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    • Myeloma Crowd Radio Episodes
    • Oct 08, 2018

    Full Show: The new GSK Antibody Drug Conjugate in Multiple Myeloma with Dr. Maria Chaudhry, OSU James Cancer Center

Maria Chaudhry, MD
The Ohio State University, The James Cancer Center 
Interview Date: September 13, 2018

Thanks to our episode sponsor, Celgene Corporation.

Summary
A new drug by GlaxoSmithKlein drew attention at last year’s American Society of Hematology (ASH) meeting for multiple myeloma patients. Learn more about this antibody drug conjugate which carries a toxic load directly to myeloma cells using the BCMA target. Dr. Chaudhry shares the outcomes of the first Phase I clinical trial and the opening of the Phase II study. The GSK drug targets the common BCMA protein found on the surface of myeloma cells and in the Phase I study, the drug was used alone with strong results, even for patients who had relapsed after common myeloma therapies like Velcade, Revlimid and daratumumab (Darzalex). A Phase II study is now underway. Learn more about how the drug works and what is involved in participating. 

Learn more about the GSK Clinical Trial

Dr. Maria Chaudhry on Myeloma Crowd Radio

Full Transcript

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 our episode sponsor, Celgene Corporation, for their support of Myeloma Crowd Radio.

Now, in the prior show, we gave you a little update on our new product called HealthTree. Our family has been on a 50-city tour. We have now done 44 out of the 50 cities and most recently, in Santa Fe and Portland. We’re happy to share that we now have over 600 patients participating in HealthTree. Now, because everyone’s myeloma situation is different, and everyone’s story is important, HealthTree is a new online tool that provides key benefits to patients. There are three main benefits. First, it helps you understand your myeloma treatment options that are personally relevant to your situation. Second, if you’re unfamiliar with myeloma clinical trials and those like we’re talking about today, it helps you find clinical trials that apply to your situation at each point in time. We’ve integrated with the SparkCures tool. Third, it will allow us as patients and researches to see patterns of responses, care, and help us find ways to live longer with myeloma.

We’re so excited to have this tool. You’ll be hearing more about it in the future. We’ll be having an intro video come out later that we’re excited to show that to you. It’s very important that as patients we become educated on specific therapies. That’s why I’m excited for this show today because the landscape in myeloma is changing very quickly. We have a lot of new drugs that are coming out into the marketplace and into early, mid and late-stage clinical trials.  The more we know about these studies, the better off we’re going to be in terms of picking studies that we want to join.

I’m excited to have Dr. Maria Chaudhry with us today from the Ohio State University and the James Cancer Center. Welcome, Dr. Chaudhry.

Dr. Chaudhry: Thank you so much, Jenny. Thank you so much for having me here in your show. It’s always a great pleasure to talk about new and exciting therapies in multiple myeloma. I would like to take this opportunity to thank you personally for your wonderful work and the great platform that you have provided for myeloma patients. It’s great work. Thank you.

Jenny: Oh, thank you so much. Well, we’d like to introduce, give you a proper introduction before we get started talking about this GlaxoSmithKline drug.

Maria Chaudhry is Assistant Professor in the Division of Hematology at the Ohio State University Comprehensive Cancer Center. She is new to the James Cancer Center having come most recently from MD Anderson in Houston. She is originally from Pakistan.

Her awards included a Georgetown University Hospital Award as Chief Fellow in the Hematology Oncology Fellowship Program.

She is a review editor, an editorial board member for blood cancers publication called Frontiers of Oncology. She’s a member of ASH, ASCO and the American College of Physicians. She serves on several committees at Ohio State University including the clinical scientific review committee.

Dr. Chaudhry has been actively working on clinical trials including new proteasome inhibitors like carfilzomib, myeloma genetics and new antibodies like the one we will be discussing today.

Again, thank you so much for taking time out of your busy schedule. I don’t know how you, as researchers, do it because you’re seeing patients, and you’re performing research, and speaking at conferences. It’s just a lot. We’re just really appreciative for all of your dedication around myeloma.

Dr. Chaudhry: Thank you so much. It’s an honor to work in this field and help patients.   

Jenny: Well, we are happy that you do. We’re talking about a specific drug today. This GlaxoSmithKline drug caught my attention and a lot of people’s attention at the most recent ASH last December. Later this year, the FDA granted them this breakthrough therapy designation. The drug name is called – it doesn’t even have a name yet – it’s a number – GSK2857916.

Maybe you just want to give us a broad overview about what this drug is and what it does. Then we’ll go into other questions after that.

Dr. Chaudhry:  This medication, this drug, is what we call an antibody drug conjugate. There is a difference between an antibody-drug conjugate, a monoclonal antibody and what we call a BiTE antibody. The difference is that this drug, GSK drug, is an antibody drug conjugate. It has a monoclonal antibody part with a payload attached to it, which means that the antibody part of the drug targets a specific protein, a specific receptor on the surface of cancer cells and delivers the drug or a toxin attached to the antibody close to the cancer cells.

