Dr. Irene Ghobrial, MD
Dana Farber Cancer Institute / Harvard School of Medicine
Interview Date: March 17, 2016
Can we prevent smoldering myeloma or MGUS from progressing to active myeloma? Dr. Irene Ghobrial, MD wonders why we are waiting until progression to treat when we have newer non-toxic therapies to use. Dr. Ghobrial shares her Prevention of Progression Clinic’s efforts to keep myeloma at bay. In this show, she shares her open (observational) study that includes all MGUS and smoldering myeloma patients. It’s easy to join – just mail her blood and marrow samples when you have your regular testing done and they will keep track of how progression happens and why. The goal of the project called “PCrowd” is to enlist the help of patients in determining why myeloma progresses in some patients and not in others with the ultimate goal of preventing myeloma from progressing in the first place. The treatment options are ever expanding for those with smoldering myeloma, particularly with the flood of immunotherapies coming and now available. This study aims to help thousands of patients with pre-cursor conditions avoid needing myeloma treatment in the future.
Clinical Trials discussed in this show:
Dr. Irene Ghobrial, MD on Myeloma Crowd Radio
Welcome to todays episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. Im your host, Jenny Ahlstrom.
Wed like to thank todays episode sponsor, Takeda Oncology for their support of Myeloma Crowd Radio and all they do for myeloma patients.
A few announcements while we get started: We recently announced that the Myeloma Crowd will be hosting day long meetings called Round Tables on High-Risk Disease in a variety of locations.
These are sessions with top myeloma experts who will cover topics that are critical to high-risk patients. Each of the meetings will discuss a specific genetic mutation that is considered high-risk as well as information that is important to patients whose disease is aggressive in other ways, like a disease that is not responding to currently avaiable therapies.
Between 15-25% of newly diagnosed patients have high-risk disease, plus as patients become refractory to treatments their myeloma typically mutates and becomes more aggressive over time. So truly these Round Tables are for everyone.
Our first Myeloma Crowd Round Table will be held in SLC in May 7th with sessions by three myeloma experts. The MAF translocations will be highlighted during the day, so if you have either the 14;16 or 14;20 translocations you will want to attend. Future meetings will occur in additional cities incluidng New York City and St. Louis with more to follow. You can find links to the SLC meeting on the Myeloma Crowd Website and watch for future meetings as we finalize the planning.
Also, we are midway through our Muscles for Myeloma program. This will run through all of April and we would love for you to join us. Doctors are segmenting patients into fit, unfit, and frail categories and tailor treatment based on those categories rather than by age. A patients ability to handle a more difficult treatments or extended treatments also typically gives them longer overall survival. Check the myeloma crowd website and click on Muscles for Myeloma link to join and set your own fitness goal.
Now on to todays show. About a year and a half ago, I interviewed Dr. Irene Ghobrial on Myeloma Crowd Radio to learn what she was trying to do to prevent smoldering and MGUS patients from progressing to full myeloma. I caught up with her recently at Dana Farber in Boston to learn more about the progress she has made with the program she calls Pcrowd.
Before we hear from Dr. Ghobrial, let me share more about her. Dr. Ghobrial is an Associate Professor of Medicine at Dana-Farber Cancer Institute at the Harvard Medical School in Boston, Massachusetts. She is a physician Scientist who specializes in the field of Multiple Myeloma and Waldenstroms Macroglobulinemia (I can never say that right), specifically in the precursor conditions of MGUS and Smoldering Myeloma. She reviews abstracts for the American Association of Cancer Research and top publications such as Blood, Lancet, and the Journal of Clinical Oncology just to name a few. Shes on the editorial board of the American Journal of Blood Research. Dr. Ghobrial reviews grants for the NIH, the Leukemia & Lymphoma Society and the MMRF and has won numerous awards including a Dana-Farber Clinical Investigator Award, the Robert Kyle Award for her work in Waldenstroms and the American Society of Clinical Investigation. She particularly focuses on the role of the malignant bone marrow niche in disease progression from early precursor conditions like MGUS/smoldering myeloma to active myeloma.
