Newer approaches for relapsed/refractory myeloma patients with Dr. Ravi Vij, MD, Washington University School of Medicine

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Dr. Ravi Vij, MD
Washington University School of Medicine
Interview Date: January 29, 2015

Summary
Dr. Ravi Vij, MD, discusses newer options for relapsed/refractory myeloma patients. He shares that little is known about why some patients become drug resistant and says that drug resistance can’t be predicted. He notes the complexities of myeloma, that there isn’t a single clone of the disease in each patient, but rather sub-clones where one could be affected by treatment and other resistant to treatment. He shares the use of the new monoclonal antibodies elotuzumab and the two new anti-CD38 monoclonal antibodies. He also shares that the newer drugs carfilzomib and pomalidomide are helping relapsed patients and may give better response rates. He mentions several other new inhibitors that may also be effective for relapsed patients including ARRY-520, KPT-330 and Ibrutinib. These are still in the early stages of study, but represent a growing number of newer options being tested. He notes that the field is maturing, with new genetic testing able to identify specific genes that are mutated in myeloma and other cancers. He describes the difference between the gene expression profile (GEP) and whole genome sequencing and tells us that the $1000 genome test is here today, but says the challenge is finding the people and systems to interpret that data. He describes “personalized medicine” and “precision medicine” and suggests that these new ways of looking at myeloma and cancer in general may require a different approach to clinical trials.

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Full Transcript
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, formerly mPatient Myeloma Radio, a show that connects patients with myeloma researchers.

You can find all past and future shows on myelomacrowd.org, and if you’d like to receive a weekly email about past and upcoming interviews, you can subscribe to our newsletter on the homepage, or follow us there on Facebook or Twitter. We will be opening it up for caller questions at the end of the show, so if you have a question, you can call 347-637-2631 and press 1 on your keypad.

Before we get started on our show today, we want to let you know about a very exciting and upcoming development. We think doctors can do more to find a cure for myeloma with our support and involvement of patients. I believe that if we sit back and wait for the next big breakthrough, we may be waiting a long time and they need our support.

So on Monday, the Myeloma Crowd will begin a new way to help find a cure for this disease with a new research initiative called the Myeloma Crowd Research Initiative. We are asking myeloma researchers to submit proposals for high-risk myeloma. We have a six-person Myeloma Expert Committee (Scientific Advisory Board) that will be reviewing the proposals and we will join that with a Patient Activist Committee of five patients. And after we select what we think are the projects that will make the most impact, we’ll create crowdfunding campaigns for those projects and you’ll be able to identify where you want your donation to go.

Now, we’re choosing high risk myeloma because for patients with aggressive genetic features or a disease has become resistant to medications that are used today, like the show is about, they have run out of options. And if we can find solutions for the most aggressive type of myeloma, it will help even standard or low-risk myeloma patients. The most exciting part of this project, I believe, is that patients will have a say in the proposals that are selected and to my knowledge, that’s the first time that’s been done really on a large scale in any type of cancer.

Now, on to today’s show, we are delighted to have Dr. Ravi Vij with us today to discuss newer options that are available for patients where the myeloma has become aggressive and has either relapsed or has become resistant to existing drugs, and when that happens, that is called refractory myeloma.

Welcome very much, Dr. Vij.

Dr. Vij: Thank you for the invitation.

Jenny: Let me give a little introduction for you before we get started. Dr. Ravi Vij is Associate Professor of Medicine at the Washington School of Medicine in the Bone Marrow Transplant section. He received his medical degree in India and did follow-up training and residency at Rush-Presbyterian St. Luke’s Medical Center in Chicago and fellowships in Oncology and Bone Marrow Transplantation with Stem Cell Biology at Washington University.

He’s a member of ASCO, ASH, the St. Louis Society of Clinical Oncology, and the American Association for the Advancement of Science. He serves on numerous national committees including the Myeloma, Transplant, Leukemia Committees of the Alliance for Clinical Trials in Oncology and the Steering Committee of the MMRC. His honors include the Multiple Myeloma Research Foundation Innovator Award in 2013 and the MMRC Center of Excellence Award.

He’s the author of over 100 peer-reviewed publications, as well as a book called Contemporary Management of Multiple Myeloma, and several book chapters. He served as a reviewer for several journals, including Blood, Journal of Clinical Oncology, Bone Marrow Transplantation, Experimental Hematology, and Haematologica.

His primary academic interests include the treatment of myeloma and stem cell transplantation for hematologic malignancies. He leads many clinical trials and has established a large myeloma tissue bank at Washington University with a strong institutional focus on studying the genomics of the disease, which are really critical to understanding what causes myeloma and how we cure myeloma.

So with that introduction, let’s go ahead and get started. Maybe we can start by talking about what we do and don’t know about what causes drug resistance.

