A Promising Future for Treating Multiple Myeloma with Bispecific Antibodies

What Patients and Caregivers Need to Know About Immunotherapy, Bispecific Antibodies, and CAR T-cell Therapy

Speakers

  • Donna Catamero, ANP-BC, OCN, CCRC (The Mount Sinai Health System, IMF Nurse Leadership)
  • Tom Martin, MD (University of California San Francisco)


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What to Expect 

To ensure patients and care partners better understand the promising future in bispecific therapies, please tune in to this Live Webinar to hear from myeloma experts as they cover key questions, concerns, and highlights.

Through this virtual seminar, you will learn more and gain a better understanding of the following:

  • What is Immunotherapy?
  • What are monoclonal antibodies?
  • What is CAR T-cell therapy?
  • What are Bispecific Antibodies and how do they work? o Are there different types of Bi-specifics?
    • How are bi-specific therapies administered?
    • What are the advantages of bi-specific therapies? o What are the side effects of bi-specifics and how are side effects managed?
  • Can they be administered in combination?
  • Where in the treatment paradigm will they be used?

The Living Well with Myeloma Webinar concludes with a summary discussion and a Live Audience Q&A.

If you missed the webinar, watch a replay now with participants' questions at the end. Click the play button on the image at the top of his page to watch now!


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Video Transcript
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- [Robin] Good afternoon or good evening. Welcome everyone. And thank you for joining us for the International Myeloma Foundation's Living Well webinar, a promising future for treating multiple myeloma with bispecific antibodies. I'm Robin Tuohy, vice president support groups. Before we get started on behalf of the IMF, I'd like to thank our sponsors for supporting this educational program and they are Bristol Myers Squibb, Janssen, and Takeda Oncology.

A quick couple of housekeeping slides here for you, so you can participate during the open Q&A, which will happen at the end of the presentation. Here are some instructions on using the chat box and we'll get to as many of those as we can. It's also very important for us to hear from you. And at the end of the survey, at the, I'm sorry, at the end of the webinar, you'll have the opportunity to provide us with your feedback. Please take a moment to do so as it really helps us to know your needs so we can continuously improve upon our programs for you.

So what can you expect to learn on this webinar? Well, look at this great list. We've got a comprehensive, but understandable presentation for tonight for all of you patients and care partners. So let's get started.

It's now my pleasure to introduce our speakers. We have Donna Catamero with us tonight. She started her career in clinical research before returning to school to get her nursing degree. In 2010, she got her nurse practitioner degree and has been working as an NP at Mount Sinai Medical Center with myeloma patients. She currently oversees the research nurses program where she's in charge of opening clinical trials that expand to underserved populations. And we're very proud that Donna is also serving on the IMF's Nurse Leadership Board. So thank you and welcome to you, Donna.

And we also are grateful to have joining us this evening, Dr. Thomas Martin, director of the Hematology Malignancies Research Committee and co-director of the Myeloma Program at UCSF Helen Diller Family Comprehensive Cancer Center. His research focuses on investigating novel therapies for myeloma, including early phase trials of new drugs, novel combinations, and therapeutics to use with transplant. He has a special interest in antibody therapy for myeloma as well as novel immunotherapies for myeloma, so obviously a perfect speaker for tonight's webinar. And we thank Dr. Martin also for his commitment to the IMF's International Myeloma Working Group, leading the Immunotherapy Working Committee with many of our other IMWG members.

So that's it for me. Let's get this started. And Dr. Martin, would you please begin?

- Yes. Thank you very much for that nice introduction. And it's really nice to have everybody here tonight, and I'm so happy to be working with Donna, who we see each other in a variety of meetings and see a lot of patients with this. So hopefully we will teach you a little bit about what's going on in the myeloma space and this is going to be targeted for immunotherapy. And at the end we're gonna have some time for questions and hopefully people will have many questions for us.

So I'll start off by saying over time, as you see on this survival chart, we've done better and better, but we still have work to do. Essentially the improvements that we've had to date have been based on five classes of drugs, but really three classes, the proteasome inhibitors, the immunomodulatory drugs and the monoclonal antibodies. And these are drugs that target basically the myeloma cells that sit in the bone marrow and try to kill those cells effectively, obviously to leave us with minimal burden of disease in a longer remission duration.

Now, till now we really have not been using the word cure for myeloma, but I think some of the data that we're gonna show you tonight and what's happening really not just in the last six months, but what's happening in the future year, two years, five years, we're starting to talk about how can we cure multiple myeloma? So the drugs that we're gonna talk about are drugs that are being used in the blue box on this treatment paradigm slide. Patients initially present sometimes with MGUS, or smoldering myeloma. And once they develop symptomatic myeloma, they then need treatment for their myeloma and we give induction-based therapy. And that sometimes involves combinations of triplets or quadruplets, a transplant, or maybe not a transplant and then maintenance therapy.