In addition, she is the co-leader of the first consortium of clinical trials for blood cancers in collaboration with the Leukemia & Lymphoma Society to form the Blood Cancer Research Partnership a consortium for innovative clinical trials of 11 community oncology sites coordinated by Dana-Farber. Moreover, she initiated a new clinic for the Prevention of Progression in Blood Cancers where patients with precursor conditions such as MGUS, early MDS and early CLL will be monitored before disease progression to see how the clonal evolution happens during disease progression.
Dr. Ghobrial, welcome to the program. Maybe you want to start by sharing why you started this research effort.
Dr. Ghobrial: So the Center for Prevention of Progression is in your initiative that we started at Dana-Farber about a year and a half ago. And the whole idea came from a very simple thing in solid cancers, in breast cancer, or in colon cancer. Were doing screening all the time for our patients. So when Im aged 40, I go for my mammogram or colonoscopy when were a little bit older. And if you see a small little polyp or if you see something in your mammogram, usually, we have things removed immediately and we dont say, Well, why dont you wait until you have lesions in your bone or you have metathesis of breast cancer and then Ill treat you?
Yet for blood cancer, we see every single day a patient with MGUS or a patient which has monoclonal gammopathy of undetermined significance or a patient with an early MDS. And we tell them, Oh, wait until you have myeloma. Wait until you have leukemia and then Ill treat you. And that whole idea of watch and wait is something that weve inherited. Weve all been taught this way, and it made sense probably in the older days when we had no treatment, we had no effective therapy, and the treatment was actually very harmful.
So if youre asymptomatic and youre doing well, it makes sense not to treat you. But these days with us understanding all the mechanisms of clonal evolution of the tumor the cells are not sitting as things that are not acquiring new mutations as we leave them alone. And as we understand better, the immune microenvironment that as the tumor cells grow more and more, theyre able to make your immune system worse and worse.
And as we understand all of this, it doesnt make sense for us anymore to say, Well, why dont we just watch and wait until you have a full-blown disease, until you have metastatic myeloma and then Ill treat you? And that whole concept is something that we need to change in our mind. As physicians, we need to change it for our patients but start to prove it also clinically. We cannot say, Yes, it doesnt make sense. We have to actually truly prove that early treatment makes a difference in the survival of patients with myeloma.
And if we prove that, then suddenly, were changing everything. Were changing the way we think of our asymptomatic patients walking around, but you can also think that 3% of the population over the age of 50 has MGUS. And thats a huge number of people that were not screening for, were not looking for them. And if we know that we can make a difference in their life, we should be starting to look for them and screen them. And instead of just doing a mammogram or a colonoscopy or even checking your cholesterol level and making sure you dont get a heart attack and you die from it, we want to make sure you dont have MGUS and you will develop myeloma in 20 years from now, and I can prevent myeloma.
And the whole idea of prevention that myeloma will happen is such an interesting concept that we can think of preventing heart attacks these days because were very good at it, and just giving an aspirin and controlling your cholesterol. It could be as simple as that in the future for us in myeloma, but we just need to make the steps. We understand the biology, we understand who would progress and who will not because we dont want to treat everyone.
We cannot treat the whole population to prevent 10,000 cases or 15,000 cases. And we need to develop the right trials for the right patients, something thats not toxic, thats not forever. We dont want to treat patients forever to prevent one case. We want to truly have more of a surgical intervention just like we do in breast cancer. But in this way, its a medical but very concise and very non-toxic therapeutic intervention for those patients.
So with that in mind, we started this initiative a year a half ago. Adrianna Perilla Glen is our project manager really running the whole show, basically. And it started with a very simple concept.
Jenny: What you are describing sounds like a completely new project or in the entrepreneurial world, it would be a startup company.
Dr. Ghobrial: Its a small thing that we started saying, What can we do to make a difference?
So we started creating a website, creating the database that patients will enter their information in. Can we have things simple so that it empowers patients. So we started the whole initiative of PCrowd. And PCrowd came with the idea that is a precursor crowdsourcing. But instead of crowdsourcing for funding we are crowdsourcing for patients to give their information and to be part of that initiative, and it came again from the idea that patients are truly the best empowerment for moving research forward.