In case of this drug that we are going to talk about today, the GSK monoclonal antibody drug conjugate, the antibody targets BCMA or B-cell maturation antigen, which is universally expressed on all plasma cells. The toxin attached to it is called MMAF. When this antibody is delivered to the patient, the CD38 part attaches itself to the plasma cells and it is internalized. The toxin then kills the plasma cells. It also stimulates the immune system because of the monoclonal antibody part.

It is different from a monoclonal antibody like daratumumab and elotuzomab. These are the two drugs, which are already approved from multiple myeloma patients in relapsed refractory setting, although daratumumab is recently approved in front-line setting. A monoclonal antibody actually targets protein or receptor on the surface of, again, the tumor cells. When it attaches itself to the tumor cells, it stimulates an immune reaction and kills the tumor cells or the cancer cells quite direct immunogenicity as wells as by activating different parts of the immune system. That’s a monoclonal antibody.

The BiTE, which stands for Bi-specific T-cell engager, it’s the antibody that attaches two cells and brings these two cells together. For example, in multiple myeloma, the BiTE antibody that is in clinical trials targets two proteins, BCMA as well as CD3. BCMA is present on the surface of plasma cells. CD3 is present on the surface of T-cells. When this monoclonal antibody is delivered to the patient, it attaches itself to the tumor cells and brings the T-cells close to the tumor cells and causes the toxicity and the cell death. That’s the difference between all these three molecules.

Jenny: Just a review, I know as a patient, it’s easy to get confused because immunotherapy means this whole realm of products. We were familiar with these monoclonal antibodies and what you’re saying is the monoclonal antibodies are going after this certain protein like CD38, like daratumumab does on the surface of the cells. Your immune system is actually what kills the myeloma cells. In the BiTE technology that we’re not talking about today, you’re joining that same protein target with another target that joins those things together and they kill each other, basically.

But this one that you’re talking about today, it’s like a dump truck. It targets that protein, that BCMA – you’ll go into this later, I hope – why BCMA? Why that target? And basically, dumps this toxin on top of it.            

It’s hard for us to keep it all straight, but we appreciate you breaking it down into different categories because sometimes people talk about immunotherapy and it covers multiple topics, so that was a nice description that you gave.

Dr. Chaudhry:  Yes, immunotherapy when we see it as a general term, it just means that any molecule, any drug, that just recruits or stimulates the immune system against a specific disease. But it can be broken down into different parts and different molecules and different mechanism of action. It’s all very, very interesting. Complicated, but very, very interesting.

Jenny: Very much so. Now, earlier in the year or a few months ago, the FDA gave them this GlaxoSmithKline drug or GSK drug this breakthrough designation. Can you explain for patients what that means and why that’s important or not important?

Dr. Chaudhry: It’s very important actually. This FDA breakthrough designation is given to a drug that treats a serious or a life-threatening condition, or is being studied to treat a serious or life-threatening condition, in which there is an unmet need. It is important to note that when this designation is given, there is already early clinical evidence which notes that the drug may demonstrate substantial improvement in terms of controlling the disease, or improving the quality of life, or other benefits over what is already available or FDA approved.

The purpose of giving this designation is to facilitate or expedite the development, as well as the review of the drugs, and eventually, approval of these medications. Sponsors or the drug companies request this from the FDA. The drug companies usually have early phase trial data, Phase I or Phase II data. Based on which if the FDA approves, gives this designation status. For example, in daratumumab, this FDA breakthrough designation status was given in 2013 based on Phase I clinical data. The drug was approved as a single agent in 2015 based on excellent clinical data that was available. The essential purpose is to facilitate and speed up the process and bring the drug, if it is active, to become available for the patients as soon as possible.

Jenny: How long typically from the time they get early this breakthrough designation to approval? I mean, does it depend on the drug and the clinical trials that have already been in place? Or is there a standard timetable once they get the breakthrough designation? I’m just curious about that.

Dr. Chaudhry: There is no standard timetable. If you look at all the cancer drugs that have been given the FDA breakthrough designation, the most effective drugs had good data earlier on. They were approved within a couple of years from getting this designation. There were some drugs that had good, effective early phase clinical data but didn’t pan out later. It’s important to note that when this designation status is given, it means that the drug may have potential, but still clinical efficacy and benefits still have to be proven.

Jenny: Interesting. I saw that it was being used in relapsed and refractory myeloma, or myeloma that’s no longer responding to a lot of different drugs that are approved, and some lymphoma. In leukemia, (in CAR T therapy) where they are going after different targets that leukemia has that myeloma doesn’t have like CD19, sometimes you can’t just move it over and use it in myeloma because myeloma doesn’t really have CD19. Does lymphoma also have BCMA as a target? I was just curious about that.