Dr. Vij: I think that we know very little at this point about what causes drug resistance. What we know is that increasingly, it is becoming clear in myeloma, like in other cancers, that there are multiple clones of cancer cells. We used to think that at least initially when cancer arose, it was a homogenous population of cells and over time, we developed mutations in these cells, which gave rise to new clones and possibly drug resistance.

We now know that these sub-clones are often existent right at the time of diagnosis. There is one clone that is dominant and is causing problems which comes under control. And then at the time of progression, often that original clone that was causing the problems remains suppressed, but it is a different clone that is emerging. And so, that brings up the issue of being able to, after treating that second clone, if patients progress a second or third time, being able to go back to drugs that they were sensitive to in the past. That is something that right now is in the realm of research, but may one day become a clinically viable test.

So the issue of drug resistance is something that we’re learning a lot about. A resistance to drug once may not mean resistance to drug forever. However, if you are asking about what we know about two mechanisms of resistance to our known drugs, we have some clues that perhaps the group of drugs, immunomodulatory drugs that is lenalidomide and pomalidomide, may work through this molecule called cereblon. A low expression of cereblon may counter resistance.

Likewise, for bortezomib, there have been mutations described in the proteasome, which is the target for the drug. Also, there have been reports of certain mutations in key molecules in the cell that are the target for proteasomal degradation that may also, once they’re mutated, no longer allow the cell to be killed off by bortezomib or other proteasome inhibitors.

There are certain proteins that cells use to pump out drugs and there are some data that certain cancer cells may up-regulate certain proteins that pump out the cancer drug and thereby make it ineffective, so those are all the subject of research. We, as I said, at the outset know unfortunately very little about this area.

Jenny: You mentioned the IMiDs. Can you track your — is it cereblon that you said?

Dr. Vij: Well, there are tests that are done right now in the realm of research, but there is a move to see if one can commercialize an assay to attract the cereblon level. That is not yet a commercially available test and it is something that may in the future become available.

People are looking at not just one gene, but are also looking to see if one can come up with some kind of a chip that can predict for resistance based on the mutational profile of a cancer, so there’s a lot of effort going on in that area, but unfortunately at the moment, we don’t have any commercially available tests to look for resistance.

Jenny: And is cereblon like a protein? What is that?

Dr. Vij: Yes, it is a protein in the cell.

Jenny: Okay, just curious about that. How do you predict whether somebody will become resistant or not? What are you looking at or what would they look at as they develop this standardized test for the genetic features or something else?

Dr. Vij: Well, I think it may be unique to each drug class if we can one day come to predict how a person is likely to respond or not to respond to a drug. It may be a drug-specific assay or it may be a very wide assay of genomics of the cancer cell, as I said at the beginning.

Over the last few years, the issue of clonal tides has become very much at the forefront and people are trying to see if they can ultimately, with the declining cost of next generation sequencing, use that technology one day to predict for what a patient is likely respond to or not, but I believe that such things are still several years away from commercialization.

Jenny: Now, a follow-up question to that. If you study the genetic profile and biology of the different types of myeloma, can you give us a refresher about what’s the difference between the next generation sequencing and the gene expression profile test?

Dr. Vij: The gene expression profile test is already a commercially available test. More than one company offers it and that is looking at the RNA expression levels of certain genes. For those that are not totally up-to-date on the way the whole process works, we have DNA, which is then coded in our chromosomes that ultimately gives rise to RNA, which ultimately gets translated into proteins, and it’s the proteins that usually do a good or bad job in a cell.

The gene expression profiles have so far looked at that intermediary, the RNA, the expression level of the RNA. It has been validated in a number of data sets that this expression of certain genes, the pattern of gene expression can correlate with prognosis. There have been small papers looking at it has a predictor of responsiveness as well. However, increasingly people are wanting to look at the DNA itself and that is where next generation sequencing comes in. It is a technology that allows us to look at the mutational profile of the originator DNA.

Also, the same technology can be used to do what is called RNA sequencing, which is giving more information than just RNA expression levels. There are others who believe that proteomics, which is a technology very much in its infancy, even less developed than the next generation sequencing technology, may in the future hold the most promise because ultimately it is the proteins that are regulating the cellular function.

Ultimately, it is going to probably be not just the one technology, but a multitude of technologies that will need to be synthesized to give a true picture. Added to this complexity is what we call epigenetics, which is that we know that there is a regulation of these genes by our DNA, which is through different processes in the cell and that are regulated by methylation or acetylation, and that is a whole different area where people are also focused on to get a better idea of how cells function.

Jenny: I don’t know that much about epigenetics. Does that have something to do with the bone marrow environment or it’s just the nature and characteristics of the actual myeloma cell?