They can truly drive the idea of collecting samples, giving information but also can drive the research. They can really make a difference in this. And instead of depending only on academic centers or physicians or having the middleman which is the physicians, and I cant complain about the physicians but were truly sometimes hindering research rather than helping it when were in the middle of something that the patients can do themselves.
Jenny: What have you seen patients do in helping to drive your startup forward?
Dr. Ghobrial: We found that indeed, if you go to the patients and ask them to be part of it, it can make a big difference. They are there to help and they were willing to help. So PCrowd started with that with an online very simple consent. You dont have to go to your doctor. Theres a way for you to receive a sample acquisition thats very well packaged, thats easy and simple for the patients to get it. And for us to also be able to track things and move along with multiple samples throughout the course.
Jenny: This is something that all patients can participate in no matter where they are located, is that correct?
Dr. Ghobrial: The nice thing about PCrowd is this is not something thats limited only to Dana-Farber or to the Boston area. In fact, we have it now nationally open and were thinking very soon it will be internationally. Everyone can participate in PCrowd. Its really for every patient and for every individual who really wants to be part of this crowdsourcing way. Right now, were collecting a lot of patients with MGUS and smoldering myeloma or asymptomatic Waldenstrom’s or the IgM-MGUS. We’re also asking patients who have very early MDS asymptomatic, as well as the early MBL, which is the early CLL cases, to be part of this big initiative. The hope is that not only them or their family members as we expand this to family members will be part of this, but this will be truly a community where they can actually be part of a true social community together to help advance the research.
The whole idea is that as we get back information on their genomics, on their information of the samples, we would be able to give it back to the patients in the website so that as every 100 or 200 or 300 patient sample information comes back, were able to curate it and give it back to the patients to see whats going on with the research.
Its also a great way for us to say, If you want to participate in funding, then go to the sources of places that are giving us funding to help us move along in the research. And again, this can help build it up more and more and it keeps expanding.
Jenny: Well, not only can you donate to organizations that are donating to this project, but facilities also accept direct donations. You can make a donation to a specific lab like Dr. Ghobrials at Dana Farber and note that you want donations to go to this project. Dr. Ghobrial, maybe you can give us an update on this project.
Dr. Ghobrial: We were starting with asking 1,000 patients. Now I think were asking maybe more and more and more. And hopefully, we will use that platform for the screening program for asking a question of, Can we screen a high-risk population thats walking around there that they do not know they have MGUS?
But we can truly identify early steps of MGUS or smoldering myeloma and define who need treatment. And then, can we make a survival difference in those patients? And if we do all of that, someday we will be going to our doctors and checking a blood test, which is a very simple and easy thing, less controversial than mammograms. And if we have MGUS, we know that potentially, we can prevent myeloma for our own lifetime, and thats a big difference for us.
Jenny: There are some people who say, if you screen everyone, you may alarm people who have MGUS or smoldering myeloma who may never progress? So what do you say to people who say that?
Dr. Ghobrial: So its an important question. If I know something is there and I cant make a difference about it, sure, Im worrying a lot of people. But I think knowledge is an important thing in our life. Sometimes we get the knowledge and we dont know what to do with it yet. But if we say, Well, then Id rather just hide and not know the knowledge, then its not a good thing.
So the first step is knowing the knowledge and knowing truly who will progress and who will not. And were not there yet. We have some criteria, the Mayo Clinic criteria, the Spanish criteria. Theyre not perfect in any sense because theyre not based on molecular markers. Theyre based on tumor burden markers, which is just how much tumor you have, of course youll progress faster.
So I think the first step is if were scared of knowing, then we will never advance the disease. Two, we know that there are so many new therapies now. So its not that we are so far away from therapy. In fact, myeloma is probably one of the best areas of great drugs, and theyre not toxic drugs. We have antibodies, we have vaccines in development, we have so many things that are not — 15 years from now, theyre now here that we can actually implement and make a difference with them.
So its not an idea thats so abstract that yes, if I screen someone and they have high-risk disease and I know that in 10 years or in 15 years, they will develop myeloma, can I prevent this with the therapy? This can happen in the next year or two. Its not something were thinking of 10 years or 15 years from now. But if we dont make that difference, we will never have that chance.