Dr. Chaudhry: This protein or a receptor, which is called B-cell maturation antigen, is universally expressed on all plasma cells, but also in mature B-cells, which are actually destined to become the plasma cells. The early phase clinical trial or phase one clinical trial essentially included all the hematological malignancies that have some degree of BCMA expression. They did include the lymphoma as well. I have not seen the results from the lymphoma cohort of the patients yet. I don’t know how active it is in lymphoma, but essentially that’s the purpose of the early phase clinical trial. It’s to study the drug and see if we can find the activity there.

Jenny: Okay. Can you explain the evolution of myeloma? Because I know they start with these early B-cells. So plasma cells are the really mature cells, correct?

Dr. Chaudhry: Yes.

Jenny: Okay. Can you explain the evolution of how a cell evolves to be a plasma cell and then where does this B-cell maturation antigen come into play? I don’t think I fully understand that. 

Dr. Chaudhry: B-cells are small white cells. They are the part of our immune system and the blood system. During the development, B-cells are exposed to the antigens and become differentiate further. A portion of these cells, a few of those mature B-cells become plasma cells. Plasma cells are the antibody producing cells, immunoglobulin-producing cells. That’s what we see in multiple myeloma. B-cells, IgG, all these different types of immunoglobulins, they are the part of our immune system. B-cell maturation antigen is expressed on the surface of B-cells that are destined to become plasma cells as well as universally on all the plasma cells. It’s a protein receptor on the surface of the cells. The function of this is when it binds to its specific molecules, then it gives a growth signals to the cells. It is important for the long-lived plasma cells. Bottom line, it is needed for the growth as well as maturation of plasma cells as well as for their long life.

It binds to few molecules. One of those is APRIL molecule. I will talk about it later. They are drugs that are targeting those molecules as well and give the downstream signals. One of the great targets is now multiple myeloma.

Jenny: Yes, it seems like it. What other drugs are targeting BCMA? I know a lot of the CAR-T cell studies right now are targeting BCMA. Why is BCMA such an attractive target? Then I have a question about the levels of expression of BCMA because I know some patients in the early days in the CAR-T trials, they would go and get tested. Some of the CAR-T trials were only accepting them if they have a certain level of BCMA. I’m curious. When all these drugs come out and they have this BCMA target, does the level of BCMA really matter?  

Dr. Chaudhry: Great question. Whenever we target a protein on the surface of cells in any tumor, it’s great if that specific target is present on the cancer cells only. Essentially, this is because we want to decrease the toxicity and off-targets effect so that the patient can get that specific drug, a specific molecule for a longer period of time and can get the benefit. BCMA is expressed, as I said, universally on the plasma cells. That’s why it’s a great target in multiple myeloma. It has been targeted by different types of molecules. You already mentioned CAR-T cells. CAR-T cells directed against BCMA are coming. There was a great data that was published at ASH that showed it was a very effective therapy. We need long-term data as well as Phase II and later line clinical trials to essentially know the future of CAR-T cell therapy, but it looks great.

Other than the CAR-T cells, we’re going to talk about a little bit more about the early phase or phase one trial data of this antibody-drug conjugate from GSK. This drug conjugate is the most developed molecule so far in terms of BCMA targeting molecules. Then there are Bi-specific T-cell engagers as well, which are called BiTE antibodies. They are again in early phase clinical trials. There is a molecule that targets BCMA on the surface of plasma cells as well as CD3, which is expressed on the surface of T-cells, which are the immune killer cells, brings them together for increased toxicity and increased cell death and increased activity. These were the Bi-specific T-cell engager. 

Jenny: Why is this one considered more developed? Is it just further along in clinical trials?

Dr. Chaudhry: It’s just further along in the clinical trials. Yes.

Jenny: Okay. Wonderful. Let’s talk about the early results, if you can, because the early results came out I think last December. Maybe they came out before that, but that’s when I heard about it. Maybe you can describe what those results were and why everyone is so excited about it?

Dr. Chaudhry:  Yes. You’re right. We discussed this trial at our ASH meeting last year, again, at ASCO in June this year in 2018. This is an early phase clinical trial, Phase I trial. I would mention that the purpose of the Phase I trial is that we have already seen preclinical activity or means that drug is active in cell lines or animal models. Now we want to study that in human beings. Essentially, the patients that are enrolled or eligible for the Phase I clinical trials are the patients who have relapsed and refractory multiple myeloma, which means that the patients are progressing on the current line of therapy or they are progressing shortly after finishing the last treatment. This is a Phase I clinical trial in which the purpose is to see if the drug is safe in a cohort of patients.

One of the endpoints of the study or one of the goals of the study is again, to look at the responses as well, but the primary is always to look at the safety profile of the drug, to look at the toxicities or side effects that patients will get. This was a phase one trial and sponsored study in which this medication was given intravenously every three weeks. It was a one-hour infusion looking at the patient population in this clinical trial.

