you agree and what's in your experience with your institute?
Dr. Berenson: Well, I would hardly agree and the problem is much research today is under the guidelines and the umbrella of the companies. Although they certainly want to do good by patients they have their own agendas and that may not necessarily be in the greater good, and you have to be careful about that. But we're shrinking the federal and so therefore we're having to run to the companies that have myeloma drugs, and they certainly don't want to hear from me, "Well, we'd like to compare using less of your drug or not your drug at all." That isn't necessarily the best interest of their shareholders so you have to be careful, but it does limit our ability to do things and many of the times they're very adverse to risk. They're risk-averse. They don't want to try new things and they basically want to reinvent many of the things that are already out there. It's frustrating.
Jenny: So how do you approach risk? You have incremental innovation, which is so many of these drugs are getting better and better incrementally. Then you have disruptive innovation, which is looking at something from a whole different aspect or area. How do you approach that?
Dr. Berenson: We try to do both, so we do try to think outside of the box. We also try to tweak things that already exist and see if we can make them better tolerated and work a little bit better. But the true test is really within a clinical trial and unfortunately there's just not a lot of trials, in my view, that tell us with absolute certainty whether one thing's better than the next. There usually aren't enough patients enrolled or the end points are really mushy. Recent example is this myeloma trial in which patients got a different treatment up front than on maintenance, it's impossible to interpret what -- in one arm they got one treatment up front and they got maintenance. On the other arm they got a different treatment up front and a different maintenance. How can you interpret that data in terms of long-term outcomes and trying to claim maintenance of one type was better than another when they got different inductions up front? We see a lot of poor trial design. I mean, if we could stop that at the beginning I think we would be very helpful to perhaps more efficiently using patients on trials.
Jenny: How do we do that? How do we improve the trials then?
Dr. Berenson: A lot of these trials unfortunately are done outside of the US and again, those trials' results are limited by the options available to the patient after they fail. So it's pretty easy to show an advantage of A, B, C over A, B that C is great when added to A, B when after that you get nothing else, whereas in most of the rest of the world you make it C and D and all the way to Z combinations. So it's become pretty complicated. My job is to keep patients, as I said, in the marathon race. Now sometimes you don't have the luxury of time. You have to throw the Hail Mary pass and hope something works. We've been seeing more of that because the deal is now there're more drugs out there. So we're seeing a lot more Doug Flutie Hail Mary passes that we saw that worked than we saw even five, ten years ago.
Jenny: Because the drugs have improved in effectiveness?
Dr. Berenson: Yeah. We know how to use them better. We were scaredy-cats to use anything with Velcade when we did the Summit trial because we used it alone. Now I've used it with everything you could think of and more, and the same has been done with Carfilzomib in the last year.
Jenny: I saw about 40 open Carfilzomib trials on clinicaltrials.gov.
Dr. Berenson: Right. We're doing about four right now ourselves.
Jenny: Well, before we turn it over to caller questions I'd like to ask the question, what can patients do to help you with your research?
Dr. Berenson: Well, if they are interested in giving us blood samples for looking, for example at our new marker, if they're interested, if they're having a bone marrow for a clinical reason then some extra bone marrow can be sent and we can study it for the effectiveness of some of the new drugs and combinations in our lab. We can also encourage them to participate in trials that may be available through their local doctors. I saw a woman today who's been on several clinical trials and she's kind of getting tired of it and I'm like, "You know, this trial that we're doing now will hopefully help a lot of patients," because the trial she's already been on have helped a lot of patients. The trial in fact she maybe just coming off of was a very seminal trial to show the people that fail one proteasome inhibitor can actually respond beautifully to the other one without changing anything else in the combination treatment. Now we're going to do the same kind of work with the Pomalidomide product.
Jenny: Well that's a hope of the series, is that by helping patients understand more about the clinical trials that are being run and how they can participate - I don't think we've even come close to tapping the impact that patients can have by participating in clinical trials in a greater percentage. I don't think we've even thought about that before as patients, so we can make such a big difference. But I'm guessing we can. Okay, John. Why don't we see if first you have a question? Do you have any questions that you'd like Dr. Berenson to answer?
John: My question is, Dr. Berenson, you're well-known as a scientist and doctor who does not advocate stem cell transplantation and this is a question every patient faces sooner or later, but it's nice to hear it directly from you - your rationale and philosophy regarding stem cell transplants.