And yes, patients are asymptomatic and theyre walking around, and knowing that you have MGUS may not be the best thing. But if you know that your cholesterol is high and you dont do anything about it because youre asymptomatic and then you get a heart attack, next year, thats a problem. And we know now that prevention makes a big difference for many diseases. In fact, probably one of the best things we should be doing is instead of therapy, its really prevention. Its intervening early before complications happen.
And thats true for all of medicine and not just for cancer therapy. Let alone cancer therapy is much more important. You know that if you have an early tumor clone that hasnt acquired all the mutations that hasnt changed the microenvironment around it you know that this one likely could be cured because you can intervene early. And it could be intervening early with vaccine therapy or with changing your immune system to kill that small tumor clone. You dont have to take toxic medications. We just have to know how to treat that clone.
Jenny: I was hoping you would say that. It just seems like with the advent of immunotherapies like vaccines and other treatments that have very few side effects and dont have to be used for a long period of time, it seems easy to use something like that. Well, how does someone get started on this program?
Dr. Ghobrial: The idea is very simple. If patients are interested and they know about it, which social media is very important for us so that they are aware of the presence of PCrowd, they will go online, sign the consent form, and then that prompts Adriannas team to have them go to the second step, which is a survey of the information, race, gender, family history, environmental questions, things that we think could potentially be linked to developing MGUS. And then that will prompt for us the sample acquisition.
So blood samples or bone marrow samples if theyre going for a clinical reason to get the bone marrow sample. Were not asking patients to go specifically to get a bone marrow biopsy for this. And then we follow them every three or six months depending on the risk stratification for those patients. And were asking for them to just keep us updated, to tell us whats going on. Now, the next steps will also involve some other information gathering about their symptoms or signs or any other things. Were still working on that aspect of having them track their health.
So thats not finalized yet and were talking to different companies about tracking health throughout their history and how to present back to them their medical information so that its easy for them to use when they go see their doctors. And whether we can also help them instead of faxing all the medical records and entering it one by one, can we do this more electronically and easier for them and for us so that were not having errors in the information, in the clinical information gathering. And then the final things will be sequencing, doing the actual work. Were collecting the data but we have to do the work.
Here, were doing not only on the bone marrow cells, so the tumor cells. We do something called sequencing. You can do epigenetics. Were leaving some of the samples for the future because five years from now, the technology that we have now will be our kid and we know that we will have better ideas. So we want to make sure that this is going on for the next years to come so that we can have a rich environment for science.
Were also looking at the microenvironmental cells, meaning, immune cell regulation, stromal cells, other things. Were up to the point of now something called single cell sequencing. You can take a single cell at the time and sequence it and get the information about it, and whether that interacts with the tumor cell and how does it do that. Then we look at the blood because the blood is a great source of whats going on in the bone marrow, and its an easier source than getting a bone marrow biopsy.
So were trying to look at circulating free DNA which is just DNA that your tumor cells will release in the blood and we can actually measure that and sequence that so that we dont have to go back to the bone marrow biopsy all the time and can we use that as a marker of prognosis or not in the patients. We also look at small little things called exosomes which are also released from the tumor cells or the microenvironmental cells and their content. They’re RNA or microRNA or genomics DNA content.
With all of that, including circulating tumor cells which are the cancer cells, just going around in the blood, we can capture them and get information about them. So the blood is a rich source for us to get all this information and its easy for the patients to give it and we can track it over time. So it makes it much easier for us to say, Every six months, whats going on with this patient? And if we see molecular markers of progression, we can develop them to say: these patients, if they have those markers, they will go on to develop myeloma in five years. We should be careful with those patients.
While others, they dont need to worry about this. Its not going to be a big problem for them. And this is the first step were doing. Were doing them behind the scenes a lot of lab work trying to truly understand functionally what those changes mean. So if you find the mutation or if you find the change in the immune cells, we cant say that these are truly causative until we actually do the validation.
