Dr. Kenneth Anderson, MD, PhD
Dana Farber Cancer Institute
Interview Date: January 22, 2016
Dr. Kenneth Anderson, MD, PhD of the Dana Farber Cancer Institute joins Myeloma Crowd Radio to outline the most important work being done in multiple myeloma in the coming year. He shares the top 5 areas of immunotherapy and the work in particular in checkpoint inhibitors (PD1 and PDL-1) that is looking very hopeful. He applauds the recent approvals of 7 new myeloma treatments in 2015 but says “our job is not done.” Dr. Anderson emphasizes the importance of clinical trials to make new treatments available in the clinic for us all. He believes that although stem cell transplant is still a very core therapy, the myeloma “backbone” of treatments may evolve to include immunotherapies like vaccines, monoclonal antibodies, and oral therapies. He notes the continued importance of studying the genomics in myeloma and continues to work on “blowing the fuse” of myeloma’s survival by altering its signaling. He believes that myeloma has weaknesses that can be taken advantage of and is working in the lab to provide ways to turn it against itself. He looks forward to a new year with better tolerated HDAC inhibitors, oral agents, vaccines, additional progress in checkpoint inhibitors and the study of how gene expressions are controlled and why they mutate (epigenetics).
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank today’s episode sponsor Takeda Oncology for their support of Myeloma Crowd Radio and all that they do for myeloma patients.
Our show today is with one of myeloma’s true great doctors and researchers in the field. Dr. Kenneth Anderson has made a remarkable impact over the course of his 40-year career in helping bring new study and treatment options to the clinic and we look forward to his giving us a very broad perspective of where we have been and we are going in the field of myeloma.
Dr. Anderson, welcome to the show.
Dr. Anderson: Yes. Thank you very much Jenny for all you’re doing with this show and helping patients really keep apprised of all the wonderful developments in myeloma.
Jenny: Well there are so many and we’re going to talk about both. But before we get started, let me just give an introduction for you. Dr. Kenneth Anderson is the Kraft Family Professor of Medicine at Harvard Medical School as well as Director of the LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. He is a Doris Duke Distinguished Clinical Research Scientist and American Cancer Society Clinical Research Professor.
After graduating from Johns Hopkins, he trained in internal medicine and then completed hematology, medical oncology and tumor immunology training at the Dana-Farber Cancer Institute. Over the last three decades, he has performed laboratory and clinical research studies on myeloma and has developed laboratory and animal models of the tumor in its microenvironment, which have identified and validated new target therapies that have quickly moved into clinical trials culminating in FDA approval. His paradigm for identifying and validating targets in the tumor cell has transformed myeloma therapy and dramatically improved patient outcomes.
He is the winner of many awards including the International Myeloma Workshop Waldenstrom’s Award, the IMF Robert Kyle Lifetime Achievement Award, the American Association for Cancer Research, Joseph Burchenal Award, the American Society of Hematology, William Dameshek Prize, the John Hopkins Society of Scholars, the Election to the Institute of Medicine of the National Academy of Science and the World College of Physicians and Pathologist in the UK, the ASCO, David Karnofsky Award, the Hope Funds for Cancer Research Award of Excellence in Clinical Research, the Robert Humanitarian Award, the Harvard Medical School Warren Alpert Foundation Prize, the American Cancer Society Medal of Honor, the Leonard Beckham Patient Advocacy Award, the Samuel Waxman Research Foundation David Workman Memorial Award and the University of Miami Sylvester Cancer Center and Annual Zobrod Memorial Award.
He has served as president of the International Myeloma Society and is President-Elect of the American Society of Hematology. We are just absolutely thrilled and delighted that you are joining us today. Thank you very much again for joining us.
Dr. Anderson: My pleasure.
Jenny: Now in your role at the American Society of Hematology and as past editor of their medical journal, you have a “general’s” leadership role about how myeloma research fits into hematology and cancer in general. Maybe you can give us a broad perspective because in myeloma, so much has happened and it’s really an example for other types of cancers. What does the myeloma experience teach the world in general in oncology?
Dr. Anderson: I think that’s a wonderful point, Jenny. Multiple Myeloma as everyone knows is a bone marrow cancer. It’s a blood cancer not unlike leukemia and lymphoma. I start with that because it’s easy to obtain the tumor cells from the bone marrow and it’s relatively speaking easy to study in terms of the biology not only of the tumor cells themselves which are readily obtainable but also to study the tumor cells in model systems of the bone marrow where they actually grow in patients. What myeloma is example for in one sense is the microenvironment, the importance of the nurturing bone marrow for the growth survival and drug resistance of the tumor cell.
The second issue is not only the biology but that in fact one can exploit this interaction between the tumor cell and the neighborhood in which it grows for treatment purposes and have targets that not only directly kill the tumor cell but interrupt its interaction with the bone marrow or even cut off nurturing cytokines or other factors that promote the tumor cell growth and resistance. It’s also a model for what importance the cells in the neighborhood play both in promoting tumor cell growth but also potentially suppressing the immune system which we may talk about later.
It’s a model of getting cells from patients, bringing them to the laboratory, making model systems both in the laboratory and in animals that allow us to understand how the tumor grows and more importantly to understand how to interfere with that growth in a meaningful way with clinical implications. The other thing that I think myeloma is a wonderful example of is the collaboration between lots of different members of the team in order to get these new observations from the bench to the bedside, clinical trials and ultimately new treatments. What I mean by the collaboration is there are investigators both clinical and basic and academia. There are biotech and pharmaceuticals. There are the funders of research whether they be the National Cancer Institute or the foundations.
There are the advocacy groups. There are importantly the regulators, the FDA and others but most importantly the patients who are really the heroes and inspiration for this team but my point would be that when all of these constituencies work together, we can rapidly have progress. The evidence for that is 16 new FDA approved treatments in the last 12 years including 7 new treatments in 2015. And that’s just an incredible track record and obviously patients are doing much, much better living three to four times longer now as a direct result. I think the examples for other cancers would be the ability to study the actual patient tumor cells and derive critical information from those studies and secondly the importance of collaborative efforts as a myeloma community and when one all pull in the right direction, we really can make progress very rapidly.
Jenny: Okay, that’s a great summary. I have noticed that there is wonderful collaboration between the researchers and everyone involved. There is a lot of enthusiasm too that it seems like more and more people are weighing in but maybe that’s just my perception. On the reverse side, are there any news trends in oncology that would help make new advances in the world of myeloma?