But over time so far, the myeloma has continued to come back and patients have had multiple relapses. And the space that we're gonna talk about tonight is really treating patients in this refractory situation where they had more than three prior lines of therapy and have had exposure to the three big classes of medicines that we just talked about, the proteasome inhibitors, the IMiDs, CD38s. When they don't work anymore, we need new drugs and we need better drugs.

Now, what I've put in this blue box that every drug for myeloma that's approved for use up until today has actually had a single agent response rate, that's been about 20 to 30% in relapse or refractory patients. So if a drug has a 20 to 30% response rate in that setting, it's a good drug and we bring it to FDA approval and then the really good drugs that have good efficacy and good safety are then brought earlier in the lines of this treatment paradigm where we try in early relapse, and then we also try a newly diagnosed multiple myeloma. And at the end of this talk, I'll tell you where we're gonna target some of these new novel immunotherapies.

So here I have a kind of a list of some of the immunotherapies that we we currently have available. And in the blue box here, are the ones we're gonna talk about tonight. And these are the bispecific T-cell engaging antibodies. I'll describe those more in a minute, but you can see that that blue box is really encompassing a small number of therapies that are currently being investigated in the myeloma space. It's really quite prolific, the amount of research that's happening now in multiple myelomas.

It is the most exciting time, certainly in my career and I've been doing this for a long time. On the far left with the cell mods and the novel drugs. We have the next generation Revlimid and the next generation Pomalyst medicines coming out. And these medicines are more potent than Revlimid and more potent than Pomalyst and potentially have less side effects than those drugs. And we have other novel drugs that we're testing in this space. In the second column are novel new CD38 antibodies. Everybody knows daratumumab, some people have heard of isatuximab, Sarclisa. These are next generation 38s, that potentially could be better than those two drugs. And those have been really great drugs, which is amazing.

And in the middle category, we have ADCs, antibody-drug conjugates. That's when an antibody brings a poison, and we'll talk more about that in a second, to the myeloma cells. And then on the far right, are the CAR T-cell therapies. You know, we now have two approved CAR T-cell therapies. Let's look at that in a minute. But all of these therapies, what they're trying to do is they're trying to invoke a immune response. They're trying to get a patient's own immune system to now target and fight myeloma. Cancer's smart. One of the things cancer does right away is it says, essentially, "Don't worry about me, go after the bad guys." Or especially in the bone marrow environment, and other environments where the cancer cells sit, "Relax, everything's good," and they calm the T-cells down, or they suppress the T-cells.

In a bone marrow biopsy with myeloma cells in it, isn't immune suppressive environment, so the T-cells don't do their job. They don't do what they should do and that is knock out the myeloma cells, but it's gonna be a combination. And I say, it's an all out war. We're gonna use the Army, the Navy and the Marines to knock off the myeloma cells and that includes T-cells, NK cells, monocytes and it's using these all together to really try to, in my mind, the goal, cure patients with myeloma, or at least get a very, very long remission duration where patients can be off therapy and not on maintenance-based therapy. So, yes.

So on this slide, on the left, I show what's considered passive immunity and that's what daratumumab and isatuximab does. Those antibodies just bind to the surface of the myeloma cell and they wave their tail like a flag. And so you have all these flags waving on the surface of the myeloma cell and our immune system passively goes around and looks for areas where these antibodies are bound. And that's how they actually recognize that as a bad cell and it'll go kill it, so those ones are passive antibodies. They're waiting for the immune system to do their job, to go around the bone marrow on the body, et cetera, to kill off cells that are coated with these antibodies like the CD38 antibodies.

On the right are the active drugs. The first active we have now are CAR T-cells. With the CAR T-cell therapy, what happens is we actually take out of the arm vein T-cells from an individual patient, autologous T-cells, their own T-cells, we take them out. We actually then use gene therapy to put into those T-cells, a gene that will do two things. One, it will point these T-cells directly to a surface protein on the myeloma cells, so it targets the surface of the myeloma cell. The CARs that we have approved right now, target BCMA, B-cell maturation antigen, it's on essentially all myeloma cells, it targets BCMA. And on the inside of that T-cell, there's another part of the gene that tells the T-cell to get very active, to get mean, to get mad and the T-cell then will activate. Once the CAR T-cell binds to BCMA, the internal signal says, "Go, go, go get all your friends," that T-cell gets activated, it accelerates, it grows, it divides, it recruits other immune cells in the area. And that's how it proliferates and grows and kills myeloma.

Those are very active therapies, CAR T-cell therapies. So we collect out the autologous T-cells, we do gene therapy, takes about four weeks, we grow them up, and then we give them back. And it's one big bolus of T-cells to do its job.

They only last about 90 days, and then they're gone and we hope it within that 90 days, we can kill off as much myeloma as possible. And with some of the new therapies, single agent CAR T-cells are given response rates in the 80 to 90% response range, pretty amazing, right?