Dr. Vij: Genetics is a broad field. We use the term relatively loosely sometimes, but increasingly, what we’re talking about is to study the cellular function of the myeloma cell at the DNA levels. This is where the information that we’re born with resides, the DNA, and it is felt that in most cases, myeloma arises from previously normal plasma cells because some genetic alteration occurs in the DNA that sets off the process.

We know based on a number of publications that have come out in the last few years that myeloma has a multitude of mutations that are there in patients. However, in contrast to some cancers where we have been able to pinpoint what mutation causes a specific cancer like chronic myelogenous leukemia being a case in point, there’s one typical translocation that occurs in the cancer cell that is present in universally near 100% of patients.

In myeloma, it has been a little more sobering in that yes, we find mutations, but the most prevalent of these are probably in less than 10% of patients, so it is a heterogeneous disease placed at the mutational level. However, we’re just starting to unravel the biology and just compiling a list of mutations is the simplest thing that we can do. Only with time can we take it to the next level where we look at the interactions of these mutations and perhaps what we call a systems biology approach to see if it is not just a specific mutation, but perhaps a cluster of mutations that interact in some way to produce maybe the answer because so far, as I said, no one discreet mutation has sprung out as the cause of myeloma.

Jenny: And it’s very complicated when there’s not a single target, it seems like. I know we’ll go into this. I want you to be able to cover what’s being done on the COMPASS trial to try to do a little more detail, a personalized therapy for everyone. Let’s talk about that a little bit later because it’s really important.

Maybe you want to start by giving us an overview of current relapsed/refractory approaches, maybe a history, what’s been effective and not effective, and then where research is headed in general with this complexity.

Dr. Vij: I think that we’ve made tremendous progress in the last 15 odd years in terms of our ability to treat patients with myeloma, both untreated and relapsed/refractory. The mainstay of the advances has been two classes of drugs, proteasome inhibitors and immunomodulatory drugs.

We’ve had bortezamib as a proteasome inhibitor, and both thalidomide and lenalidomide as immunomodulatory drugs available commercially for nearly a decade or more now. However, we’ve had new additions to these classes of drugs including carfilzomib, a new proteasome inhibitor, and pomalidomide, a new immunomodulatory drug in the last two to three years, which are helping patients who are often refractory to this earlier approved compound, so I think these drugs are still being explored to get their full potential with carfilzomib, different doses of the drug.

Over and above the current licensed drug dose may provide additional benefit in terms of better response rates. Certainly, combinations of carfilzomib and pomalidomide, either between the two drugs, or independently carfilzomib combinations and pomalidomide combinations are showing high response rates than the drugs alone, so I think that the best way to give these drugs is still the subject of investigation.

In terms of drugs that are not yet approved, there are some that are very promising. That group, the monoclonal antibodies probably hold the most promise, and their elotuzumab has been in development for a few years. This is a monoclonal antibody to what was formally called CS1, now called SLAMF7, and that is something that may finally be approved in the year to come as the trial that has been done to get it approved in relapsed/refractory disease has finished accrual a few years ago and it is expected that the trial may read out sometime later this year.

The other target for monoclonal antibodies is CD38 of which two different compounds are in development, daratumumab, and the other one does not yet have a name, but goes by SAR650984. Both of these seem to be fairly comparable in their efficacy, the two CD38 antibodies.

What we are also realizing is that both these classes of monoclonal antibodies, elotuzumab and the CD38 antibodies perhaps work best when combined with immunomodulatory drugs, and perhaps the CD38 combination with proteasome inhibitors may also be valuable, but it appears that the class of immunomodulatory drugs gives a boost to the immune system. That is what these drugs rely on for either a majority or a significant proportion of their potential activity. I think that this class of compounds will provide the next major advance in therapy.

There are other drugs that are being looked at, that will also I think help patients, and these include the oral proteasome inhibitors. Ixazomib is the one that is further along in development in phase three. It is an oral drug similar to Velcade. Oprozomib drug similar to carfilzomib has also been in development for a while, but has had little delay in its development due to GI toxicity. However, this may be something that with those modifications, stepped-up dosing and increased used of antiemetic now become more tolerable.

Oral proteasome inhibitors would, I think, offer the convenience of long-term administration of drugs and in a disease where it appears increasingly that long-term therapy rather than start, stop and start again may be the better paradigm. So I think there are certainly a host of other drugs that are also in development. One that one can mention is the ARRY-520 compound, which also is seeking approval in relapsed/refractory disease. This is a KSP inhibitor, which has shown activity in patients who have failed multiple other therapies.

Another drug that is looking somewhat promising is KPT-330. It is a drug from a company called Karyopharma that has shown activity when combined with dexamethasone in patients. It does have some issues around GI toxicity and tolerability, which needs to be worked out, but at least it’s showing promise.