Dr. Anderson: Yes, I think there are. The one really most exciting area in oncology now are the immune therapies. The excitement probably is very recent but the idea of trying to stimulate a patient’s system to recognize and reject their own cancer is not a new idea. It has just been very frustrating to do so for many decades. But I think myeloma is now benefiting from the work that was really initially shown in solid tumors for example melanoma and lung cancer whereby checkpoint inhibitors, the so-called PD1 camouflage on an immune cell reacting with something called PDL1, a camouflage on the myeloma cell. The PD1, PDL1 interaction therefore or circuit being a brake on the immune system can actually be broken now with antibodies to PD1 on one hand or antibodies to PDL1 to take the brakes off of the immune system and allow the patients on immune cells to react against their cancer.
This has been pioneered in mice and now has really translated to wonderful advances in human cancer and in particular in melanoma, lung cancer and other solid tumors. Early data from many laboratories including hours and early clinical trials are now showing the importance of, if you will, checkpoint inhibitors in terms of allowing this immune response to occur. That’s one very important message or learning that we’ve had from others. Another example I might quickly mention is in the genomic analysis. Clearly myeloma has had extensive genomic analysis in and of itself so have some of the other cancer solid tumors but where we can learn for example would be in melanoma, the skin cancer, there is a mutation called V600E BRAF in those patients and there is a medicine called vemurafenib that can be used in these patients and they do very well with the medicine that targets this mutation.
What we learned in myeloma from our colleagues in melanoma is when we found the same abnormality in myeloma cells, we can borrow the same medicine from them and in fact achieve some benefit. I think we have been blessed in myeloma. We have been sort of a model system for as I mentioned a minute ago for the microenvironment, for the ability to study the tumor cell including genomics and for the collaborative efforts.
And on the other hand, we have learned from our colleagues and solid tumors because often time, the mechanisms, the circuits that allow those solid tumor cells to grow and survive and resist drugs or the abnormalities in those circuits so-called mutations or other abnormalities that either prolong the tumor cell growth or don’t allow it to die like it should, those abnormalities are common across many cancers. As a consequence if the mechanisms are the same, we can borrow and fast-forward progress on the treatment side as well. It’s a back and forth process and it can’t help but fast-forward progress in both areas as a result.
Jenny: And then borrowing a medicine might already be through that FDA approval process saving you a lot of time.
Dr. Anderson: Absolutely.
Jenny: Before we move on to the bone marrow microenvironment because that’s where I want to ask the questions next. Let me just ask you about the checkpoint inhibitors. I know at ASH there was a lot of excitement around the checkpoint inhibitors. But when I was reading the papers, it seemed like some of the results were like a 30% response rate. I was wanting to understand more about why they were so exciting although I know they are exciting. It’s just my lack of knowledge about what makes them so exciting.
Dr. Anderson: I think what makes them so exciting is as I alluded to a minute ago or introduced anyway is that for the first time, there is an ability to allow patient’s own immune cells which already are stimulated to recognize and react against the tumor. There is now for the first time a way to allow them to be functional and actually reject their cancer cells. I guess I would just back up for one minute and say in the immune area, there are multiple potential treatments. Checkpoint inhibitors are one but let me mention that we in myeloma have now multiple ways of if you will overcoming the immune suppression in patients.
Those of you who are patients will know that is their consequence of your myeloma, the immune system is really not working as efficiently as it should. We call it immunocompromised and as a result, you are more susceptible to infections and other complications. Well, some of the drugs we use are able to restore the Achilles heel or the immunosuppression and allow the immune system to function much better. The immunomodulatory drugs; lenalidomide, pomalidomide and others work in part by stimulating the patient’s immune system to react against their own myeloma.
We recently had monoclonal antibodies, daratumumab and elotuzumab FDA-approved and those are a second class of immune therapies. They are given by vein. They go in and recognize a fingerprint protein on myeloma cells, bind to them and allow the patient’s own immune system to reject their own myeloma. A third class of immune therapies are what you mentioned, Jenny, the checkpoint inhibitors. As I’ll just review, there is PDL1, this camouflage on the myeloma cell and there is this coding on the immune cell called PD1. When those two things interact, PDL1 and PD1, there is a brake on the immune system and now with antibodies against PD1 or PDL1, medicines which your antibodies against either of those two can blow the fuse on that interaction, take the brakes of the immune system and allow it to work.
The fourth immune strategy besides the iMiDs (the Revlimid and pomalidomide) the second one being the antibodies and the third one, the checkpoint inhibitors, the fourth one are the vaccines and there is real excitement in myeloma nowadays because we can vaccinate patients against their own myeloma. We can get immune responses which then can be amplified or turned up by using Revlimid or by using the checkpoint inhibitors or by using either one and wouldn’t it be a really happy day if we could get an immune response that would be long lasting and what we call memory immune response so that each and every time a patient’s myeloma tried to return, the immune response would recognize it and prevent that from happening.
That’s really special. The immune side is special also because it’s very potent and very selective and it’s very adaptable. We all get a cold today and we get better. Tomorrow we get an earache and we get better. It’s because the immune system is so adaptable. Finally there are, as a fifth kind of immune therapies, there are these CAR T-cells that many of you may have heard about. In plain English those are taking cells, immune cells from the blood of patients outside of the body, expanding them after teaching them or programming them to recognize a particular fingerprint protein on the myeloma cell. Take the immune cells from patients outside the body, program them to recognize their own myeloma, grow them up in large numbers and then simply transfuse them back as their own immune army against their own myeloma that’s called CAR T-cells.
But why I say all of these different five categories is that I think in the future, we’ll be using combinations of immune approaches just like we started many decades ago with combination of conventional chemotherapy and more recently, we’ve had combination of targeted treatments, Revlimid, Velcade, etc. Now, what I’m talking about is combinations of immune therapies. Already at the American Society of Hematology we had combinations of lenalidomide and checkpoint inhibitors, lenalidomide and monoclonal antibodies, lenalidomide and vaccines but you will see more and more combination therapy and again the holy grail of achieving a reaction, an immune response in patients that is called a memory response against their own cancer would be a really special advance. You can see it coming with combined immune approaches.