On the right side, are these bispecific T-cell engaging antibodies where the antibody now has two arms and one arm anchors itself to the myeloma cell and they other arm actually binds to CD3, it's a protein on the surface of the T-cell and it brings the myeloma cell and the T-cell very close together, we call it an immunologic synapse. That's the CARs that we're gonna go to next. It's an immunologic synapse. It's on the far right of this slide, this immunologic synapse, where you bring in the T-cell and the myeloma cell really close together. That T-cell was sleeping in the bone marrow environment or wherever that myeloma cell is, that T-cell is sleeping and now we're activating it and it's going to whatever it's close to, and it's gonna try to kill it. And that's how these bispecific T-cell engaging antibodies work, they're very potent.

Now, they come in a variety of different sizes and shapes, and every company has a little bit different in the way they've engineered these antibodies. Some of them have dual binders to BCMA on one arm, so it binds twice to the BCMA. It really, some of them bind to CD3, really on a low level, low activity level and so it only mildly activates the T-cell. And some bind, and really try to, with full strength, activate the T-cells. The difference is if you activate the T-cells too much, you made up too much side effects. If you activate it too little, you might not get as good a response.

But in essence, almost all of these, we've been seeing really nice responses. So once we bind to the T-cell and the T-cell becomes active, that's when people notice symptoms, that's when people can have side effects. And Donna's gonna talk to you about all those side effects in a minute. The immune therapy toxicity, there's multiple, there's from activation of the T-cells, there's some neurotoxicity, there's cytopenias, there's infections. And I am gonna turn the podium over to Donna, and Donna's gonna take you through all that. And I'll see you guys back in a little bit. Go ahead, Donna.

- Thank you, Dr. Martin. So with newer approaches to therapy, we have unique side effects. So as Dr. Martin, so eloquently described what CAR T-cells is and CAR T-cell therapy has been in the spotlight lately because of the two recent approvals in myeloma, both are CAR-T products, target BCMA. And then just to piggy back off of what Dr. Martin was saying is with CAR-T therapy we harvest the patient's own T-cells, re-engineer them so that those T-cells will now target a receptor on the myeloma cells. So the T-cells are infused backed into the patient, will target the myeloma cell and destroy it. With bispecific antibodies it's very similar mechanism of action, but we're using a monoclonal antibody instead. So one arm of that antibody is binding to a receptor on the myeloma cell and the other arm is binding to a receptor on the T-cell. So it's bringing that T-cell to the myeloma cell so that it can destroy the myeloma cell.

So with these similar mechanisms of actions, you have similar side effects or similar toxicities. And as you can see in this illustration here with these therapies, you have a release of cytokines and cytokines are immune substances that have various effects on the body, but when they're released in a large, rapid quantity, we have symptoms and I'll go into what that looks like. But bispecifics, the future is here and we're literally expecting our first FDA approval in a matter of weeks, so we're very excited. And so these bispecifics do target different receptors on the myeloma cells, so BCMA, GPRC5D and FcRh5, and we have at least 10 in clinical trials. So Dr. Martin showed you that table, but with each of these targets, there's a potential for unique side effects, but they all do have one thing in common and again, it's that cytokine relief syndrome. And you can see here on this slide, almost up to 90% of patients had CRS.

But what we are seeing with bispecific therapies is it's mild cases, so low grade. Unlike what we see in sometimes CAR-T therapy. So again, cytokine release is when you have a rapid large release of cytokines and it causes a cluster of symptoms and the hallmark symptom for cytokine release syndrome is fever. But then that can progress to maybe more severe symptoms, such as a low blood pressure, rapid heart rate, shortness of breath, or difficulty breathing. But again, but the bispecifics, we're seeing mild cases and patients will often present with fever. So we wanna try to mitigate the effects of CRS and typically how we are doing this in clinical trials is we'll start patients off with a lower dose and gradually increase that dose every 48 to 72 hours, until we can reach that target dose.

And on clinical trials, we have been monitoring patients as an inpatient in the hospital. It remains to be seen how these drugs will be FDA-approved and what will be required from monitoring. But right now we are monitoring patients in an inpatient setting so that we can recognize early onset of CRS and quickly intervene and provide supportive care. So what does that look like? So in my institution with the first line of CRS, we'll actually initiate treatment with Tocilizumab, which is a drug that we historically used for rheumatoid arthritis, but we see that it's actually an anti-cytokine agent and it really dampens the effect of cytokine release without affecting the efficacy of the drug, so this is a good antidote, I like to describe it as.

So the key is with bispecifics, we're seeing mild cases, easily managed and we quickly intervene. Another comment side effect that we see in both CAR-T therapy and bispecifics is neurotoxicity. But however, the case is we don't see this across the board, and it's very rare and we don't see high grades of neurotoxicity, so they're mild cases. The mechanism of how this and why this happens is really not clearly understood, but patients will often present with headaches, confusion, maybe difficulty speaking or word finding, in more severe cases patients will have hallucinations. But it's important to understand that the overwhelming majority of patients, this is reversible and we manage patients with steroids and they recover quite quickly and well.

Another important complication of bispecific antibodies in particular, bispecific antibodies that target BCMA is infections, so the slide, the box is a little off, but if you look at the infection line right above that box, you see that we have a high level of infection, especially again, with those BCMA targeting bispecifics as high as almost 80% of patients will experience an infection. And these are both viral or bacterial infections and as you saw on the previous slide up to a third of patients will have serious infection.