We presented some data on Ibrutinib, which is a drug approved for chronic lymphocytic leukemia and some lymphomas, and when combined with dexamethasone especially, it seem to have responses in refractory patients, so more work needs to be done with all these compounds. The ones that I’ve gone over are not by any means an exhaustive list. There are a number of other monoclonal antibodies and small molecules that are showing activity.

Jenny: It’s a lot that’s happening. To maybe recap what you said, you have the option of using more of a type of drug for relapsed patients. You have an option of combining the different drugs together or using them in different combinations. Let’s say you’ve been on bortezomib and lenalidomide or something. You could try maybe carfilzomib and pomalidomide and get a different response, right?

Dr. Vij: Correct.

Jenny: And then the monoclonal antibodies are using your own immune system to fight the myeloma, the oral proteasome inhibitors and then other different types of inhibitors. So before we go on to a little more detail about some of those, I’m just wondering how do you as a clinician and a researcher try to come up with the best option and alternative for a patient that walks into your clinic that’s been relapsed. What are the steps or the thoughts that you go through to try to pick the very best option for the patient?

Dr. Vij: I think that is dependent on a number of factors, patient-specific, disease-specific, and other. I think one has to take into account the age of a patient. Certain drugs are harsher on the body, have more side effects than others. One has to take into account the performance status, which is often more important than the age. A patient’s ability to perform activities or daily living is often a good indicator of the ability to tolerate certain classes of drugs.

One looks at what other health problems a patient may have whether he has significant heart problems, kidney problems, liver problems. Those can often affect our choice of drugs, and then one looks at the biology of the disease. Certain chromosomal features of the disease may be more likely to respond to a certain class of drugs like the t(4;14) translocation, and to some extent, the del(17p) may be something that responds better to a proteasome inhibitor than an immunomodulatory drug, but again, this is by no means that immunomodulatory drugs don’t work for this patient population. They do and often you combine them.

There are other factors that we consider that are very mundane like the ability of a patient to visit a doctor’s office to get a drug or whether a patient has the social support. Sometimes, insurance-driven issues like the ability to afford co-pays, which often are a little more stiff for oral drugs than drugs given in the doctor’s office may also drive our choice of therapy.

I think that myeloma is somewhat unique among diseases in the heterogeneity of approach that we have for treatment of relapsed and refractory disease. If you get ten experts around the table, they will have a little bit of difference in how they approach a patient, and even within a doctor’s practice, how he treats an individual patient as heterogeneity in myeloma. It is more marked than for some of our other cancers where there’s more of an algorithmic approach that you do this, then you do this, and then you do this.

Myeloma is as much art as it is science. The good thing is that most patients are able to tolerate the currently approved drug and often it ends up being a question of how you sequence these over time rather than truly choosing between them.

Jenny: That’s really important. I think that just goes to the point that you really need to have a myeloma specialist in your corner, that does this all day long for patients because they know about all the different options and drugs and things that are looking promising.

It seems in clinical trials, relapsed/refractory is the first group that gets new drugs just because the drugs aren’t working, that existing drugs aren’t doing what they need to for the patient. Can you first talk about a little bit — let’s go back a little. You mentioned that sometimes when you give a drug, you can go back later and it doesn’t mean you might be refractory to it later. Can you explain how that works?

Dr. Vij: Again, this is I think something that we still are learning. I don’t say that it is something that we can actually predict or we can go back to use a certain drug for. What we know is that historically, it had been more anecdotally reported that if a patient got lenalidomide with dexamethasone, and then after the disease got resistant, bortezomib with dexamethasone, and then the disease got resistant, when you give the patient a three-drug combination of bortezomib, lenalidomide, and dexamethasone, the patient often had a response again because of certain — perhaps now what is being realized is previously suppressed clones that had reemerged after we would do a drug.

The cancer, as I said at the beginning, is not a homogenous entity. It’s not as if every cell in a cancer has the same genetics. We’re realizing increasingly that not only myeloma, but in any other routine-aging process, our bone marrow undergoes mutations. If you look at people who are in their teens versus people in their 70s and 80s and have no cancer and you sequence their bone marrows, you will find more changes in patients who are older than they are younger, so that tells you that even in normal life, our bone marrow is undergoing genetic changes perhaps due to things in the environment.

And then it is felt that some specific change occurs allows a certain group of cells to become independent of signals and then the cells take a life of their own. What we don’t know is what these so-called founder mutations are of and we’re starting to get some idea in certain diseases as to which of these may be.

And then additional mutations occur, which are what we call passenger mutations, which then propagate with the cancer. It may not be as important in the biology of the cancer. So when we do next generation sequencing of cancer cells, we pick up all these mutations. The next step is to figure out which of these mutations is actually important in the survival of the cancer cell and which of these is just background noise.

That is going to take years to, unfortunately in a lot of cases, decipher because then you have to go back to the laboratory and often develop cells in the laboratory or mice that lack certain genes or have certain genes overexpressed to see if a particular mutation really causes a cancer in the laboratory. A lot of these mutations do not do anything in the laboratory, so they tell you that these are probably just background noise to which if you were to target your efforts, they will probably not bear fruit.