Jenny: Well I love the idea of letting the immune system do its job in eliminating the things that are from the myeloma that are causing it to either shut down or be inhibited. So I love the multi-step-approach and I know with the complexity of myeloma that’s very likely to have these combined immune-approaches. That would be amazing. Well let’s talk for just a minute about the microenvironment research because you really pioneered this field of understanding the bone-marrow microenvironment – what’s happening to support the growth of myeloma. Could you give us any idea about how your thinking has been changed or what you have learned about that bone marrow microenvironment and how to target it?
Dr. Anderson: Surely. It’s more — My thinking has been — if anything more affirmed or strengthened in terms of the importance of the microenvironment. As I mentioned at the outset, the ability to understand what it is in the bone marrow that is nurturing for myeloma cells allowing them to grow, survive and resist drugs has allowed us and others to interrupt those processes. Now as the years have gone by, there are multiple, favorable factors in the bone marrow. Some of them are other cells, something called plasmacytoid dendritic cells or another cell called the myeloid derived suppressor cell. The names are not particularly important but those cells are our enemy because on the one hand, they support the myeloma cell growth, survival and drug resistance.
On the other hand, they suppress the patient’s immune system. When we develop treatments now, we can target these accessory cells and on the one hand inhibit myeloma cell growth and on the other hand restore immune function. I think it has never been more true than it is today that the microenvironment is critical. I will just cite the experiments that are now from the early 1980’s really demonstrated that drugs can work in isolation against either patient myeloma cells or myeloma cell derived lines. However, if you bind them or put them in the presence of bone marrow stromal cells, you can completely attenuate or abrogate the ability of the drugs to work. Dexamethasone is a good example for commonly used to treat myeloma completely abrogated does not work at all in the microenvironment.
When you develop systems and then you screen drugs and you understand how things — what mechanisms are in place in the bone marrow microenvironment, then you can interfere with those things. That’s really helped a lot in terms of the progress of myeloma. Obviously, the immune cells are part of the microenvironment as well and I have just described many different ways that we’re targeting the immune system. So I think there has never been more emphasis on events in the microenvironment that are tumor-promoting and there are lots of efforts now, therapies directed at trying to correct what’s wrong in the microenvironment.
Jenny: You mentioned earlier about the BRAF and I know that BRAF and NRAS and KRAS are all very specific. I don’t know if those are specific to the bone marrow microenvironment. But I know that in 2013 I was reading an article in the Wall Street Journal about those targets in the lung cancer like you were mentioning. How has that evolved over the last few years now that we’re in 2015. Are those BRAF and other targets still equally applicable?
Dr. Anderson: Yes. Certainly the initial genomic analysis and solid tumors and in multiple myeloma as well have held up with time. The problem in multiple myeloma in particular is that there are many abnormalities. Firstly, there are many kinds of myeloma but within that context, there are many, many genetic abnormalities right from the outset at the time of diagnosis. Even furthermore as a confounding problem, as the disease progresses, further genomic abnormalities occur underlying ultimately the myeloma relapsing or returning.
Now, the molecule you mentioned, the BRAF is part of a pathway that mediates tumor cell growth. That’s true in melanoma, it’s true in lung cancer and it’s true in myeloma as well. That’s true. It can be turned on with a switch that is stuck in the on position by a mutation. It can be turned on by myeloma cells just binding to the bone marrow. It can be turned on by factors such as interleukin 6 that help the myeloma cell grow. But that biology which is not new any longer has held up. The issue that comes that as the genomic studies become more and more sophisticated, the number of abnormalities that we’re finding really is honestly somewhat daunting. It says on the one hand that we need to absolutely use combinations of treatments to treat the abnormality such as BRAF and others that we know about at the outset but also add in drugs to try to anticipate the escape routes that myeloma might use to allow relapse of disease.
It’s a little bit like the infectious disease model of tuberculosis or HIV and others where we can combinations of approaches to not only treat but avoid resistance. The second trend that this analogy teaches us is to go as early as possible, so take the most effective treatments and use them earlier and earlier in our newly diagnosed, maybe even in smoldering multiple myeloma. But again, I think that the genetic analysis ongoing in myeloma, there are many analyses that are happening, the MMRC and MMRF have an extensive COMPASS trial. There is analysis ongoing in the US that some of the major medical centers this included and in Europe, but all of us are finding that there tremendous heterogeneity and complexity in multiple myeloma. As I say it’s somewhat daunting.
The one thing I will tell you though, is that in myeloma, when you find these genetic abnormalities, we can sometimes capitalize on the vulnerabilities that they really program into the cancer cell. Let me be very plain about that. So myeloma cells have for example over-expression of a gene called C-MYC and it causes them, especially a subset of myeloma, to grow very, very rapidly. As a consequence, they are under a huge stress because of this rapid proliferation and they activate what’s called a stress response. What we and others have shown is if you can block that stress response with medicines, you can overwhelm the ability of the myeloma cell to deal with the stress and it dies.
Another example I’ll mention to you is a recent observation that since these myeloma cells have so much genetic damage, so the original observations held up, but what I’m trying to describe is as more and more studies are done, there is additional and much more complex genetic abnormality than we might have anticipated. So why is it with all these gene damage, the myeloma cells don’t die like they should if they have all these damage. We have recently been studying and shown that there is a fuse in the natural death circuit which would otherwise result in the death of these cells with all the gene damage. It’s missing. If we can replace that fuse with a medicine, then these cells that are stressed out because of all the genomic abnormalities would die a natural death.
So the genetics on the one hand can tell us well, we’ll try to use combinations of medicines, but the other implication I am trying to describe is because of the genetic abnormalities, there are vulnerabilities, there are weaknesses, there are Achilles heels I call them that we can attack and turn the myeloma cell against itself.
Jenny: Wow, perfect. I mean it sounds like you have multiple strategies to try to ensure that because it’s so complex and there is such a variety that number one, you don’t miss anything. Number two, you get it early before it has time to mutate in a devilish way and then just like you said, you need to turn it against itself. Well we talked a little bit about this before we started the show but with all the good news coming out of the most recent meeting, everyone was very, very excited and I think everyone has caused to be very grateful to people like you who were making these things happen. But also are there specific issues where you share the optimism and also where would you be cautious I guess?