Dr. Berenson: Well, I think that John, the reasons for that I kind of made a little bit clear in the last 40 minutes and that is you got to stay in the race. Back in the '90s when my brother was inventing this device for transplant, the patients had no options. They had transplant and that was about it. In the last dozen years we have a slew of new drugs and dozens of combinations and if your body's been really pummeled by a transplant procedure it's very hard for you to tolerate a lot of those future therapies, not only your bone marrow but perhaps your lung, your heart, your other organs. Although I would say to you that transplants may be a home run in 3% of patients -- 3 not 30, and I do have a couple of those examples in my own clinic, transplanted in the days of the '90s we were doing them -- but number one I would say that 3% actually get worse from the transplant. It makes the disease worse, and in 94 it really didn't help and all it did is cause injury. But it turns out today I have patients that have been on Velcade-based regimens for that dozen years as well that are still in complete remission. They never got transplanted and the deal with them is, they have a much healthier body to go through therapies that they may need as we find the cure, if you will, or the cures which may be the case. I would also say to you that we've also used often a surrogate for a longer life as the time of the progression of the disease, and if you mash the bone marrow marker down below detectable, you may be at a place you're in a, quote, complete remission. You're certainly not cured in both circumstances. So it may take longer for that marker to reappear than the guy who's got measurable marker to show progression. Where you can measure going, say, from one to one and a half whereas the guy who's below zero it may take longer for that to reappear, it doesn't necessarily mean that they weren't relapsing. We also know that the randomized trials that have shown benefit, most of them were done before we had the new drugs. In fact, all of them were. The one recent one that's been done from the Italian group doesn't show any advantage to high-dose therapy over even Melphalan, Prednisone and Revlimid which looks to be no better than Melphalan and Prednisone without Revlimid maintenance. So even the post-new drug era, we're not really seeing -- especially in the post-new drug era, we're not really seeing the benefit in an overall population in favor of transplant. I certainly believe people need to stay in the marathon, so I'm not going to treat 100 patients to benefit 3. It's like going to Vegas and playing the roulette table and think number 38 is going to be yours when the other 37 are likely to come up, and one of those 37 by the way may be one number that makes your disease worse. So I don't recommend transplant for anybody anymore.
Jenny: Thanks for your question, John.
Jenny: We'd like to open up the discussion to caller questions. So if you'd like to ask Dr. Berenson a question about the research, please press 1 on your keypad.
Gary: This is Gary Petersen. Can you hear me?
Jenny: We can hear you Gary.
Gary: Hi, Dr. Berenson and Jenny. I would like to say thank you for putting together this program. I know it's a great educational opportunity for the myeloma patient community and Dr. Berenson, you've become somebody who I respect and find has provided some of the best survival rates in the world.
Dr. Berenson: We're about to update those in the next couple of months. In the next few months you'll have updated data.
Gary: Well, it's already the best so is it better than the best?
Dr. Berenson: It's going to be better than the best. It will be even better, I can tell you.
Gary: Oh, that's fantastic. Now, you've done this without transplant. You've talked about that and you've also --
Dr. Berenson: Well, I don't want to tell you Gary, that none of those patients have, not everyone in that group is -- some of those people have had a transplant. I mean, these are all everybody I've seen, so some of those came in from elsewhere.
Gary: It seemed to me that over time, you're kind of one end of the spectrum for treatment and probably Little Rock is at the other extreme along with the people who do the allo transplants and I thought over time it was becoming more and more that people were kind of getting away from transplants. I would say in the last two years or so, there seems to be more and more people kind of going back to saying there is an advantage to one transplant and then even dual transplants and that this has a survival advantage. How do you rationalize this conflict?
Dr. Berenson: I don't know where that's coming from. There's no data to support that. I'm not sure. I mean, the highest complete remission rates are from the Carflizomib, Revlimid, Dox trials. They're not even transplant trials. Of course the transplants, or you've had a transplant on the back end, they do even better. It's kind of interesting.
Gary: So, you know, I'm frankly confused a little bit and it maybe because I don't know the information as much as you do but it just seemed like, for example, the Duries and those people are kind of going more towards away from just using drugs and back to going for transplant and maintenance. Going to more is better as opposed to yours which is, "Less is best," so I guess I'm getting conflicting messages.
Dr. Berenson: Yes. No, I understand. I mean, if you have no options you better get a transplant, right? Because you're not going to get all the different options you’re going to get in this clinic. I think the myopic view of many people does not allow them to give all the options we find available for our patients. We're coming up with new concoctions almost monthly and I won't tell you some of those have improvement in trials but you see patients who've seen everything you can think of and you try something novel and they have beautiful responses and know you're onto something. Sometimes it's hard to convince companies to do a trial because they really have a limited agenda. My agenda is to keep patients alive longer with better quality and I think we're doing a darn good job of it.
Gary: It’s upping your numbers.
Dr. Berenson: Yeah. I mean, the proof is in the numbers and I think we do great and I think it's not only the numbers. It's having patients like Jeffrey going off to climb the Himalayas next month. I mean those kind of people, or my patient who just did the Leadville Bike Race or that kind of thing. So I think you have to think about people having a life. They need to have their life.