Patients had received multiple lines of therapy. Before, more than half of the patients, about 60% of patients have received five lines of therapy. About 40% of patients had received daratumumab. Their myeloma had progressed on that.

Jenny: Forty percent, you said?

Dr. Chaudhry: Forty percent had received daratumumab. Most of the patients have also received immunomodulating drugs, which are Revlimid or pomalidomide as well as proteasome inhibitors, which are, bortezomib (Velcade) and carfilzomib (Kyprolis). This was the patient population, which was very relapsed and refractory.

Looking at the results of this trial with this medication, the response rates were impressive. Overall response rate was about 60%, which is great in this population.

Jenny: Yes, that’s great.

Dr. Chaudhry: Half of these patients had very good partial response, which means that they had more than 90% reduction of their myeloma proteins or better. That was great as well. Forty percent of patients who have progressed on data before have responded in this trial. Progression-free survival, which means the amount of disease control that we caught, was about 7.5 months.

Then there is another endpoint that we looked at. It was duration of response, which means when the patients were on the drug, for how long did they get the clinical benefit? At the time, the study was presented, which was about six to seven months of follow-up, a duration of response was not reached, which means that the patients who were responding we’re doing well and continue to have clinical benefit. 

Jenny: Right. They hadn’t relapsed yet. That’s great.  

Dr. Chaudhry: They have not relapsed yet. They were still on the drug.

Jenny: How long was that study?

Dr. Chaudhry: The study is still ongoing. They will keep updating us with the results, but when the results were presented, median follow-up was about 6-7 months.

Jenny: That’s great. Well, that’s terrific. That’s very exciting as a new option for patients who are relapsing through the myeloma therapies and especially through daratumumab. I know patients can get really frustrated when they relapse through that.

Dr. Chaudhry: That is true. As you know, myeloma is an incurable disease. Most of the patients, at some point, relapse. Once patients have exhausted or received proteasome inhibitors, immunomodulating agents and daratumumab, their prognoses tend to be dismal. We need better therapies with different mechanism of action. That’s why such good response, even a new drug with a different mechanism of action is very important.

Jenny: I think what makes those results so impressive is that it happened as a standalone drug. You weren’t getting that in a clinical trial. You weren’t using any other drugs with it. You were just using it by itself.

Dr. Chaudhry: As a single agent. You’re right.

Jenny: Yeah. That’s amazing. The trial that you currently have open and you have it open at the James, correct?

Dr. Chaudhry: Yes. 

Jenny: How many centers have this open? Then can you explain more about the trial that you currently have open using this drug right now and all the added details behind the current study? Because that was the Phase I study, right?

Dr. Chaudhry: Yes. That was the Phase I study. Now, this drug is moving towards the Phase II part. This study is actually going to be a multi-national study. It is open at multiple institutes within America, as well as some international areas like in Europe as well. The Phase II study is open for patients who have, of course, multiple myeloma, but relapsed and refractory disease, which means that the patients who will be eligible for this trial will be the ones who have failed at least three prior lines of anti-myeloma regiments. Which should include anti-CD38 antibody, which will be daratumumab or any other drug in the clinical trials that target CD38 alone or in combination. The patients who are refractory or who have progressed on an immunomodulatory drug, which will be pomalidomide or lenalidomide as well as refractory to a produce on inhibitor which will be Velcade, ixazomib or carfilzomib. Essentially, the patients who have progressed on at least three prior lines of anti-myeloma therapy and patients who have good performance status. Because it’s an early phase clinical trial so patients who are able to get out of the bed and take care of themselves. Good activity status is important as well. These are the patients who are eligible for this trial.

Then another thing that I will mention, that in the Phase I study, there was a reporting of side effects, ocular toxicity or eye side effects. A percentage of patients did get blurry eyes, dry visions and increased sensitivity to light. That was one of the most common side effects that was observed in Phase I clinical trial.

In the Phase II clinical trial, when we will be treating the patients, we will have our eye department or ophthalmology department work with us. Patients will be getting eyedrops as well as eye exams whey they come in for the infusions. This is a very important trial. It’s a good trial for the patients who have progressed on daratumumab because this is a patient population who do not have many treatment options available. The prognosis tends to be dismal. Different drugs with different mechanism of actions are needed.

As I said, this trial is open at multiple centers. It’s very easy to find the centers by going to clinicaltrials.gov. At Ohio State, we have just recently opened this trial as well.

Jenny: How many sites are available in the United States? You said multi-national. I’m assuming there will be a lot of different sites open, but do you know how many?

Dr. Chaudhry: I think it’s already open in about four to five. I do know that it’s open in New York. It’s open in Atlanta and Indiana I think. Other places on top of my head, I cannot think, but I think that it’s in a process of opening at a few other cancer centers as well.

Jenny: That’s okay. We suggest that patients, instead of clinicaltrials.gov, they use a tool called SparkCures because it’s much easier to navigate. I know that study is in there. It will show all of the treatment sites or clinical study sites, but the James is obviously one that it’s available at.