And what is the serious infection? This is an infection that requires IV antibiotics or hospitalization. We are also seeing an increased risk of serious COVID complications, even cases of death due to COVID and this is despite patients having been vaccinated, fully vaccinated, against COVID. So our patients who are on BCMA bispecific antibodies, we wanna check their antibody levels to the COVID vaccine. If they have low or no immune response to the vaccine, we can consider prophylactic treatment with an monoclonal antibody called Evusheld and depending on the availability. So I'm in New York City, I'm competing with several major hospitals, even within my own hospital, this is a very sought after prophylactic therapy for COVID, I'm often referring patients back to the community hospitals to get this treatment.

And again, it's very effective for patients who again have low or no immune response to the COVID vaccines. If a patient does have active infection with COVID, we wanna promptly treat those patients with a combination antiviral agent Paxlovid and we wanna start treatment within the first five days of symptoms. We wanna do our best to prevent any further complications of COVID. So for patients on bispecific, the key is prevention, so we wanna try to avoid any high-risk activities, large crowds, proper hygiene. We monitor patients counts and provide supportive care if patients have low white count, we also wanna give IVIG for hypogammaglobulinemia. So what is that? So that's basically a low level of healthy IgG. So for patients who don't have IgG myeloma, it's pretty easy to understand how low your IgG level is.

So anyone who has an IgG level below 400, we would initiate a monthly infusion of IVIG to prevent infections, especially through the winter months, but for patients with IgG myeloma, how do we calculate that? We take their M-spike and subtract it from their IgG levels, but really that's not for you to do the math. You just wanna make sure you're informed and you ask your healthcare team what is my IgG level, do I need IVIG? and we see that does provide good protection for patients. We also wanna stress that patients are up to date on their immunizations and this also does include COVID vaccines, so patients can amount a response to the COVID vaccines.

And I always say some protection is better than no protection. So we do encourage patients get vaccinated with all their boosters. We wanna make sure our patients are up to date on their pneumonia vaccines, and of course, seasonal flu vaccines, we also recommend shingles vaccination as well.

So just a quick word about COVID exposure and respiratory viruses. It's spread through droplets of being close contact with an infected person. And really the best way to prevent infection is wearing high quality masks and what are high quality masks? So cloth mask is better than no mask, a surgical mask is better than a cloth mask, but a high quality, the best type of protection, is gonna be your N95 and or your KN95 masks. And fortunately they are readily available in pharmacies or even on Amazon. And I like this slide, because it shows how well they protect. So if you are wearing N95 mask and you are in close contact with someone with COVID, you can be adequately protected for two and a half hours.

And if you're both wearing N95 masks, you have a protection of over a day, so these masks work very well at preventing the spread of COVID. So another complication from bispecifics are low blood counts, so that means low white count, low red cells and low platelets. This is more common in the first few cycles of treatment, but rest assure that your healthcare team is very experienced in managing low counts. We give growth factor support, which are injections to boost up your white count or your platelets to give you that adequate protection. And then just for remember, regardless to whether a patient is responding to therapy, this is a true side effect of the treatment, but it can also be present and be caused by cytokine release syndrome.

So moving on to other toxicities. So there are several of the bispecifics that are injection, so an injection underneath the skin. So we do see injection site reactions in up to about a quarter of patients. And this will typically be with the first few doses, and this is a red raised rash, but we can manage these rashes with topical steroids or oral antihistamines such as Benadryl or Claritin and patients recover quite well. Other skin toxicities that we see in particular Talquetamab, which is a bispecific that targets the GPRC5D receptor on the myeloma cell, so not BCMA-directed therapy. We do see skin peeling with the hands and feet. This is typically or usually painless and we can manage this with barrier creams or ammonia lactate, patients do quite well with these lotions.

Patients will off also present with brittle peeling nails. So for this we recommend over the counter nail lacquer or vitamin E oil can be helpful at times. And then other oral toxicities that we see with Talquetamab are oral, so altered taste, a dry mouth, difficulty swallowing and this can lead to patients not wanting to eat, so there may be associated weight losses. So which we try to manage this with either saliva substitutes, sprays, or rinses, but sometimes patients will need a dose hold or a dose reduction. And so this is my last slide.

So bispecifics or T-cell redirection therapies are really generating an unprecedented response rates in especially patients who have had multiple lines of therapy, but with this exciting efficacy comes unique side effects. And I think we studied these drugs for quite some time, so we're getting good at mitigating some of these side effects. So CRS is known to be a side effect, and we mitigate this again with step up dosing, so gradually increasing that dose, and then quickly intervening if someone does present with a fever or other symptoms from CRS.

And we do know that bispecifics that target BCMA are associated with an increased risk of infection. So especially, we wanna be very mindful with COVID infections, if patients need prophylactic therapy and also to be promptly, notify your team if you have symptoms of COVID so we can initiate treatment right away. And then there are other targets for bispecifics, Talquetamab is one such novel agent, but we see that there are unique side effects with this agent such as oral and skin toxicities, which we're getting better at managing.