We’re just at the beginning of this process. We validated a technology. The cost of the technology has come down tremendously. The first human genome took ten years to sequence. It was a race between a federal government effort led by the NIH and Craig Venter, who had his own Celera Genomics. After ten years, both of these groups independently came up with the first human genome. It took a billion dollars plus to get the first human genome. Now, you can sequence an entire human genome in under a week and the cost of sequencing the genome is down to a thousand dollars, so the thousand-dollar genome that is often talked about is here, but the issue often is the fact that you have to add $9000 to pay the people that will then be able to make sense of this genome.

To put it in perspective, one human genome produces four terabytes of data, and that is what a lot of systems can’t hold. So what you ultimately end up doing is holding the data in big supercomputers and what you have to do is not then sequence one genome, but sequence hundreds of genomes from patients with a certain disorder to really make sense of what the data is going to look like.

You can imagine an Excel spreadsheet with three to four billion columns because that’s how many base pairs our genome has, and then several hundred rows of patients. You don’t even know which cell in that Excel spreadsheet to start focusing on. You’re actually now reliant on mathematicians and computer scientists to drop algorithms to query such large databases.

The bottleneck is really not now in the ability to sequence. A sequencer cost now just a few hundred thousand dollars, probably less than what an MRI machine or a CT scanner cost. Literally any institution can buy a sequencing machine now, but the real bottleneck is in the manpower that has the ability to make sense of this data because this requires people with a background knowledge of both biology and computer science to be able to write programs to query databases.

That talent pool is very small even in large institutions like ours. Washington University was one of the three institutions that led the federal effort to sequence the human genome. It was a combined effort that was led here at Washington University, at the NIH, and at Sanger Institute in England, and that produced the first human genome. Even at our own institution, we don’t have enough people to interpret data.

We have a facility that is two blocks by two blocks, full of supercomputers that holds data, and we just don’t have the people who will be having the time to spare to be able to look through that data. It’s really unbelievable. We even have the money often to pay for these people, but you just don’t have the skill set available. These people are wanted by everybody, somebody who’s working on breast cancer, lung cancer, colon cancer, and somebody who’s working on myeloma, and everybody wants their time.

Jenny: It sounds like a massive filtering effort that may not be possible in one institution.

Dr. Vij: Well, it has to be done — it’s a combined effort, and some of the things that are our efforts, which you mentioned, like the COMPASS project is actually a very big effort in big data analytics, open source, where the data is actually in a public repository available for anybody anywhere to access and interpret. The fact is that unfortunately, a few people have the ability to do that today.

It’s a true case of data overload. There are large multinational corporations that are getting into this field of bioinformatics right from IBM to Google. They’re realizing that this is an issue that has to be solved. It will be in due course of time, but it is just something to put in perspective. The sequencing of the human genome is a very easy thing now. It is just an investment of a few hundred thousand dollars, perhaps $200,000 to buy a machine. The next step, interpretation of the data that is produced by that machine is where the problem lies.

The fact is that a lot of institutions have started focusing on known areas that they look for targeted mutations. That certainly has become very feasible. In CLIA-certified laboratories now, a set of anywhere from a few dozen to a few hundred genes can be sequenced and data provided. Companies like Foundation Medicine are at the forefront of this effort, but one needs to put in perspective that they are looking at something that is just a very small portion of your genome, which they think has already provided us some information. “Let’s just look at these 200 genes,” but you have 25,000 odd genes.

In a certain patient, it may not be one of those 400 genes that they have on their panel that is important. It may be one of those tens of thousands of genes that are not important for the majority, but in a certain patient may be important. So how do we get to that level of analysis on a wide, commercially available, and clinically applicable basis? It’s going to be something that will take the better part of a decade or two to get to.

Jenny: It’s a massive effort and very, very complicated.

Dr. Vij: It is however something where the answers are going to come from. Most of the drug development to date is what we call empiric, which is you come up with a drug and you give it to patients with variety of cancers, what is called phase one development.

And then you get a signal that a certain kind of cancer seems to be responding, and then you go ahead and enroll a few dozen patients with that specific kind of cancer, try to get what the true response rate it, and if it’s still promising, you move to the phase three large studies that compare it to standards of care and then get the drug approved, but then you spend 20 years figuring out why that drug worked in the first place.

For example, bortezomib and lenalidomide have been on the market for more than ten years. To this date, we do not know why they work. We have some postulates of why they work, but that’s the old mechanism of drug development, empiricism. The new model is valid, identify a target, and then you go and develop a drug to the target.