I think people need to consider traveling for these types of studies and can travel — so what are the travel requirements? How is it administered? As an infusion, every three weeks? How long are you on those? How long do you get the infusions for?

Dr. Chaudhry: Great question. The infusion is every three weeks. The infusion lasts for about an hour, but after the patient finishes the infusion, the patient will be just observed for 2-3 hours more, then we let the patient go.

The requirement is that when the patient is eligible for the study and the patient agrees to get enrolled for the studies, they will have some screening studies that we can consolidate and do together in few days. After that, they will be travel every three weeks. Another part of the study is the eye exam because of the ocular toxicity or eye side effects the patients had with the Phase I clinical trial. In the Phase II part of the study, the sponsor prefers that patients get the eye exams as well. The patients will be scheduled in the eye clinic the same day they’re coming for the infusion for the eye exam. In general, the infusion is every three weeks. It’s not that frequent.                        

Jenny: Then how many months do you provide treatment on the study?

Dr. Chaudhry: Essentially, the treatment continues as long as patient tolerates, which means that patient is not getting any toxicity that will prevent us from treating the patient or when the previous patient progresses.

Jenny: Okay. That makes sense. I know there are these long waiting list for these CAR-T studies, but in my mind, studies like this may be a great option for patients because it had such a powerful effect. It may be a great option for patients. I don’t know. I would seriously consider that if I were in that situation. 

Dr. Chaudhry: I agree with you. It’s a Phase II study. When the spots are available, patients can just be enrolled, which is a bit different from Phase I in which we enroll a certain number of patients and then wait. Follow them. Make sure that they don’t have any side effects that prevent us from continuing further. It goes by cohort by cohort. But in a Phase II study, the spots are open and the patients, if they’re eligible and if they agree, they can be enrolled right away.

You’re right. CAR-T cells are a little bit different because patients have to be seen and then cells have to be prepared and then infused.

Jenny: Right. This is off-the-shelf approach.

Dr. Chaudhry: This is, more like that, yes. 

Jenny: I know in this phase two study, you’re looking at patients that have had these prior lines of therapy and they’ve relapsed after getting like Revlimid, or Pomalyst, or Velcade, or carfilzomib, and daratumumab and those types of drugs. It doesn’t make sense when you’re testing it in the phase two study to combine it with anything else, but is there any indication if you could use it earlier before patients have relapsed on those other types of drugs? What it might pair with well, I guess? If you were to use it in combination, what other types of combinations could it be considered in?

Dr. Chaudhry: That’s a great question. Actually, we have already started thinking about that. The sponsor has already started the work to combine this drug with other anti-myeloma therapies. When the patients with myeloma relapse or when they progress, the disease tends to become very diverse, very genetically unstable and hard to control. Using the combination of drugs targets the disease from different mechanism of actions and from different angles. We have seen in the past that it controls the disease better. It’s a great idea to combine an effective drug with the other myeloma medications that are already approved. Combinations have to be rational and safe at the same time. This medication can be combined with proteasome inhibitors like Velcade. It makes sense because of the mechanism of action as well as it should be studied with lenalidomide and dexamethasone as well.

Actually, there is a trial that the sponsor is going to bring forward. It’s going to be a Phase I trial, but the medication, this GSK medication or BCMA antibody-drug conjugate will be combined lenalidomide and dexamethasone or with Velcade and dexamethasone. I think it’s a great idea to combine this drug with daratumumab, which is an anti-CD38 monoclonal antibody to target both the BCMA antigen with this drug as well as CD38 receptor with daratumumab.

Jenny: Oh, that makes sense; going after two different protein targets instead of just one. 

Dr. Chaudhry: Yes. Then there will be another trial that will combine this anti-BCMA antibody with the PD-1 inhibitor. As we already know, the T-cell exhaustion or immune cell exhaustion happens in cancers especially multiple myeloma when patient’s immunity weakens and they cannot build an immune response against the cancer cells. PD-1 inhibitors actually release the brakes on these T-cells. They can target and recognize the cancer cells. It makes sense to combine the monoclonal antibodies with the PD-1 inhibitors as well.

Jenny: Well, you have a lot of experience with PD-1 and PD-L1 inhibitors at the James so that would be a great study for you all to run. I’m sure.

Dr. Chaudhry: That would be great as well. There are different things that we are looking at combining these medications with other anti-myeloma therapies. This is all very promising. I think this drug will transform the treatment paradigm for multiple myeloma patients. I hope it will, and hopefully will improve the disease-free survival for our patients as well. 