And with that, I'm gonna turn that over back to Dr. Martin.

- Great. That was awesome, Donna. We have a bunch of questions. Thank you everybody for sending in the questions. We have a bunch for you also, Donna, in the chat, you can look some of those over.

And so with the next 10 minutes or so, I just wanna kind of go over what is the data now? What's the data for these bispecifics? How good are they actually in clinical trials? And then where do I think, where should I think these be directed in the future? So let's start with teclistamab. And Donna just said that teclistamab is weeks away from being FDA-approved.

We're hoping that in September, we'll be able to administer this therapeutic as an off-the-shelf therapy for patients where patients don't have to wait for any manufacturing of T-cells, et cetera, they can get it in the doctor's office. We don't know yet how the FDA is gonna let this roll out. And what I mean by that, and Donna told you in her talk too, is patients likely are gonna need to be in the hospital for the first few administrations as we do the step up dosing and then can be outpatient.

And so I don't know how broadly the local docs are gonna jump on this and be ready to do it in September 1st. I don't think so, but certainly at your local specialty myeloma center, we'll all be ready to go. And we'll all be ready to start people on these therapies, 'cause we know a lot of patients have been waiting for the next class of drugs and that is the BCMA therapeutics class of drugs, which is, in my mind, gonna be one of the best classes of drugs we've ever had which is just great.

So let's go over some of the data. So teclistamab, again, is this bispecific T-cell engager that binds post the BCMA on one arm and to CD3 on the other arm and creates this immunologic synapse where the T-cell sends out these toxic cytokines to the myeloma cell and kills the myeloma cell. Now it was initially, basically it under underwent research in a Phase 1 trial to find the appropriate dose and also the step up doses and now we know there's been presentations and publications of a Phase 2 study.

So a Phase 2 study takes what we say is okay, here's the dose, this is the dose that we're going to use and let's treat a hundred or so patients and see how they do. So this is the MajesTEC-1 study and there was an update that was just presented at ASCO and it was presented also at ASH in 2021. And the primary endpoint of this study was to look at overall response rate. And I told you in this relapse refractory space almost all prior drugs, the single agent response rate, the expected one to be really excited about a drug was 20 to 30% and here's what we got from this. So the overall response rate in fact is 63% an amazing overall response rate.

And essentially the majority of these responses are very good partial responses, meaning they've had a 90% reduction in their myeloma protein burden or better. And on the right, we call that a swim lane plot. And we look at people who started on therapy, what happens over time and all the little arrows you can see up on the right are patients who are continuing on therapy. And these patients are continuing on therapy for more than a year, more than 16 months, in fact, right now the median duration of response is 18.3 months, that actually, and those are in responders and that may actually be longer, we just have to follow these patients over time.

Now what happens is patients typically have an initial response in the response deepens over time. So a 63 response rate, there's never been an agent, short of CAR T-cells, that have had such a single agent response rate, these are really active drugs. Now these drugs, or this teclistamab, it's available, are gonna be used in the relapse refractory setting, but we're starting to do them now in other settings, we're starting to do them in combinations. And so we have some studies where we're combining teclistamab together with daratumumab and we're gonna do a randomized study to compare teclistamab and daratumumab versus daratumumab, pomalidomide and dexamethasone. And this is in an earlier line of therapy. This is not in the relapse or refractory, it's an earlier line of therapy.

And then there's also a study called MajesTEC-4, it's gonna be a Phase 3 study where you have teclistamab in combination with lenalidomide versus lenalidomide alone in patients with newly diagnosed myeloma, and this is gonna be as maintenance therapy following autologous transplant, so this is frontline therapy. Patients get their initial therapy, get a transplant and then afterwards they're gonna get a doublet with teclistamab or just Revlimid, what we usually do. So these drugs are already being thought about moving into earlier lines of therapy. And we think when we have an active drug, we should move it into an earlier line of therapy.

Now there's another one and down further there's 10 plus of these. The best part about it is there's so many of these because it's a race, that means the drug companies wanna get these to market and get these approved use as soon as possible, the quicker to market, the quicker their drug's gonna be used and it's gonna benefit patients. And so when it's a race and a lot of there's a lot of agents around, it just makes the speed of development much faster.

So this one elranatamab is from Pfizer and this is also a BCMA CD3 bispecific and also is tested in a Phase 1 trial where they did dose escalation and step up dosing. And essentially they had a report at ASCO this year, where again, the response rate was about 70%. These are data from the initial cohorts using a weekly dosing of this therapy versus a every other week dosing of this therapy. And that these bispecifics do differ on whether they're weekly, some are every other week and some are actually every three weeks, but we all think that over time we can probably use less and less of this. Maybe we can do it every four weeks, maybe dosing could even be every six weeks. That's what we're gonna learn post, I call it post-marketing, post-approval. We're gonna learn how to use these drugs better and how to give less of the drugs and hopefully cause less side effects, including less infections.