Gary: That's very important. Which brings me to another question and I happen to know that one of your patients was treated extensively with Velcade, Revlimid and Dex with little to no success and you did your “mix and match magic”, I'll call it, and finally found the magic bullet that had done the trick and made a big impact on his condition. Now, why does this work for you where others seem to give up? Dr. Berenson: I think because oncologists in general have the rather limited view that if drugs don't work, like Velcade, say, with Cytoxan, they're not going to work with any other agent. Certainly not the case. The same is true the other way around. The patients who failed Velcade won't respond to the drug in the same class, Carfilzomib. Not the case. We've seen the same thing now with Revlimid failures and you would think they wouldn't respond to Pom but they do. So these drugs, even though they may look alike and supposedly in the lab hits the same intracellular targets, they don't. It's much more complicated.
Jenny: So they might be not necessarily just next generation drugs?
Dr. Berenson: No. There're a lot of other target things going on here. They're very hopeful for patients but the problem is it's very hard to take risks. I did my early work with Carl Sagan the astronomer and I like to think out of this world and I think if you can do that, you're going to make lives longer and better for your patients. But you have to be willing to not follow the cookbook. I can do that because I think myeloma only. It's hard for Dr. Smith or Dr. Jones to see his colon, lung, breasts, prostate and a little myeloma to be confident enough to try an alternative regimen for a myeloma patient without a little bit of me pushing them along, coaxing them to do that.
Jenny: I think having a myeloma specialist in your corner and Gary says this too is really critical.
Dr. Berenson: I really do now. It wasn't so critical ten years ago. I didn't have that many options. Today it is absolutely required and I mean, somebody's in the clinic there are a lot of purported experts including names you've mentioned in the last hour who don't really see patients. It's a lot different being in the clinic. I was at UCLA for nearly two decades and I was a full professor and ran the Hema and Onc program there but I wasn't really in clinic very much. I basically had fellows and residents and interns who took care of patients. It's a lot different now. I understand the nuances much better of taking care of patients, dealing with issues with respect to their labs, side effects of their drugs, what it means for them, and what they really go through.
Jenny: Thank you very much and thanks Gary also for your questions. Okay, we have one more question.
Gary: Thank you, Jenny.
Caller: Well, thank you. This has been an awesome interview to listen to and really appreciated Gary's comments a few minutes ago. He asked actually a couple of questions I had, but doctor, I do appreciate your taking the time and I love your approach. I love the comment that you made about taking risk and not following the cookbook. I mean, that just sends chills down your spine thinking about taking a patient-centered approach. I have two questions and the first one is, isn't that kind of against, you know, most doctors don't do that because you have this code of ethics that says, "Do no harm," and in doing no harm, it's following the cookbook, it's follow the proven process you have established out there and so --
Dr. Berenson: Well, all you have to do is look at the number of people who have neuropathy from drugs that you know about because they're used to standard dose on schedule and then say, "Wait a second, these people's qualities of lives are affected negatively. Maybe there's a better way to do it," and then to actually study and find out yes, there is and then you begin to start being more cavalier about doing things and thinking about the box. Or drugs like Doxil causing a lot of mucositis and swollen and red and blistery hands and feet, and looking at different ways to do it and see the outcomes everyday in clinic of people that are healthy and happy with drugs that are reported to be just devastating, and I've seen it with side effects. And then to be willing to take patients who've seen everything and say, "Wait a second, maybe there's something else we can try," and not give up. Now, I'm not going to say to you and Gary knows this and John knows this that we're perfect. We're not. We lost a patient yesterday, a very nice man although he'd been even been more out there with what he wanted to do and was many times resistant to even us treating him. Everybody's got to do it their own way but, you know, and I remember a recent patient who we had failed on and had gone elsewhere and had gotten a few more months out of more -- well, it isn't necessarily conventional myeloma but conventional chemo drugs. We're not always right. We make mistakes. There maybe are people who can do it better for some patients than I can do it. I'm not going to tell that's not the case, but we do our best. We like to say keep our eye on the ball and the ball's the patient. It's not our CV, resume or pocketbook. I mean, we try to keep that in mind when we take care of people.
Caller: That's an admirable and gutsy approach and I commend you for it. Question I have around, as you're thinking about the future research, the cost of the map of the human genome is approaching $1000 and there's a race to get it down to $100. How does this ability to map the genome and understand what the -- as opposed to looking through a fuzzy window we're looking now through a microscope, and the detail especially if we can understand the genetic profile of a patient and their disease -- how does that affecting now or could affect this disease? How far off are we from customized applications for a patient?