Jenny: Oh, I know there’s so many things like this coming out that are so exciting. I think there’s a lot of hope for myeloma patients. I just have a few follow-up questions for the Phase I study. I know they’re looking at safety when they’re testing in Phase I. You’re also looking for some indication of how well it works. They can have these great results come out. Do they ever go back and look at the genetics? Like for patients who had the better responses, what sort of myeloma genetics have they had so they can see if it’s better for a specific type of patient? I know by the time patients have relapsed multiple lines of therapy like that, the genetics of their disease are pretty complicated. They might have more mutations than they had before or different combinations of mutations, but was there any insight there about the genetics of myeloma that you know?

Dr. Chaudhry: That’s a great question. With the Phase I study, nothing has panned out. But with the Phase II study, we will be collecting the patient samples to look for genetic mutations and correlate those with the responses. Because it will be great to know which patients respond better than others. It would be great to know. But we don’t have any information from the Phase I study yet. I would also add, I think you asked me about BCMA expression as well.     

Jenny: Yes.

Dr. Chaudhry: In the Phase I study, the patients were enrolled irrespective of their B-cell maturation antigen expression on their tumor cells because we have seen activity in patients or in tumors that have low BCMA expression. Because the binding of this antibody-drug conjugate with the myeloma cells are very strong. Even if there is low expression, it still works. For the Phase II study, there is no cutoff or limit for BCMA expression. 

Jenny: What does that mean anyway, the BCMA expression level? I guess, I don’t understand the relevance because it seemed to be this big deal when the CAR-T stuff was first introduced maybe a year and a half, or two years ago. Now, it seems to be like, “Well, it’s going to work regardless of the level of expression.” Can you help answer that question? What does that mean, the level of expression anyway? Is it important at all? It doesn’t sound like it is.

Dr. Chaudhry: Level of expression means using a specific testing, staining on the cancer cells. We look at the samples and see how bright the expression is. The pathologist and oncologists give it a number like there is 10% expression or 50% expression, which means that this is the percentage of cells that express that particular antigen. Most probably are this is how bright the staining was for this specific antigen or for this specific protein on the cancer cells? Because the thought always is that if there is a weak expression, if there is weak staining, is the drug going to work or not? 

Jenny: Right. 

Dr. Chaudhry: Because if the staining is weak, then do you need more high doses of the drug versus low doses of drug or it’s not going to work at all. That’s what the concept is. When the drug was started at the baseline, sponsor, as well as the investigators, were looking at the BCMA expression and seeing if they can correlate this with the responses but didn’t pan out that way. Does it make sense? 

Jenny: Yes, it does, completely. Because if there’s a lot, will it work? Or if there’s little, is there anything for it to go after anyway? They tested in the Phase I and Phase II also the study you’re currently running, they measure everybody’s BCMA levels. Was there any indication in the outcome data on the Phase I if they measured the BCMA levels? Like, “Oh, patients with really heavy BCMA expressions seemed to respond better.  They had more durable responses.” Or was there any relationship there that they saw or is there any relationship that you’re seeing in the Phase II?

Dr. Chaudhry: For the Phase I study, when they presented, they have not reported in terms of the BCMA expression the results that I remember, but they did mention that the degree of response had no association with a BCMA expression. Again, the reason being the antibody binds with the receptors tightly, irrespective of the degree of expression. The drug still works.

Jenny: You talked about this at the very beginning that it delivers this toxic payload of MMAF. Do you want to explain what that is? I don’t know. I’ve always heard about MAF in myeloma. It’s not related, right? You talked about the MAF translocations in myeloma. That’s not related to this type of toxin? It just happens to have a similar name?

Dr. Chaudhry: No. It is not related to that. This toxin itself cannot penetrate the cancer cell, cannot penetrate the myeloma cell. The mechanism of action is that it’s an anti-tubulin agent, which means that it inhibits the cell division and cell synthesis.  This antibody delivers that toxin and then it’s internalized. It’s taken up because it binds to BCMA. It is taken up inside the cells and that’s how the toxin gets inside the cell.

Jenny: Well, that’s nice because it’s specific delivery. That’s what we want with myeloma.

Dr. Chaudhry: Specific delivery into the cell, yes. It’s a very, very smart concept.

Jenny: Well, we love it. We’re looking forward to it. It sounds like a really fabulous study and one that patients should really consider joining. Is there anything else that you want to share about this study in particular in terms of how patients get into the study or anything else patients would need to know about joining the study?

Dr. Chaudhry: I think if the patient is coming from a long distance or if they have to travel in order to get to the cancer center who has the study, then it’s important for them to know if they will be eligible based on what they have received before and other factors. I think SparkCures, as you already mentioned, is a good resource for that.

We have this trial here at the James Cancer Center. I’m happy if anyone wants to contact me directly.  I can give my email.  My email is my first name maria.chaudhry@osumc.edu. Patients can approach me as well and then go from there.

It’s very important to enroll in the clinical trials. I always encourage- at any stage in their disease – I always encourage patients to enroll in the clinical trials. This way, we can get better drugs approved, but also the patients can get drugs on the clinical trial that will be later approved and will be available in the community. They can get drugs earlier while they are on the trial. I always encourage that.