The other drug that Donna talked about was Talquetamab this is a drug that doesn't bind BCMA but has a different target, it's GPRC5D, this is also widely expressed on myeloma cells and other plasma cells. And I think Donna told you this also, that they've seen less COVID issues with people on Talquetamab versus the BCMA bispecific, less infections and less problems with COVID. And maybe the Talquetamab has less infectious potential than a BCMA bispecific. And these are things, again, we have to learn over time.

There are many questions in the chat is can you go from one right to the next one? And the answer to the question is we don't know, but probably yes. And in clinical trials we've taken some people that have gone from a BCMA therapeutic to Talquetamab and have had a really good response rate. And those data have been presented at summit meetings, including at this past ASH. Now Talquetamab as a single agent had an overall response rate in the recommended Phase 2 dose of 70%. That's 70%. This is single agent. This is not in combination with steroids. We give steroids just for the first few doses and then patients don't need steroids anymore. 70% response rate from one agent.

And the question is, is what else should we combine it with? And how do we make that, how do we get it up to 90 or a hundred percent if we're, but we say, if it's 70% in the relapse or refractory, it's probably gonna be 90% or higher in the earlier lines of therapy, especially in combinations. Very exciting.

Now, if I look at the summary here of the bispecifics, in terms of in this purple box, the overall response rates in some of these drugs, I told you teclistamab 60 to 63%, another one from Teneobio it's now owned by AbbVie TNB-3838, overall response rate, 60%. A Regeneron BCMA bispecific 75%. One from Amgen bispecific, 83% response rate. It's really all of these are showing much higher response rates, these bispecifics, than we've ever seen with any single agent myeloma therapeutic. And though we have two at the bottom here that Talquetamab, which I told you about, response rate of about 70% and then Cavostamab, which targets even a different cell surface marker FcHR5, which is another marker that's on the majority of myeloma cells, which shows an overall response rate of about right about 60% also. And it is possible that we might be able to go from a BCMA to a GRC5D to a FcRH5 therapeutic one after another after another, and maybe not without any waiting period, it's yet to be seen. These are things that we are gonna test over time.

Now, if we compare our options and again, we have a lot of options. Right now, coming in September, we're gonna have to choose for every individual patient, which BCMA therapeutic are we gonna give? Are we gonna give people a CAR T-cell therapy? Are we gonna give them a bispecific T-cell engager like teclistamab? Or are we gonna do an antibody-drug conjugate, which the current one that's approved, and somebody's asked some questions in the chat is about belantamab mafodotin. Belantamab mafodotin also binds BCMA with an antibody, but attached to an antibody is a poison. And that antibody gets taken into the cell instead of grabbing another T-cell, the poison goes into the cell and it tries to kill the cell from inside. And that's like a standard toxin-mediated myeloma cell killing.

Now the big side effect from belantamab is ocular toxicity. And somebody asks, "Why does belantamab cause ocular toxicity?" In the poison, which is MMAF, for some reason we still don't know the actual mechanism, for some reason is very sensitive to the surface cells in the cornea. So it gets into the teardrops, and then it gets into the surface cells and it causes a toxicity and those cells die and cause little microcysts on the surface of the eye and that's what causes the ocular symptoms. It's reversible, essentially it is reversible. It's a very active agent. I have a number of patients on it who've had good responses and very minimal ocular toxicity. It just, in my mind, requires a lot of work to watch toxicity and to dose adjust as needed based on ocular toxicity.

But right now, what are we gonna use? Well, the truth of the matter is the CAR T-cell is not off the shelf and there's not a lot of slots available for it. And so each individual center and actually Mount Sinai is a bigger myeloma center than we are, probably twice as big as UCSF in terms of the myeloma patients they have in New York City. They get more slots than us, but still are limited, they're very limited in the number of these slots and then we're limited in number of slots we get. We don't have enough slots for all the patients who need them.

So CAR-T's in my mind should be reserved for patients who can come to the treatment center can stay in San Francisco for 30 days, can have a caregiver with them for those 30 days and can handle the inpatient and outpatient mechanics of all that, logistics of all that therapy and so that's the ideal person in my mind for that. And it might be a younger person and one that's more fit that can handle three days of chemo prior to getting the CAR T-cell therapy. The bispecific it's gonna be off the shelf, so I think anybody could get a bispecific.

I do think people have to still be in pretty good shape. They might have to spend a few days initially, in the hospital, so they still have to be able to walk in the hospital and walk around the hall and they still have to have good performance status and not be on oxygen or not be having significant cardiopulmonary comorbidities. And if they don't and are in good shape, then that's a great therapy for patients. And then the BCMA ADC in my mind is also a good therapy, as long as patients can come. It's a once every three to four week administration and can go see their eye doctor before each administration. I think that does it for my a actual slides in terms of describing the agents.