Increasingly, what we’re realizing is this targeted drug development is probably also a little bit too naïve a concept because often, we develop a drug to a target based on rational drug development. It works and then you figure out that it’s working not because it works on the target we thought it was targeting originally, but perhaps on a different target or on more than one target. It’s fascinating, the field.

Now, what is going to be in the future challenging is that as we break myeloma into smaller groups, as you were saying, there are patients who have different genetic abnormalities, how are we going to get the drugs that are going to work for particular patient groups? There’s one thing called personalized medicine, which is yes, you’re looking at a patient’s tumor and you are trying to get a drug specific to that patient, but I think what people don’t realize often is — another word that is used often interchangeably — precision medicine is a little different than personalized medicine.

Precision medicine is a one step further than personalized medicine. We haven’t even conquered personalized medicine and we’re already talking about actually branching into precision medicine, which is that you become agnostic to what your tumor is. You don’t care if a patient has breast cancer, lung cancer, colon cancer, or myeloma for that matter. You are developing a drug to a particular mutation. And as long as the patient’s tumor has that mutation, you will try the drug.

Case in point, BRAF, which is now known to be one of the more commonly mutated genes in myeloma, albeit only 5% to 6% of patients carry that, is a gene that is mutated much more commonly in melanoma. We have seen melanoma skin cancer often actually confused with myeloma by some people that these drugs did very well and got approved. There are more than one BRAF inhibitors approved. Now, we’ve learned that in patients who have BRAF mutations in myeloma that these drugs work as well.

The thing is that now, there has to be a different paradigm of drug development where you are actually going to go to the FDA and say, “I have a drug that I want approved not for myeloma. I want a drug approved for patients with BRAF mutation.” Right now, the FDA is not even set up to think along those lines. They’re cognizant of it. They’re starting to say that that is probably where we’re going to be heading in the future. Just recently, a certain trial started where people are enrolling patients irrespective of cancer types with certain mutations.

I think what is going to happen is then that you’re going to have smaller groups of patients within a disease, but perhaps if you have drugs to a mutation that is disease-agnostic, you can still justify the economics of drug development because otherwise, if myeloma — we have only tens of thousands of patients each year in the United States and we break it into groups of 500. Drug companies are often not going to think it is worth an investment to bring the drug out for patients with a number of 500 in the United States.

But if you can say that it’s going to help patients with myeloma, breast cancer, lung cancer, a subset of each of them, then maybe it will still be economical. I think it’s something that is going to happen. We’re in the beginning of that era, but it is going to be there soon.

Jenny: Well, I think that’d be fantastic because then you could separate everybody out. I mean, you still need the myeloma-specific expertise, I think, but you could knock it down.

Dr. Vij: Yeah. I think it will need a specific expertise for sure. The fact is that there are these things that are being called N-of-1 trials that are also something that are increasingly getting placed. Previously, you give drugs to patients and you enroll 200 patients and hypothetically, if 50 of them responded, the drug was approved. But if 40 responded, the drug was not approved.

However, those 40 who responded, you forgot that they responded and some of them entered a complete remission and there was probably a reason why they responded. Now, people are saying that actually even if one patient responds in a trial, you need to study his genome and figure out why he responded because there may be something there that may help a lot of other patients.

Jenny: That can be shared, and you just don’t know why, but you should find out why. Well, I just want to give you a minute to finish talking about — or give us a little more detail about the Ibrutinib.

I know you presented at ASH in December and you mentioned that it came out of chronic lymphocytic leukemia, so that’s an example of borrowing from another type of cancer to find the drugs that might work in myeloma. Do you want to explain that? And then we’ll open it up for some caller questions.

Dr. Vij: Sure. Ibrutinib is a drug that targets a specific receptor called the BTK receptor, Bruton’s tyrosine kinase. We have known for a long time that in certain lymphomas and also in chronic lymphocytic leukemia that it’s targeted or expressed, and it was one of those very rational methods or drug development that was pursued and what was found to be successful.

It was then shown in certain laboratories that the normal plasma cell doesn’t express BTK, that malignant to plasma cells, myeloma cells, actually do express the receptor to some extent, but more so that the environment of the cancer especially certain components of the bony environment and the stroma that the myeloma cell lives in actually express the receptor.

Previously, we had actually a couple of years ago presented a poster at one of the ASH meetings to show that it seemed to be modulating favorably certain cytokines, chemicals in the microenvironment that are responsible for myeloma cell growth. At that time, we did not have the clinical data. Now, it appears that when combined with dexamethasone especially that there are some patients that are responding to the drug.

These patients are heavily pre-treated. Quite a few of them have actually had a fair amount of dexamethasone before, so people think that attributing the response to dexamethasone alone may not be the reason why they’re responding. So we’re trying to see I think in a larger subset if this signal holds true. There are other trials that are combining ibrutinib with other drugs like carfilzomib and I think that one has to wait until a little more data is available to see how the drug develops for myeloma or whether it has the potential to become another drug for patients with myeloma in the future.