Jenny: Well, we’re huge advocates for that. That’s actually why we started this radio program because I think 3 to 5% of myeloma patients join clinical trials. Now, we have these great drugs like daratumumab and these CAR-T cells drugs and this GSK drug coming through clinical trials. The faster that you can have patients participate, the faster we can come to conclusions about what’s going to be potentially curative for us.

I agree that at every stage, if you are newly diagnosed or in your first relapse or multiple relapses, there’s really a lot of different studies that you can consider. SparkCures does have a concierge service where you can call a phone number also if you want to join a clinical trial.

But you’re very generous to give out your email. We will include it in the transcript so people can email you directly about it. That would be fantastic. Are there any other studies at the James that you want to talk about? I do want to also leave some time for some caller questions if people have questions.

Dr. Chaudhry: I can quickly mention two trials since we are talking about multiple relapse and refractory patients. There are two trials, which include two monoclonal antibodies. One of these trials has this monoclonal antibody. Again, it’s a Phase I trial. I will mention that. It’s an APRIL antibody. APRIL is a molecule which binds with the BCMA. BCMA is a receptor on the surface of plasma cell. APRIL binds with the BCMA and increases the signaling through that BCMA protein. This antibody targets the APRIL. Again, this is the Phase I clinical trial. We are enrolling here at the James in that trial.

The second trial includes, again, a monoclonal antibody. It’s a very smart molecule. It’s a antibody-drug conjugate. The antibody part targets CD38 on the surface of myeloma cells. It’s an anti-CD38 monoclonal antibody with a cytokine molecule attached to it, which is a toxic molecule. It’s an interferon alpha. This antibody delivers interferon alpha close to the myeloma cells by attaching itself to the myeloma. Both of these studies are phase one clinical trials for the patients who have relapsed on three or more lines of therapy.

Jenny: Okay. Whose drug is that? I’m just curious.

Dr. Chaudhry: One drug – the antibody-drug conjugate is from Takeda. The other drug, the APRIL antibody is from a pharmaceutical company called Bion.

Jenny: Okay. Those are both Phase I studies?

Dr. Chaudhry: Yes, both Phase I studies.

Jenny: Well, it will be so interesting to see what happens because hypothetically, you could take two of these like this Takeda drug plus the GSK drug. They’re both these antibody-drug conjugates that are delivering these toxic payloads, but to different targets. Of course, that’s in the future, but it’s so fascinating.

Dr. Chaudhry: Or target the BCMA with a BCMA antibody as well as APRIL, which is the molecule that binds to the BCMA with an April antibody so two monoclonal antibodies. I think these are great concepts that bring hope for the patients as well as for the clinician.

Jenny: It’s really incredible to see the progress. It’s so exciting to watch this constant stream of new drugs be developed for multiple myeloma. It’s not a club that any of us want to be in, but it is hopeful. It’s exciting, but there’s so much happening in myeloma. That is wonderful. We will have patients, if they’re interested in these other two also, also email you for more information if they would like. With that, we’d like to open it up for caller questions.

If you have a question for Dr. Chaudhry you can call 347-637-2631 and press the number 1 on your keypad. Please go ahead with your question.

Caller: Hi, good morning, Dr. Chaudhry. How are you today? Thanks so much for taking the time. I appreciate it. 

Dr. Chaudhry: Thank you so much. I’m good.

Caller: Yes. I have a question concerning the BCMA expression. I understand that you do test for it. It is reported, I guess, as being brightly expressed. Then they give you a percentage. That’s really testing the actual cells from the bone marrow biopsy. Is that correct?

Dr. Chaudhry: That is true.

Caller: Okay. Is there any circulating BCMA within the serum (blood) that they test also?

Dr. Chaudhry:  Yes. You are right about that. There is an enzyme that can break off that protein from the surface of plasma cells. There is circulating BCMA in the peripheral blood as well. Researchers have shown in past that high circulating BCMA is associated with poor prognosis in multiple myeloma. In the trial, we did draw a lot of research blood and do a lot of testing and look at the serum as well as the bone marrow BCMA expression. The expression, to my knowledge, has not panned out to be associated with the degree of response as of now.

Caller: Okay. I see. What about circulating plasma cells? The cells that actually managed to, I guess, become so aggressive that they leave the bone marrow microenvironment. I guess that’s how myeloma actually ends up metastasizing to other sites. How did a drug like this target those or does it?

Dr. Chaudhry: That’s a very good question. Plasma cells, when they break away, they lose a protein from their surface and then break away from the bone marrow microenvironment and come into the blood. When they exceed a certain percentage or certain number, it becomes a plasma cell leukemia. That’s a patient who has a lot of plasma cells in the blood. So far, as the drug is experimental, these patients are not included in the trial.

Caller: Okay. I see. I understand. Is this the type of drug, which you need to continue to use to keep myeloma under control? Does it have a half-life or do you take it for a certain number of cycles and then you could stop it?