Here's where I'll tell you what I think, what were in myeloma for the next five to 10 years. These BCMA therapeutics and these bispecific antibodies are gonna be part of all our treatments. They're gonna be part of frontline therapy. They're gonna be part of maintenance therapy. They're gonna be part of early relapse therapy, and they're gonna be part of late relapse therapy, 'cause we're gonna be able to target different antigens on the cell surface. And hopefully we're gonna be able to rev up the T-cells and they're gonna be used in combination.

And so what I've put out for right now is what we're gonna do is quad induction therapy for the stem cell-eligible patients, the really robust patients. They're gonna get a quad induction, probably daratumumab RVd, or maybe Teclistamab RVd at some point in time and then a CAR T-cell instead of a transplant as trying to get to minimal residual disease and then maintenance therapy with either Revlimid or new novel cell mod, the drug's called iberdomide with or without a T-cell engager. And maybe we target BCMA here and for maintenance maybe we target Talquetamab. But the goal being to stop therapy after a certain period of therapy, maybe 18 months, maybe 24 months and then we stop.

We have people that hopefully are MRD negative, we can't detect anything. And we give patients a break and hopefully some of those patients will be cured. I think we will be able to cure a fraction of patients. For the less stem cell transplant fit patients, so the ineligible population, I think still, some of those patients will still be eligible for our CAR T-cell, 'cause that CAR-T can be done in older patients.

But transplant's tough, the CAR-T's a lot easier than a transplant. Or we may just be doing T-cell engagers in the not-so-fit patients as their consolidation therapy and potentially their maintenance, where they can actually then have short therapy, short maintenance and then go back to golfing, tennis, tandem biking, et cetera, go back to life, so they don't have to worry about it. Our best chance to try to get the myeloma to the deepest MRD negative status is right at the get go. So we wanna try to focus this in the early lines therapy. Now there's been a bunch of questions in the chat about high risk. This particularly is for high-risk patients, in my mind. We don't know if the immune microenvironment, the bone marrow right now, works as well in high-risk patients as in non high-risk patients. We don't know if the T-cells are as fit in high risk as the non high risk.

We're gonna find that out though. That is part of the research we're doing is to figure out if it is. And if so, if the T-cells aren't as fit, then maybe we do have to activate the T-cells with combination therapies. T-cell engagers plus iberdomide or some of the novel cell mods that really activate the immune system. And so that is our future. I do think there was some questions also about smoldering myeloma? I do think we will start using T-cell engagers in smoldering myeloma. There are, if you go to clinicaltrials.gov, there are trials now that are registered, that are testing T-cell engages in smoldering myeloma. Let's get rid of myeloma before it even starts and let's do it by just invoking an immune response. Let's not give toxic agents, toxic agents to the bone marrow, toxic chemotherapy agents, let's just give immune therapies to knock it out. I think we'll start with T-cell engages first and maybe we'll use some CAR T-cells in smoldering myeloma in the distant future, but these therapeutics will be used early on in newly diagnosed patients it'd be early relapse and then in late relapse.

I think in that I'll end and say, immunotherapy, a dramatic entry into the relapse refractory myeloma space. The only elephant in the room in my mind is can we afford it all? Is these things are gonna be so, myeloma therapeutics are so expensive. I say to everybody, it's gonna be affordable if we cure myeloma, having people off medicines is the best way to save money.

And with that I'll end. And Donna, what do we have for questions?

- So I think you addressed a lot of them, but maybe, Dr. Martin, you can speak towards MRD rates in the trials.

- Yeah, Very good, so that's a great question. In the CAR T-cell trials, like for cilta-cel, which was published on basically, 97 patients received cilta-cel, the overall response rate was over 98%. And of those people that had disease that was measured, be able to measure by MRD, 90% of them are MRD negative, so quite a few. So their myeloma burden went straight across and then straight down once they got the CAR-T.

Within a month or two months, patients were MRD negative, it was very rapid. In all of these bispecific T-cell engager trials and those that are MRD accessible. It's about 50% patients that are becoming MRD negative in the trials, there's some variability from trial to trial, but we think over time as patients have decreased disease burden, as these T-cells continue to knock off myeloma that those numbers will go up. Donna, I had one for you that they asked, and that is for IVIG, do you recommend IVIG for all of these patients, and then should you be worried about COVID with IVIG?

- So IVIG, especially again, with the BC maturated bispecifics, if patients have low IgG levels, we are initiating IVIG and this is very similar to what we see also in CAR-T patients where they do, their IgG levels drop rapidly. We initiate IgG levels, IVIG. But yes, we are giving it to everyone who have that low level of IgG. In regards to COVID if patients have active COVID infection, we're managing their COVID infection, but we would continue IVIG if that was part of their course.

- And do you after CAR, or with the bispecifics, what do you recommend for COVID vaccines?

- So we are vaccinating. I believe our time point is we try to vaccinate after 90 days post-CAR-T. But yes, we want all our patients to be fully vaccinated, so that's too vaccines with the two boosters. So like I said, patients might not mount a full immune response, but they might have some antibodies against COVID. And like I said before, some protection is better than no protection, so we still are recommending COVID vaccines to all our patients, regardless of their immune response.