Dr. Anderson: I think everyone should be very excited, palpably excited about the progress in myeloma. There have never been better treatment options or more treatment options than there are today. So overwhelmingly positive. I think the ability to use target protein degradation with the proteasome inhibitors, bortezomib, carfilzomib, now Ninlaro, the ability with the immunomodulatory drugs to target cells and also stimulate the immune system with lenalidomide and pomalidomide, the antibodies elotuzumab and daratumumab as I mentioned earlier to target the cells, label them and allow the immune system then to reject them. The HDAC inhibitor, panobinostat, especially together with the proteasome inhibitor block protein degradation.
Never has there been a more exciting time. That’s all to the good and I think it is directly the reason that patients with multiple myeloma are living on average three to four times longer and we have many patients who have lived many decades. My longest complete responder in myeloma is from 1983. So we have a lot of people now doing extraordinarily well. That’s all to the good. I do want to though acknowledge and be absolutely realistic. We are still privileged to see patients quite a lot at our center and in spite of all these medicines, we still have myeloma returning and resistant, et cetera. I think that that is sort of a call to action. I think our job isn’t done.
I think the wonderful collaborative efforts that we’ve had especially over the last 15 to 20 years need to continue and I do think there are extraordinary opportunities. I mentioned the immune area, and I think the genomics to point us the right vulnerabilities we need to target would be my two favorite areas but the opportunities are extraordinary for future progress. This just reminds me to say that patients are the reason that all this progress happened because patients were willing to be the heroes and go on clinical trials and try new medicines. I will share with you, I’m privileged to take care of the first patient that ever went on Revlimid for multiple myeloma and he is still on it 15 years later.
You need to be, in my opinion, courageous and honestly inspirational to say that you’re willing to try a medicine and no one has tried before and that is going on day in and day out in the myeloma community trying new medicines, new combinations and back and forth from the clinic where patients are willing to do this back to the laboratory where mechanisms are being understood for why medicines work or not. That to-and-fro from bench and bedside and back – it’s called translational research – but that’s really what’s happened. I’m very excited on the one hand people are clearly living longer having milestones with their families and it’s just such an honor and privileged to get to know patients and their families and celebrate these successes together. On the other hand, we are more obsessed quite frankly than ever because we are getting closer and closer. It’s a chronic illness now but we are quite obsessed to really do even better still. Much optimism but still work to be done.
Jenny: Well, we’re glad that you’re obsessed. This series was started because we wanted to encourage patients to participate in clinical trials. If you think about getting people to participate and then having that accelerate the pace of research, we could really double down on the piece of research if more people would participate in the clinical trials and I know a lot of people think perhaps should I do it or should I not? But what you are typically comparing myeloma is the standard of care versus something even better.
Dr. Anderson: It is said that minority of patients perhaps 5% of fewer patient’s percent participate in clinical trials. In the distant past, it used to be that new drugs that came along, they were going to be used and clinical trials in often in the case of patients whose cancer had returned many times. These drugs were not as promising as we have in myeloma over the last 15 to 20 years. To say that more directly, Velcade, Revlimid, the very first patients treated with these agents responded. These were life-saving phase one early clinical trials.
So I want to emphasize that I think nowadays especially in multiple myeloma, when drugs make it to clinical trials, they are very promising. They have made it through many pre-clinical test and screening and they have been selected to be effective and we in myeloma maybe are spoiled but when we talk about this new clinical trial, we expect these drugs to work and these combinations to work. I think the other thing is that the clinical care that patients receive when they’re on a clinical trial is extraordinary. It’s not only standard of care. Often it’s much more because genetic analyses are done, immune analyses are done or special testing is done much more in the way of imaging or other test and otherwise would be done. I think it’s good for the patients themselves to go onto clinical trials.
It’s obviously good for all of us a community because that’s the way we improve the standard of care. So we really want to encourage people to participate. I think in some of the myeloma centers, it’s really the percentage of participation is way up high. I know at our center, it’s probably in the range of 500 patients go on protocol each year. Itis the reason, I just want to highlight, that we as a community have been able to make the progress we have.
Jenny: Well I agree and I would encourage patients to consider clinical trials and there is tool called Spark Cures that helps patients find clinical trials easier and make sense and we really encourage that. Now another question. I know at ASH there was a lot of anticipation, understanding the IFM study from the French group about the role of transplant so you see all these drugs come out and you think wow, could we avoid transplant at some point? What advice would you give a patient considering a transplant today and how do you see that projecting into the future because I know it sounded like transplant was still very core treatment.
Dr. Anderson: This is a very burning issue in multiple myeloma. The trial that you referred to where we’re actually part of here. The IFM is the French National Myeloma Group and the other part of that is Dana Farber Cancer Institute leading honesty multiple institutions in this country who are participating in these trials. But the basic observation that was presented at the American Society of Hematology is the patients received Revlimid, velcade, dexamethasone. They then got all of their stem cells collected in a randomized way. Half of the patients went on to get an early high dose melphalan and stem cell transplant followed by one year of lenalidomide maintenance.
The other half of patients had additional courses of RVD and then lenalidomide maintenance for one year saving the transplant for later. What this study showed was that those patients who had the lenalidomide, Velcade, dex stem cell collection went early to high dose melphalan and transplant followed by one year of maintenance of lenalidomide had a progression free survival or time without active myeloma advantage of about nine months. At least as of this time, there was no overall survival advantage. It did demonstrate that minimal residual disease that getting a response if you will that’s very major (fewer than one myeloma cell in one million normal bone marrow cells) was more commonly achieved with the transplant and if it was achieved either by the transplant or after maintenance, it portended for a much better outcome.
The third thing it showed besides the transplant prolonging progression free survival and more commonly achieving MRD negativity is that sequencing, looking at the genes in the myeloma cell rather than studying the phenotype by immunofluorescence. The sequencing seems to be more sensitive at picking up a residual myeloma. Anyway, based on this particular finding, it did support the use of stem cell transplant and so we still think that’s a standard of care. In the United States, we have a very parallel trial that’s almost finished led by Paul Richardson. It’s the same trial except maintenance with lenalidomide is continued until progression.
I mentioned earlier, I’ve had a patient on lenalidomide for 15 years. Many patients in the post- transplant setting in North America are on continuing treatment. This trial started in 2009 and as we said, it’s comparing transplant or not, everybody getting maintenance and it’s still ongoing almost finished. But I mentioned that because what it tells you is in the setting of continuous maintenance, there can’t be major differences between the transplant arm and the non-transplant arm. If there were, the study would have been interrupted. Either way whether the transplant did better or not, these studies are monitored carefully. What it tells you is both groups, the people who got the transplant and those who did not must be doing extraordinarily well in any event.