And that comes up with lab work, mice experiments where we actually put different cells in different mice or use transgenic mouse models of myeloma and ask truly the question, is it causative or not? Is it really causing this or its just an association which can happen in a lot of things? And these are a couple of steps that try to understand disease development and why would someone progress or not. And these are important questions because we dont want to just treat everyone. We truly want to define progressors and non-progressors to myeloma and only treat the progressors of myeloma.
Then the next questions would be therapy. So were talking to a lot of pharmaceutical companies, as well as foundations to have sort of an umbrella of therapeutic interventions that we can think of and that are available now. We dont want to wait five years from now. The fierce urgency of now is very important for us. Again, one thing in mind is we want to make sure that these are not toxic therapeutic interventions. We would not cause damage of stem cells ten years from now.
So immunotherapy and vaccine therapy is the first thing we thought of and theres already vaccine trial thats ongoing. Were developing other vaccine trials. Were talking about immunotherapy with antibodies, elotuzumab, daratumumab, PD-1, all of the immune checkpoint inhibitors because you harness the immune system so that it can really kill the tumor cells, and thats very important.
And then were starting to also look at the new things that are coming out and whether these would be useful for us or not. And then of course oral therapy because its easy and well-tolerated. And with all of these in mind, we want to make sure the therapy is only limited. Its not forever. Its either six months. Its eight doses. Its whatever it is that we can kill the tumor clone and not cause resistance or cause long-term damage.
And then we would still follow all the patients and ask the questions, did we do good or not? Did we change the survival or not? Did we kill all the tumor cells or we left some behind, and why did we leave them behind? Are they acquiring resistance? Are they going to cause more damage in the future or not? These are all very important questions so that we dont come back in a year or two from now and have the same problems.
Jenny: This is participation in a clinical trial, which we always advocate. The more of us that get involved in research, the faster experts like you can do your job to help find new treatments and ultimately a cure. This is not a treatment clinical trial but is an observational clinical trial. Why should patients participate in a clinical trial like this? What is the advantage?
Dr. Ghobrial: So I think one important thing to patients is to be part of that. Participate in those trials because it will make a difference for them. I always say to the patients who want to be on a trial, Well, Im doing that for the good of humanity. And I say thats good but it should be the good for you. You are the most important person in this and it should be for you. You have to be selfish in that when youre going on the trial. And the reason for that is were hoping this will truly make a difference for the patient.
Its good for humanity, absolutely, and its good for all of us. But I think its also good for the patient. In general, we know that patients who go on trial do much better than patients who do not go on trial. Thats well-known. And we think that if you have high-risk smoldering disease, the chances of progression are really high. I think that probably in the next couple of years, it will become standard of care that we treat patients. Its becoming too obvious for us.
We dont need 500 randomized trials. Its becoming so clear that those patients do progress very fast and we should do something now about it. So well see what happens with all those trials. I think in the next two years, this would be interesting how we change completely the way we think of high-risk smoldering and maybe even earlier and earlier in the disease progression of myeloma.
Jenny: Do you want to share other clinical trials you have open for smoldering myeloma patients that are treatment trials?
So we have several clinical trials for smoldering myeloma. Right now, many of them are in the high-risk area, so high-risk smoldering. One of them is elotuzumab, lenalidomide, and dexamethasone. So thats an FDA approved combination already in the relapsed setting. And the whole question is, can we bring it early? Can we ask patients to try those drugs earlier and see if we can use the immune system with elotuzumab and Revlimid to truly prevent progression and maybe cure the disease early?
Then we have many other trials, of course the vaccine trial thats ongoing, the daratumumab trial. I think Im very excited about the dara trial in low-risk smoldering and high-risk MGUS. This would be the first time we actually do a study in this earlier disease stage. So most of us are doing in high-risk smoldering. Now were taking it even earlier and asking eight doses of daratumumab. Would that truly control the clone or even cure the disease early? And that will be one of the questions were asking in this trial.