Jenny: Great. Well, thank you for covering that. I wanted you to be able to share that. Now, my final question is a quick one. What is the impact of clinical trial participation by patients for you in your research?

Dr. Vij: I think that it is tremendous. We always encourage patients to enroll on clinical trials. Clinical trial enrolment unfortunately nationally, only less than 5% of patients who are treated are on a clinical trial. We know that we cannot develop new drugs until patients are on clinical trials and patients are able to use drugs that are proven because in the past, one day someone had agreed to go on a clinical trial, and clinical trials are vetted by not only scientists, by ethicists, by patient advocates before you can actually enroll patients on clinical trials.

There are a few trials where patients are getting a sugar pill, a placebo, when most of these trials are looking at adding drugs to existing active options. So I think there’s some hesitancy on some patient’s part on enrolling on clinical trials because they think they’re going to get an effective therapy. It’s usually not warranted because the trial designs have been pretty much adjudicated by a lot of people both scientific and other people from non-scientific fields to make sure that they are sound and ethical.

Jenny: Okay. Great! Thank you so much. Well, we’ll open it up for caller questions. And again, if you want to ask a question of Dr. Vij, please call 347-637-2631 and press 1 on your keypad.

Our first caller, go ahead with your question.

Caller: Hi! Thank you for taking my question. Great show! Out of all the new drugs you’ve described, what do you believe is the most promising? Is it the monoclonal antibodies that you’ve talked about or is there something else?

Dr. Vij: I think again, certainly the buzz is around the monoclonal antibodies, but it doesn’t mean that the other drugs are not good. It also may be that certain drugs work better for certain patients than others. We don’t perhaps even know how to identify those patients today, but a short answer would be I think that the monoclonal antibodies, among the drugs that are further along in development, appear to be the most promising that will probably provide the next improvement in the survival of patients with myeloma.

Caller: How long would you think that it might take to get some of those drugs to the general public or to the general myeloma patients?

Dr. Vij: Well, elotuzumab is maybe among the first to be approved and it is possible that the trial reads out this year as anticipated. We can’t guarantee it, but it could be there on the market by the end of the year or early next year. I think that the CD-38 antibodies at large depend on how the FDA looks at the data.

There are certain trials that are single-arm, phase two studies that are trying to prove to the FDA that daratumumab, and for that matter, even SAR potentially has activity in an unmet medical need population. If you can show that, then the drug comes to market sooner as early as perhaps again late next year, but if the FDA feels that you need to do a large, randomized phase three study, then it could be two or three years or longer before that class of antibody comes to market.

Caller: Okay. I have one more question. Are there any costs to cancer clinical trials that include myeloma like the BRAF mutation that you mentioned?

Dr. Vij: Yeah, there are a few of them. The BRAF mutation trial is being run through Novartis Pharmaceuticals that takes patients irrespective of cancer type. There are other trials that are also starting.

For that, however, you need to often first be able to know whether one’s tumor type expresses that mutation, and that is usually not done commercially. It has to be done specifically for purposes of trying to get on the particular trial. There are some barriers often with insurance unfortunately in getting these tests paid for on a commercial basis, but if it is for a trial, often the costs are covered.

Caller: Okay. Thank you very much.

Jenny: Okay. Great! Thank you so much for your question.

Caller: Thank you very much. You may see me on there a couple of times and that’s because I got disconnected.

Jenny: That’s okay.

Caller: Okay, so there’s only one call. Thank you, doctor. I really find this very instructive. I have two short questions and they both have to do with my own history, so if I can just give it to you in a 15-second summary.

I had a tandem transplant ten years ago. I had seven years of CR on 5 mg Revlimid and then relapsed, and I’ve been on Velcade and dexamethasone for two and a half years in a PR.

My question — there are two questions. One is having to do with what you were referring to with clonal tides and reuse or re-challenge. Do you have any experience personally about readministering Revlimid at a higher dose after, let’s say, a two and a half year period and getting decent results? I can’t get a straight answer from anybody about this.

Dr. Vij: What we know is that certain people who are on 5 mg or 10 mg Revlimid as maintenance and have slow biochemical progression, we will often increase the dose at 25 mg and often add dexamethasone, and patients do have responses. They’re usually not very long-lived, but the fact is that they do respond. Now, what I’m alluding to is trying to increase the dose of the drug immediately as a lower dose is failing.

Now, what I had talked about in terms of clonal tides is trying to go back to that drug, say, a Velcade-dex fails or you have some other drug, pomalidomide for that matter, and then failing and a lot of people say, “Let’s try Revlimid again,” I’ve not done that. Obviously, as I said, there is now emerging data for certain patients that may be a feasible option, but the issue is that we’re not able to do that clinically for patients. We don’t unfortunately get these tests done in real time for patients to see if they have a clone that is sensitive to the drug.