Over time, we’ll figure this out together as a community. I personally think that ultimately when we have combinations, maybe it’ll be four drugs, classes. Maybe it will be five but probably over time, the transplant may not be necessary. For now, at least with a one year maintenance, what the French trial showed was more time without active myeloma, more likely to get MRD negativity and probably the best way to measure MRD is by looking at the gene sequencing but I would ask patients to stay tuned because there is many more studies to come to really answer this question.
Jenny: Well that’s great. Now, I know stem cell transplants are considered part of a backbone therapy. When you hear about backbone, you think well an iMiD like Revlimid or lenalidomide or you think of proteasome inhibitors, the Velcade, carfilzomib. Do you think those backbone therapies changing over time with the advent of the newer drugs?
Dr. Anderson: Yes, so I think that’s a super question, Jenny. I mean you know the history in myeloma as we start traditionally with novel agents primarily in patients with relapsed refractory myeloma often multiply relapsed. It’s very tough for agents to show efficacy in patients whose myeloma is very resistant. Nonetheless, that has been done many times. We mentioned 16 approvals in 12 years but what then rapidly ensues thereafter is to move those active agents in the far advanced patients into the earlier disease course, relapsed and ultimately newly diagnosed. Nowadays, even into the smoldering multiple myeloma area. In any event there are backbones as to use your word and what the American Society of Hematology showed in a randomized trial this year was that lenalidomide, an immunomodulatory drug and bortezomib, a proteasome inhibitor and steroids is better than lenalidomide and dexamethasone for initial treatment.
Many of us around the world have really purported that triplets, three drug classes are the standard of care and I think that’s true. So a backbone for initial treatment would be an immunomodulatory drug, proteasome inhibitor and steroid. The original proteasome inhibitor was bortezomib but as you all know, there were two new proteasome inhibitors, carfilzomib (Kyprolis) or ixazomib (Ninlaro) but both of them are now FDA-approved in relapsed myeloma together with lenalidomide and dexamethasone. Right now, that’s being used in the relapsed setting. Over time, and already clinical trials are testing this, they may very well move up into the front newly diagnosed setting as well just as occurred with bortezomib.
For right now though, I think one would say for practice that lenalidomide, bortezomib, dexamethasone would be a common first backbone. In the relapsed setting, carfilzomib, Ninlaro, pomalidomide on the immunomodulatory drug would be standard relapsed treatments and then after that, the antibodies probably will come into play because so far at least they have been approved in relapsed myeloma especially daratumumab the multiply relapsed myeloma (3+ relapses). I would expect to answer your question directly that the platforms will change over time, that’s a good thing that reflects progress and we will not only have more active drugs used earlier but my sincerest hope is we are going to have oral and well-tolerated drugs, that to me is the future and I think the oral proteasome inhibitor now together with an oral immunomodulatory drug, steroids maybe or maybe not but all oral treatment is quite exciting for us as caregivers but really quite exciting for patients because it makes it so much more user friendly. So yes, the backbones are going to change and they are going to improve for sure.
Jenny: All oral just means less time in the clinic which is just a great thing all the time.
Dr. Anderson: Absolutely.
Jenny: You talk about triple combinations. I see a lot of papers on the triple combination and adding a fourth like a monoclonal antibody is pretty easy because you are not seeing more toxic effects in adding that fourth. People would love to get to the day where you are taking dex out of that triple combination just replacing it with a vaccine or something.
Dr. Anderson: I think those days are coming. Let’s see with time. That’s going to have to be done carefully and it will be obviously data driven. We certainly don’t want to sacrifice efficacy but what I would say just to highlight what you did, the least favorite medicine for our patients is high dose dexamethasone. If we could come up with steroid free regimens, I think the patients and even more importantly probably their families would be happier. I do think that these templates are going to change over time. Antibodies are going to be added. Immune approaches. I personally think that HDAC inhibitors, there are some more tolerated HDAC inhibitors that would look very promising now. So we have new classes of drugs that are often oral that will probably make their way into team here.
Jenny: Well great. We look forward to the day when immunotherapies are replacing dex because I know they suppress the immune system so maybe just you get a double whammy or something by doing that. As you know, if we may know we have a Myeloma Crowd Research Initiative and we’re trying to crowd fund for two immunotherapy projects one in of course for Germany and the other at your alma matter John Hopkins. I know there are others. You gave us a very nice overview of the immunotherapies at the beginning of the show. If you had to evaluate the different kinds of immunotherapies and you mentioned checkpoint inhibitors specifically, what is most exciting to you? What do you think is coming closest to the clinic or fastest with clinic and the most effective out of all of those?
Dr. Anderson: I won’t go through all of that again because especially in the interest of time but I think the idea of immune therapies is already in the clinic in myeloma. Lenalidomide, pomalidomide are immunomodulatory drugs, they are here. Monoclonal antibodies, daratumumab, elotuzumab, immunologic treatments are already here. The checkpoint inhibitors are not approved in myeloma but they are in clinical trials and looking promising as I mentioned at the American Society of Hematology combined with immunomodulatory drugs right now.
The John Hopkins group, Ivan Borrello has a very exciting vaccine program in myeloma. We also have a very exciting program here with my colleague Dr. Nikhil Munshi and David Avigan. In both of those cases and others in Israel and in Europe, the vaccines have been shown to be able to get an immune response. But as I mentioned earlier, the real excitement is that you can amplify that immune response by combinations with a checkpoint or combinations with lenalidomide and maybe even convert it to a memory response. Those things are happening. The other exciting thing are these CAR T-cells that I mentioned earlier even though it’s very early days, very impressive responses are being achieved.
So it’s hard to pick out which one of these is going to be the best. I really think that it’s going to be a combination. Get an immune response with a vaccine or use a monoclonal antibody to target the myeloma and in either case then turn up or amplify the immune response with lenalidomide and/or a checkpoint inhibitor. The CAR T-cells work acutely but you want to be able to maintain some level of T-cell immunity. Maybe checkpoint inhibitors and lenalidomide will help there. It’s not going to be just one modality, Jenny, is what I’m trying to say. It’s going to be combinations I think that ultimately win the day.