Were doing all oral regimens with ixazomib/Rev/dex. And then were using the immune checkpoint inhibitors because we know that the immune system will be very important to harness early on. So were developing a PD-1 which is nivolumab plus Revlimid and dex trial. These are just the trials were doing here at Dana-Farber. Were also working with many other people in the MMRC consortium, with MD Anderson, with Memorial, with the Spanish group to really ask questions of different clinical trials so that we put them altogether in the end. And hopefully, a year or two from now, we can say, Yes, we made a difference in the survival of patients and here are all the options that we can use.
I dont think there is one right answer. I think we have to have choices for our patients so that one person would benefit most from this combination versus another would benefit from something else.
Jenny: The vaccine clinical trial is the OncoPep vaccine, correct? Can you share a little more about this vaccine?
Dr. Ghobrial: So its a PVX trial which is a combination of genes that are well-known in myeloma XBP1, CD138 and so on. And these are all combined together to develop a vaccine thats generic. So its not specific for the patient for myeloma. And this, as a single agents trial, it shows that indeed youre changing the immune system and now were adding to it Revlimid or we are adding to it a PD-1 inhibitor or potentially adding other drugs in the future.
So we will see how the data looks, but its an easy thing to try as a generic. You dont have to take your own cells and develop specific vaccines and then see if that makes a difference or not.
Jenny: Dr. Ghobrial thank you for sharing the progress of your Prevention of Myeloma Progression, or Pcrowd. Maybe we can ask Adriana to give us a few insights into how someone would join. Adriana is masterminding the logistics of the project and has even helped build the software which is really amazing. Adriana, how does someone join the Pcrowd study if they have MGUS or smoldering myeloma?
Adriana: So becoming a part of the Pcrowd study is really quite simple. You can go online. The process is there. You simply click on the Register Now button and then you go through the consent form and you fill out your information of data, of demographics, etc., what precursor condition you have. If you are willing to give your authorization of our team to contact your medical providers; for us to get all of your medical history information you can sign that consent there as well. And then the final step is a survey that takes you to all of the medical history for your family and anything that we think might be relevant to your disease. This process only takes about 45 minutes to complete and once you complete that process, you are registered officially into the Pcrowd study.
Jenny: And then once someone registers, how do they send in samples to you?
Adriana: So once you are registered into the study we send you out 2-3 collection kits depending on what your condition is. So for MGUS patients we want to follow them every six months. That means that MGUS patients usually are followed by their own medical provider every six months so they will probably get their blood drawn at that time. So we would ask MGUS patients to send us samples when they are being drawn for their precursor clinical condition. For a smoldering patient, sometimes they are seen more often, so like every three months or so. So we would also send them kits for every three months. For MDS also six months and MDL also six months.
Basically what I do is that I send you these kits that contain all the materials that you need. This means it contains the test tubes, the instructions, all the packaging materials that you need to send us a sample back and all the shipping airbills. So really the patient does not have to pay for anything. All they have to do is go into the clinic that they are being seen at on the day of their appointment and ask the technician to draw a courtesy blood, which happens after youve gotten all of your clinical samples drawn. The technician will then draw three extra tubes. And once you have those tubes, you follow the instructions on how to package it. Theyre really simple. It has pictures that guide you through the process and you just put it in a FEDEX box and take it to FEDEX or even have FEDEX pick it up at your house.
Jenny: And sometimes Ive had my own facility send blood samples to another facility if I ask them to. Is that possible?
Adriana: So if the patient has a good relationship with their doctor and usually I would think that the smaller medical centers are more flexible with that. Ive had patients ask their doctors to send a kit and thats not a problem for them.
Jenny: Is there anything else that patients need to think about as they are getting samples taken at their facility?
Adriana: When you are getting your blood drawn, make sure that your appointment is between a Monday and a Thursday just because we need to receive your sample up until Friday. Were not open on weekends, so you want to make sure that your sample is drawn then so that when it comes to us, it should come the following day after it was drawn just to make sure that the sample is viable for processing.
Jenny: Well thank you to you both. Dr. Ghobrial, we look forward to sharing what you are doing because we think it is fantastic and we look forward to seeing your study results. We hope that this goes a long way to prevent myeloma from ever occurring in the first place.
This study is a great example of just one of the ways we think that patients can help accelerate a cure and we thank you for listening to another episode of Myeloma Crowd Radio.