It may be possible in the future, and not too many people who has it go back to the same drugs because in myeloma fortunately, there are quite a few drugs and you’d rather go to something that you haven’t tried rather than going blindly back to a drug that has failed once. If you had some surety that it was going to work based on some laboratory test, then you’d be more likely to do so.

Caller: Okay, I understand. The second question really has to do again with the time period, having had a tandem ten years ago of the value of another transplant, a rescue transplant at this point, from the point of view of safety and the point of view of efficacy. It’s a planned tandem resulting in —

Dr. Vij: The thing is that certainly people get often three transplants, sometimes a very few, even more in their lifetime. What we generally say is for patients who have had a two-year progression free interval after their first transplant, be it a single transplant or tandem, that it may be reasonable to consider re-transplant at the time of disease progression.

In fact, there was a recent trial published in The Lancet Oncology a few months ago, which was a randomized study where patients who had previously had a transplant progressed or randomized to another transplant on progression or chemotherapy, and there was actually a rival advantage to using transplant.

The trial design has been faulted by some because of the chemotherapy given the control arm, but by and large, I think most people would agree that a transplant at progression is a reasonable option for those who have had a reasonably good progression-free survival after an initial single tandem transplant.

Caller: I see, and you put single and tandem together and consider that one.

Dr. Vij: True.

Caller: Right. I mean, the third was — I understand what you’re saying.

Dr. Vij: Yeah, third transplant —

Caller: And who’s the author of that? If I could ask you one more question, that Lancet Oncology article?

Dr. Vij: I forgot the name of the author, but if you just Google “Lancet Oncology myeloma transplant at progression”, I’m sure you’ll come up with a hit.

Caller: Thank you, sir. I appreciate it very much.

Jenny: Okay. Thank you so much for your question. We have time for one more question and I can’t tell the number, so we will take your call and listen to your headpiece, but you are live with the question.

Caller: Hello?

Jenny: Yes, go ahead. Go ahead.

Caller: My question is a simple question. I’m just wondering how to treat a bone lesion with a renal insufficient patient? What drug do we recommend with people who have bone lesions, but they are renal insufficient patients like with a light chain myeloma?

Dr. Vij: The thing is that again, generally there are patterns or guidelines for dose reduction for patients with renal insufficiency, for the bisphosphonates. Generally, it is not an absolute contraindication to give bisphosphonate adjusted for renal dysfunction. That is the only known, proven class or drug that one can advocate to preserve bone health.

Certainly, denosumab, a drug that is approved for metastatic disease from solid cancers to bone, is something that hasn’t been approved for myeloma. That drug is currently being looked at in myeloma trials, but may offer an option in the future as a very active drug that has no renal toxicity at all. It is an approved drug, but not for myeloma currently.

Caller: Okay. What’s the name of it?

Dr. Vij: Denosumab.

Caller: Okay. So you recommend either do a dose reduction for the —

Dr. Vij: As for packet guidelines — correct.

Caller: So you are saying there might be some drug in the future that will be available with —

Dr. Vij: Renal toxicity, yes. Now, there are two bisphosphonates that’s currently approved. There’s pamidronate and there’s Zometa. Now, sometimes renal toxicity occurs due to the drug and it is important to know that both those drugs have different mechanisms of renal toxicity, so if the renal toxicity is not due to myeloma, but due to the bisphosphonate, then switching from one bisphosphonate to the other may be an option. You’d have to discuss with one’s doctor.

Caller: Okay, so switching bisphosphonate with —

Dr. Vij: If the renal insufficiency is due to the drug itself, then yes, that may be one thing to try. If it is due to the myeloma, then obviously it’s not probably going to matter that much.

Caller: That’s great. So what kind of drug can we switch to?

Dr. Vij: Well, if you are on Zometa, you can go to Aredia. If you’re on Aredia, you can go to Zometa in that case and try. There are two drugs, Aredia and Zometa. Pamidronate and zoledronic acid are the generic names.

Caller: Okay. That’d be great. I’m just here learning, but thank you so much. I appreciate your help.

Jenny: Okay. Thank you so much for your question. Dr. Vij, thank you so much for joining us today. We are just so grateful for your hard work and your brilliant efforts for myeloma patients, and are just so thankful for all you do for us.

Dr. Vij: And we’re thankful for the patients who go on clinical trials. We’re just trying to help patients.

Jenny: Well, you’re doing a great job, so thank you so much, especially for patients that have relapsed, coming up with new approaches.

All right. Thank you for listening to another episode of “Innovation in Myeloma”. Join us for our next Myeloma Crowd Radio interview as we learn more about how we, as patients, can help drive to a cure for myeloma by joining clinical trials.

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About Author

Jenny A

Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio and the CrowdCare Foundation.

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