Jenny: There is no one silver bullet it sounds like. Well, I have so many other questions. I know we’re getting close to the end of show time. So I’m going to try to be efficient with my questions. I know you have been working on a vaccine, OncoPep. If there is something you want to share about that?
Dr. Anderson: It’s again against these fingerprint proteins that are on myeloma cells. The excitement is that and very quickly as you can vaccinate patients with smoldering myeloma and you can show you can get an immune response against their own cancer cells. You can then vaccinate patients with the same vaccine but this time with Revlimid also and not surprisingly, you get more of an immune response. Where we are right now is we are about to begin the same vaccine with Revlimid plus a checkpoint inhibitor. The reason I am so excited about that is that in our pre-clinical studies and the laboratory, if you stimulate patient’s own T-cells against their own myeloma in the presence of Revlimid and in the presence of a checkpoint inhibitor, you get what’s called a memory immune response both a central and an effector immune response.
In plain English, when you get vaccinated against tetanus or small pox, you get a memory immune response. If you ever get exposed to tetanus or small pox later, you don’t get them. If you could get with a vaccine plus iMiDs, plus checkpoint inhibitors or maybe some other strategy, but if you could get a memory immune response and patients against their own cancer, that’s huge. If you could do it in smoldering myeloma, one of my dreams forever has been maybe patients will never get active myeloma. Wouldn’t that be a happy day?
Jenny: Yes, amazing.
Dr. Anderson: That is really exciting.
Jenny: Totally amazing. Now earlier in the show, you mentioned the importance of genomics and I know you have done quite a bit trying to segment patients out or understand the genetics behind it so you know how to treat. Do you think that it need s to be more better defined so that we can start treating patients personally? I know all doctors will say they want to treat patients personally and try to the best of their ability. Especially for high risk disease, what are you finding that’s coming next?
Dr. Anderson: I think these are super questions, so I think it’s not easy to talk about in a short period of time but myeloma —
Jenny: Well, take your time.
Dr. Anderson: Right, I know. It could be days here. But myeloma genomics are very complicated as I mentioned before. I already mentioned the COMPASS trial by the MMRF and MMRC and other large studies, our big transplant trials et cetera here have all had much fancy and deep sequencing and other genomic tests done. As I mentioned earlier, it’s a very heterogeneous disease. The more in depth you look, the more abnormalities you find and then they keep changing. The concept of precision of medicine or treating with personalized medicine is a very attractive one. My caveat was that we’re going to have to have put together all of our data. It’s called big data from all around the world regardless of the source, academia, the foundations, the industry, whoever has the data where going to need to pool it and see if we can try to make some sense out of it.
What I would say is that I personally believe it’s going to help to get this data put together primarily to identify those circuits that are wrong in myeloma. What I mean by that is what are the circuits that cause it to grow, resist drugs, survive, migrate, et cetera. There may be multiple abnormalities in a given circuit but if you can define these networks that are responsible for the abnormal behavior of myeloma, we can then interrupt those circuits but I think it’s going to be quite more complicated than we ever anticipated. It’s exciting. We and others are very excited to help as much as we can push this forward. I do think it’s a daunting task and it does tell you the importance of detecting cancer as early as possible before genomic evolution has occurred. And on the second, it really highlights the importance of using medicines as early as you can to treat the abnormalities that are there but try to anticipate those that might be used later.
The other quick point I’ll mention about the genomics is in myeloma, there are not only a lot of abnormalities, there are at least three to five different clones or abnormal family members of the myeloma right from the diagnosis. What can happen over time is one or more of those clones can become predominant, can act out and be the drug resistant clone, or in fact, new clones can emerge. It’s really — we and others are trying to understand what is the fundamental hallmark abnormality that accounts for all of this gene instability, we have just finished writing a big grant with Dr. Munshi about this. Can’t there be some common abnormalities that we find that is fueling this continuous genomic instability because if we could target the fundamental problem, then we could maybe stop this evolution from occurring.
Precision medicine just in summary is a wonderful goal to the President Obama. The Vice President Biden, the National Cancer Institute and others are very generously supporting and really increasing funding for these efforts and you’ll see a lot of efforts made in this direction, but I do think we have to be careful and not have expectations too high because it’s a very complicated and daunting problem.
Jenny: Definitely. What should your patients know about their genomics and which tests do you recommend that they have performed?
Dr. Anderson: Patients should participate in protocols and many, many protocols are incorporating genomic analysis at our institution. Pretty much genomic analysis is done on all the patients that come as new patients. Right now, the number of times that it makes a difference in the way people are treated is very few. But the way we will learn over time how it might make a difference is from having this screening done, this genomic analysis and then correlating it with response to this treatment or that treatment, what’s the outcome? Did this person respond, did this person not respond et cetera? So I think the way to make sense of this is to participate in protocols. If you have a chance to have the genomics performed, I don’t think in the majority of cases that right now, the genomic analysis is going to make a difference in your primary treatment today.
I want to mention one quick word. You have mentioned high risk myeloma a minute ago and everybody knows that high risk myeloma has traditionally, for example one characteristic would be the 17P deletion, chromosome 17P deletion. These high risk patients respond but the response doesn’t last very long. I mention this because the new treatments, pomalidomide, the monoclonal anti-bodies, daratumumab and elotuzumab seem to work in 17P deleted multiple myeloma. My point in stating this is that high risk myeloma is being redefined as we’re here on the phone because the medicines work when no other medicines worked before. So it’s only common sense that what was high-risk myeloma before is not high risk myeloma anymore and that’s a good thing.
Jenny: Yeah, a great thing.
Dr. Anderson: Another example of the value of the profiling of patients is to understand in 2016 what really is high risk myeloma given all the different medicines we have today.
Jenny: That’s so interesting and I’m a huge advocate for patients knowing what they have because I attended the patient conference in about a few years ago but only about 10% knew their genetic features and sometimes you can lose those features after you’ve been treated. So you may not know what you’re dealing with if you don’t get it done (genetic testing) early. Well I have one last question for you before I open it up to some caller questions and I’m hopeful that you’ll just stay with us for a few minute. What are you finding significant enough to work on next?