Dr. Berenson: Well unfortunately, we're pretty far off because we're not willing to take the next step and that is to incorporate it within trials with different regimens based on some of these profiling. It's a long process and they did it in childhood ALL before we even had any of these high and low risk and have a lot of cured kids today fortunately who have brains that are now intact, whereas in the early days in the '50s and '60s we squashed a lot of these kids' minds with too much therapy. We haven't been able to do that with myeloma. We haven't been willing to do it. We come up with risk-adapted therapy approaches based on no outcome data. There's data from some groups that actually suggest that the patients you should hit the hardest are those with the lowest risk because those are the ones you can actually cure or lead to the best results, exactly the opposite of what you've been told in some of these guidelines. So we need outcomes' measurements, outcomes of survival, progression, free or better yet, overall. We don't have them. We just report. See, one of the problems of the whole system, the system has no ability to delay gratification. The drug company wants, "My CR is bigger than your CR and my CR is faster than your CR to appear," and that's not what the patient wants to know because they know they have a long survival in most cases. So they want to be climbing Mount Kilimanjaro like this gentleman did or they want to be climbing the Great Wall of China, and they want to be doing that ten years out and not ten weeks out from their diagnosis. So I mean, I think you have to be very careful what the outcome measurements are because what the club of drug companies, what may be true in the academic setting may not be what the patients care about. That is a very, very important point and I'm talking against the dogma but as I say, I keep my eye of the ball and it's the patients.
Caller: But if you're going to increase the outcomes, then you have to include the patient which includes patient-reported outcomes and close that feedback loop with the patient. Unless we have the patients participating in the patient-reported outcome system, there's really no way to close that loop cost-effectively, at least in our lifetime.
Dr. Berenson: Yeah, but who's recording long-term outcome measurements? You see, that's one of the problems and already outcome comparable in a country where there is no second option to my patients who get 25 options. Can I take data from a trial in Eastern Europe where the patient is told that you go in the trial or you get nothing, to my patients who have free choice in the US and in Los Angeles. You got to be very careful with the setting the trials are done in, what the outcomes are, the group they are treating, with the clinical setting is, all that is very critical.
Caller: Just a last comment to that point, because since I've been on this show I've looked at the myelomasurvival.com, Gary's blog here, and I've looked at the SEER data of the different trials and in the comparison of the SEER data, you're showing 89.7% survival after five years and so you're doing something different. Now, what you're doing in context of the patients needs to get out there but how do you deliver that information, something that you're doing? Maybe it's something the patient's doing on the outside and they're taking Coumadin or something and that's just affecting the treatment.
Dr. Berenson: Well, it could be. I agree, there are a lot of things they do additively that may contribute to survival. There are drugs that we now know have anti-myeloma effects, drugs like Celebrex, Metformin, the statins. I mean, who knows how these all play and I agree with you. People don't want to hear about that but I think all this is important. The other thing you have to be very careful when you look at outcomes data from some of the tertiary centers, and I won't name names, is they actually have to have patients that are wealthy enough, in good enough quality of life shape to come visit their center. That doesn't necessarily represent a population in general, number one. Number two, they measure outcome measurements in patients they don't really care for. So when I give you outcome measurements for our patients which we are now doing on our own group, we're going to be giving outcome measurements in patients I actually take care of because I shouldn't be taking credit for the patient I see once a year who flies down from Oregon or flies over from Chicago. I'm not really taking care of him. In addition and equally important to point out is that those patients at tertiary centers, and I see this in my own group, they don't often follow up, to find out if that patient unfortunately died in the interim. They are still considered alive even though they're not. You have to be very careful about that, whereas if it's my own patients, it's an accurate representation of their outcome. I'm taking care of them. I know when they are doing well and when they aren't, and when they finally pass away. It's much more accurate information than data generated through tertiary center where they're not really taking care of them.
Caller: All right. Thanks for taking my question.
Jenny: Yes. Thank you so much for asking the questions. Well, Dr. Berenson, thank you so much for taking the time to join us today.
Dr. Berenson: Sure.
Jenny: We are grateful for your great efforts and your dedication to treating myeloma and we wish you continued success. Dr. Berenson will be listed in our Myeloma Doctor Directory shortly. If you would like to contact him directly, you can click on our Myeloma Specialist Directory at the bottom of our home page and search the directory for Dr. Berenson. You can send him a private message that will go straight to his clinic. So thank you, Dr. Berenson.
Dr. Berenson: All right. Everybody enjoy their weekend.
Jenny: Thank you for joining us for another episode of "Innovation in Myeloma" on the mPatient Myeloma radio show.
about the author
Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical research. Founder of Myeloma Crowd by HealthTree and the HealthTree Foundation.
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