Dr. Chaudhry: Unfortunately, as we consider myeloma incurable and the patients on the trial have relapsed multiple times and are refractory to multiple therapy, these patients stay on the drug as long as they can depending on their tolerance as well as depending on the response. I will tell you that because of the eye toxicity, some patients had to have those delays. In the patients who had those delays, the response continued. If the dose was delayed, they didn’t lose the benefit.

Caller: Because of the ocular toxicities, the drug needed to be discontinued. Those side effects actually resolved, but it didn’t seem to have any effect on the efficacy of the previous? Oh, that’s very interesting.

Dr. Chaudhry: But then in most of the patients, they were able to restart the drug.

Caller: Did the side effects then come back or was it just a transient, which was corrected and then they were fine?

Dr. Chaudhry: The side effects were managed in different ways. Whenever the side effect goes above a certain level, we grade the side effects. Whenever it goes above a certain level, then the drug has to be – because it’s an experimental drug — the drug has to be stopped. The side effect has to be improved up to a certain level. Then the drug is restarted. The side effects were managed with steroid eye drops.

In the Phase II part, we are using the eye drops prophylactically, which means the patients will get the eye drops before they start the treatment.

Caller: That’s a wonderful approach. Are the cells responsible for myeloma relapse being targeted by this type of drug? Do those cells always express BCMA even perhaps at a lower level? Do we even know which cell is responsible for relapse at this point?

Dr. Chaudhry: It’s a very interesting question. Whenever myeloma relapses, it’s very diverse and very genetically unstable. Again, the relapse is because of the plasma cell, essentially.

As a part of the screening studies, patients always get the bone marrow biopsy. Then we look at the BCMA expression in the bone marrow as well. BCMA is universally expressed in all plasma cells including cancerous plasma cells and other plasma cells as well.           

Caller: Healthy plasma cells as well.

Dr. Chaudhry: Yes. 

Caller: Oh, I see. This targets the healthy plasma cells as well. Would that then present another line of side effects, so to speak? Because if you don’t have a healthy plasma cells and you don’t develop the antibodies to protect you from infection, would a patient then require, let’s say, IVIG treatment?

Dr. Chaudhry: That’s a great question. To patients, we do IVIG treatment in patients who get recurrent infections. But the plasma cells, if a drug targets the healthy plasma cells, plasma cells can be replaced. Mature B-cells can replace those plasma cells and still produce immunoglobulins.

Caller: Oh, they can. Okay. Do you actually see this drug moving into earlier disease trials? Obviously, if it’s effective for the relapsed and refractory, would you see it eventually? If yes, how soon could we see it, maybe even in newly diagnosed myeloma patients?

Dr. Chaudhry: I think this drug has great potential, but we have to do the Phase II trial as a single agent and then combine it in relapsed refractory patients before we move it to the front line. I do see a future for this drug looking at the data that we have so far.

Caller: Very good. Dr. Chaudhry, thank you so very much for your time. Jenny, thanks so much for permitting me to ask all these questions. I appreciate it very much. Have a great day, guys.     

Jenny: Great questions. Thanks. Okay, we have a caller, go ahead with your question.

Caller: Thank you guys very much, Jenny, again, for all your work. This is Eric Hansen. I had a question on this BCMA target. There’s been some research, I understand, that myeloma cells have the ability to either withdraw the BCMA target from the surface back into the cell so it isn’t expressed or that it can actually shed this BCMA target from the surface so that it can evade these drugs that are targeting BCMA. Could you talk about that a little bit? 

Dr. Chaudhry: That’s a very interesting question. The mechanism of resistance to this drug is still an area of ongoing research. We still don’t know when the patients stopped responding, why do they stop responding?

I think some early research has shown that the patients, even after they become a refractory to these drugs, still have BCMA expression, which is a little bit different than other antigens like CD19 and lymphoma. The plasma cells still express BCMA but they develop other mechanisms to bypass that pathway and become resistant to the drug. But this still remains an area of ongoing research that why this happens. There is more information in terms of patients who have become refractory to BCMA CAR-T cell, but still remain an area of ongoing research. 

Caller: Okay. Thank you.

Jenny: Okay. Thanks Eric. That’s a great question. Dr. Chaudhry, thank you so much for joining us today. We are just thrilled to learn more about this drug. It sounds like a very interesting clinical trial that patients may want to consider especially those who are relapsing on multiple lines of therapy. We really appreciate you taking the time to talk to us about it in great detail. It’s just so nice being able to hear from you.

Dr. Chaudhry: Thank you so much. It was a pleasure, Jenny. Thank you.

Jenny: Well, we really, really appreciate your time and your focus on multiple myeloma and your care for all your patients. We thank you.   

Dr. Chaudhry: Thank you. Okay. Bye.

Jenny: We thank our listeners for listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest myeloma research and what it means for you.

 

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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