Dr. Anderson: Well as I said, we are quite active in what I call bench to bedside research. In the clinical trials, we have about 25 to maybe 30 trials open here at any one time and they’re about new targeted treatments. They are about immune treatments. There are stem cell transplant kinds of treatments or they are supportive therapies helping patients with bone disease and other things. So those are four categories of clinical trials. In the laboratory, we have just talked about it but we and others have huge efforts in genomics. We similarly have an effort in immune treatments. We have a large effort in targeted therapies, defining new circuits that cause myeloma to go and survive and resist drugs.
We’re very excited about if you will blowing the fuse or interrupting those circuits at more than one place because we think it’s very important there is a loop, an abnormal circuit, and oftentimes we’re finding in our research that you have to block more than one spot to really make a difference. And then finally there is a whole field called epigenetics which is to understand how ultimately gene and the expression of genes are actually controlled. To put that in plain English, we’re going back further and further to understand again fundamental abnormalities that may account. Not only for example finding that there is a gene that is over-expressed in myeloma like this C-MYC that I mentioned earlier. But why is it over-expressed? Is there something wrong in its regulation? So those should be the major areas.
I do think and I’ll just say quickly in closing but to me, myeloma has a bunch of Achilles heels. They have some weaknesses and we have already together exploited them and we will exploit them in the future. One I haven’t mentioned but proteasome inhibitors; Velcade, carfilzomib now ixazomib. How do they work? They block the ability of myeloma cells to deal with all these protein that they are making. Literally the myeloma cells fill up and commit suicide because of all this protein that’s turning the myeloma cell against itself. The second Achilles heel is this immune suppression and I have described five different ways where we’re trying to overcome the immune suppression and then finally, in the area of genomics, what I was trying to get across is that it’s complicated but as a result of all of the abnormalities and the genes, there are vulnerabilities. They myeloma cell is stressed because it’s growing so rapidly.
So let’s make it impossible for them to deal with the stress or if there is so much gene abnormality, why is it that the cell doesn’t die like it should? Let’s figure that out and let that natural death occur. I call them Achilles heels but it’s really — Let’s find out what’s wrong in the biology and let’s really exploit it and I think that’s really coming. I honestly just in closing, I think it’s a hugely exciting time. I want to very much thank you for doing this because I think in the area of such progress, the only way for patients to keep up in my view is to have venues like this where they can really hear up to date information long before they might hear it or it might be published in some other way. A hearty thank you for all that you do.
Jenny: Oh, well thank you. It’s a privilege to talk to people directly and understand exactly what they are working on. It’s just completely fascinating and it doesn’t sound like you are going to be taking a vacation anytime soon.
Dr. Anderson: That’s probably right.
Jenny: So I would like to open it up just for a few minutes if you have time for some caller questions. If you have a question for Dr. Anderson, if you could call 347-637-2631 and press 1 on your keypad. Okay, our first caller. Go ahead with your question.
Caller: Oh. Hi, Dr. Anderson. Thanks for taking my call. I wanted to know how you managed to balance new options that may not be proven yet with existing options that may be proven to be effective without the multi-year data to draw from when you suggest something new over something older.
Dr. Anderson: That’s a really good question. I would encourage you. We have standards of treatment and what I mean by that is and Jenny mentioned it earlier. So a platform of three medicines for example, RVD for initial treatment. Those to me remain the standard of care. I think we are blessed with such standards of care because they work very effectively and often novel drugs would be used as I mentioned earlier in patients whose myeloma has returned so called relapsed or even relapsed/refractory. In randomized trials, the new agent is either compared or added to an already effective regiment compared against an already FDA approved regimen. I think the issue is for caregivers and patients alike, you don’t want to go in medicine that isn’t proven when you know there are already hugely effective proven medications.
I think that we do novel treatments right in newly diagnosed myeloma, for example, but what we try to get across and what is true is that when we add new agents to or we tried new agents in the setting of newly diagnosed myeloma, it’s usually adding them to what we already know as an effective regimen. So Revlimid and dexamethasone have been added to Velcade. RVD is now being studied with monoclonal antibodies added but I think we’re blessed because we have effective treatments and we always want to do new things but we also want to make sure that you as a patient get the benefit of what we already know with proven treatments and a track record of many years of success.
Caller: Thank you. Thanks for answering my question.
Jenny: Okay. Thanks for asking the question. We have another caller. So go ahead with your question.
Caller: Hi. First of all, I’d like to thank you for your work through many, many years with multiple myeloma and also thank you for taking time out to talk with us today. We really appreciate all that you’re doing. My question has to do with CAR T therapy and I have seen lots that indicates that that could be very beneficial and important in the future. But I have a hard time understanding from a pharmaceutical company point of view, how they would be able to scale that kind of therapy and scale that up and essentially make money off of that because it seems to be so individualized.
Dr. Anderson: Yes, no. I think I hear you loud and clear. In that spirit, there may be more generally applicable ways to turn on people’s cells, own immune cells against their own myeloma. Many other ways are being tested right now. But back to your question, I do think that although the CAR T-cell concept is very labor intensive, several of the major pharmaceuticals are already far along in doing this really scaling up to use your word, the cell collection, the cell genetic programming, the cell expansion and supporting clinical protocols. There are multiple companies doing this. It’s quite competitive. The CAR T-cells concept has a basic component but it’s also being modified to try to improve it. The different targets on the myeloma cell are being used as well. CD19 was one of the original ones that was used in leukemia, lymphoma and some patients with myeloma. That’s another target that we and others really like a little more because it’s more selective and specific for myeloma called BCMA.
There are three centers that I know of that already have trials open for that. So you’re going to see industry pick-up on this. It’s very labor intensive in terms of how they are going to make profit on this, I don’t know but I have no doubt they will figure that out. But I do think the idea of getting your own immune cells to react against your own myeloma is tremendously appealing and this is one more way to do that. So I would very much stay tuned. Right now, it’s primarily used in relapsed myeloma. It’s not being used as an early treatment but that may change with time if it becomes effective and more safe, et cetera.
Caller: Okay. Thank you. That could help.
Dr. Anderson: You’re welcome. Thank you.
Jenny: Great. Thanks for your question. Okay. Caller , go ahead with your question.
Caller: Hi, Dr. Anderson. I was wondering – a lot of myeloma specialists disagree on the opinions of allogeneic transplants in treating myeloma. I guess my question is, do you do them at Dana Farber and when is it that you recommend them if you do? I know some places, when they have their younger patients, they really push those allogeneic transplants and hopes to actually cure.
Dr. Anderson: No. It’s a super question. The answer really is that there is no question that allogeneic transplant can really work in myeloma. I mentioned that I have a patient since 1983 in complete response and that’s somebody who had an allogeneic transplant. So when it works, it can really work. The problem is that in most centers they are still in my opinion and most people’s opinion sort of an unacceptably, at least for newly diagnosed patient, risk. It’s about a 10 to 20% but at least 10% mortality, chance of dying related to the procedure.
Frankly, in today’s world where we have such novel agents, it’s not usually used early because we have things that can have patients living many years without it. Having said that, there are protocols at our center in many around the country, Seattle is a huge place and Memorial Sloan Kettering, MD Anderson and others and this is our center too where there are efforts to, in protocols, exploit this donor of the marrow immune effect. It’s called the graft-versus-myeloma immune effect, while avoiding the attendant side effects, graft versus host disease and others.
So we have protocols. To answer your question directly, it’s usually in patients who have relapsed myeloma and it’s often been in the setting of high risk myeloma. I do think it’s getting safer to do it and we may see things in the future. The previous caller asked about CAR T-cells, well maybe they’ll be CAR T-cells that are allogeneic (donor) CAR T-cells someday. I think it’s a very rapidly and exciting evolving area. The time we use allogeneic transplant right now is primarily in the context of relapsed disease and it’s usually in a clinical protocol so we can try to enhance the efficacy and then also improve the safety.
Caller: Okay. Thank you very much.
Jenny: Well thank you so much for your question. Okay. We’ll take one more question.
Caller: Dr. Anderson, thank you so much for taking your time and being on the show. It’s been a pleasure listening to you. My question has to do with the complexity of treatment with all the treatments that are in the market. I am counting seven new treatments in the last 12 months, new approved drugs. How do the specialists, let alone the general oncologist treat the disease with the complexity of all the potential combination therapies that are out there right now. How do you deal with that? There is a tidal wave of new information and where is the training coming from or how do these practitioners know what to do?
Dr. Anderson: Well, I think it’s a super question. As a community of caregivers, we have our national meetings, American Society of Hematology. Otherwise, we have foundations, Multiple Myeloma Research Foundation, International Myeloma Foundation, Leukemia & Lymphoma Society and others that have education for caregivers and we have a variety of other ways. I would just say I think that this is the honestly happiest problem in my lifetime anyway that we actually have so many options now. It turns out that when you just sit down one on one with a patient and you look at the different options, there are some standard things such as RVD for initial treatment.
Some of the drugs right now are most commonly used in relapse: Ninlaro, carfilzomib, pomalidomide and the antibodies which are new kids on the block are usually used after that. It’s a moving target but these things allow us to have effective therapies for almost everybody. Somebody comes in nowadays for example with a neuropathy. We now have proteasome inhibitors that can be used to help them. We didn’t use to have that. We have now first patients who find it difficult to get into the medical center. We now have an oral treatment, lenolidamide, Ninlaro, steroid.
Caller: I wish you would have had that a few years ago because we were traveling from Mexico to the United States to get the infusion and it was very expensive.
Dr. Anderson: Yes. Just to quickly summarize this, you might say it’s too complicated et cetera but it really is not. I’m part of something called the National Comprehensive Cancer Center Network where we design these algorithms that lay out the different options to treat patients with newly diagnosed, relapsed, relapsed/refractory and maintenance myeloma. Treatments, those can serve as a framework both for treatment but also guarantee access to those of you who are patients to these medicines which is really important. But it’s the importance of having a myeloma expert on your team because it is hard to keep up. You can have a local oncologist but I would strongly recommend to have somebody who is doing myeloma to express an opinion and help guide your care over time as well.
Caller: Yeah, the data shows that you live years longer with a specialist on your team. Where could we get access to that framework that you’re talking about of those treatment paths. How is that available?
Dr. Anderson: There is a website. I think it would be www.NCCN.org. That’s just one of the sets of guidelines but I mentioned that one and Jenny, I think you must know it well. But it is very current because it makes evidence-based options available. It’s not going to tell how an individual patient should be treated but for newly diagnosed patients, it lists the options and in various categories that are appropriate to use. For example, we had seven new treatments approved last year in myeloma. Those new treatments are already in the guidelines right away. We already did that and that’s a good thing for caregivers because they can see that in the guidelines. It’s a good thing for you who are patients because many of the third party pairs including CMS, our government, used those guidelines to reimburse. We need to make sure if we have new medicines we can let you, who are patients, have access to these drugs.
Caller: All right. Well thank you so much. I appreciate your time.
Dr. Anderson: You are very welcome.
Jenny: Thank you so much. I have one quick write in question. Her name is Gratia and she read a book by the former Directory of the NCI who was concerned that the FDA has more oversight than it should – that its primary job was to assure the safety of new drugs and that he was concerned that it was regulating the research and practice of oncology. I know you’re involved in the NCI and wondered if you had any comments on that.
Dr. Anderson: I want to be a cheerleader and pay high compliments to the FDA. There is no question that there would not be 16 FDA-approved drugs in the last 12 years or seven new drugs or new treatments approved last year if it were not for the absolute commitment and proactive patient care that is the focus of the FDA in blood cancers in particularly in myeloma. In my view, the FDA is the unsung hero. I think there may have been problems in the distant past but I can assure you in the last 15 to 20 years, the FDA is absolutely on your side. They are very aware of myeloma. They helped to design the trials so that they can be done as quickly as possible. They are innovative.
Now that we have so many medicines that the ways, the trials are done in order to prove efficacy and safety have evolved over time but I do want to really shout out these are the unsung heroes, those folks that worked for the FDA in terms of making sure – there is just an astronomical number of cancer drugs that have been approved in the last year. Many, many patients are benefiting as a result.
Jenny: Well this year was a series of FDA priority reviews. It seems that things were really being fast tracked in my opinion.
Dr. Anderson: Yes. It’s absolutely the happiest time of all but it’s a call to action for all of us too.
Jenny: Well Dr. Anderson, we have kept you way over our time but I just want to express my appreciation for all you do for myeloma patients every day, for the amazing career that you had treating patients and doing research on all these different aspects to help provide better therapies and treatments for us. Thank you.
Dr. Anderson: Thank you very much and best of luck to all of you.
Jenny: Thank you so much.
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