- Yeah and I will totally agree and say that CAR T-cell therapies, we've had a kind of an FDA warning, and we knew this, that in people getting BCMA CAR T-cell therapies, there is a risk of having very severe infection from COVID and dying and there have been some deaths. maybe upwards of 5 to 10% of patients who've had COVID very soon after CAR T-cell therapy have died of their infection. So it is really important after a CAR T-cell therapy that you do stay very seclusive and you very stay away from any kind of risk, in my mind. And the masks, like Donna showed you the masks, very important, hand washing, et cetera. Someone on shingles vaccine, do you recommend shingles vaccine for these people?

- Yeah. We've been giving it for our patients.

- And take them off acyclovir, or they continue acyclovir.

- We have been keeping them on acyclovir.

- Yeah, same with us.

- Might have it, yeah.

- Yeah, 'cause yeah, it's hard to know if the vaccine worked for that, so you might as well keep them on the acyclovir, yes. So in all, there are still a bunch of questions on high risk too, and yes, there were a bunch of patients that were high risk on the trials, including the CAR T-cell trials and the bispecific T-cell engager trials. So far, it's really hard to tease out the difference in statistical analyses it may be that the really high-risk cytogenetic patients on the cilta-cel trial were the ones that were more likely to have relapse, okay. And as these data mature, we're gonna find out if high-risk cytogenetics is associated with a shorter remission duration than those people who don't have high-risk cytogenetics. So these are really good studies and really good questions. And so we'll figure that out, I think, over more time.

- Mm hmm, there was one question about how do I know if I've had a response to the COVID vaccine? So in our institution, we are doing monthly antibody checks on our patients. So there is a test that are looking for antibodies to the COVID vaccine, and you can get this done probably at your institution and at our institution, we're checking monthly for certain patients. And then there was another question about CRS CAR-T versus bispecifics. So we do see high rates of CRS in both CAR-T and bispecifics, what's unique with CAR, sorry, with bispecifics, is that it tends to be low grades, so patients will present with a fever. And because we are gradually increasing the dose of the bispecific, fever we can intervene right away. So more low grades in the bispecific category.

- There are a couple questions about basically MRD and when do we say somebody's cured? And there isn't, we don't have a definition for that, we really don't. There are quite a few pharmaceutical companies right now that are trying to put together protocols that said, can we put together a protocol, design it for individual patients, maybe those with high risk, maybe those that are transplant eligible, maybe those that are transplant ineligible and design a trial like I showed you on the last few slides, the paradigms, can we put together some of these novel agents now, some of these immunotherapies, and can we do it with a cure, with a goal to cure patients? And then how do we say they're cured? When are we gonna say, you're cured? And what we came up with is we'd say if you're five years of sustained MRD negativity, that that's what we would consider being cured.

And the old definition was well cure means that you're not worried about multiple myeloma, you're not getting active treatment myeloma. And then something else gets you like natural causes, people die of natural causes, that's cure to myeloma when it's not myeloma, that is in the forefront of everything. And we hope that these drugs can take myeloma out of the forefront of everybody's thoughts and day to day, that's what we really wanna do is make it a chronic illness, hopefully be able to cure it, but if not chronic so that you don't have to worry about it and you can just go about your life, the way you wanna go about your life.

- And then there is a question about age limitations. So there are no age limits or upper age limit. I have patients in their eighties receiving bispecific therapies, even CAR-T therapies. There's no unlike stem cell transplant, where some institutions have that cutoff, with bispecifics in CAR-T there's no age limit per se. And then there was another question in the chat what do we think the indication for bispecifics will be? I think, meaning what line of therapy will this be? And it'll probably, and you can correct me, Dr. Martin, probably come in at the fourth line, right where the CAR-T therapies are.

- Absolutely. And there's a randomized trial with CAR T-cell in a one to three prior lines of therapy versus a Phase 3 versus it's a dealer's choice, two different triplet regimens, for the standard regimens for one to three prior lines of therapy. And the thought is towards the end of 2023 CAR T-cell, the hope is that CAR T-cells win, 'cause you can be off therapy and the thought is that towards the end of 2023, the CAR T-cell may be approved for use in the earlier lines of therapy, in one to three prior lines of therapy. And the bispecific T-cell engager trials are just a few months behind the CAR T-cell trials right now. So maybe early 2024, we're thinking that a CAR, one of these bispecifics, maybe even earlier, could be approved in an earlier line of therapy, like one to three prior lines of therapy. So pretty amazing, actually.

- Right. Right. And I think, is there anything that we didn't address?

- So yeah, there's a question on the sustainability either CAR or bis, how long is the average remission duration and then what about an exceptional responders? It's a great question and patients ask me that all the time. And so I still have, we were part of the initial KarMMa studies, so at bb2121 that got Ide-cel approved. And I still have three of my, I call it three of my all-star patients who are now three and a half years could push in four years status, post their CAR T-cell therapy. And none of them have had any therapy since and they're MRD negative. And we can't detect any myeloma by any means, by pet scan, by bone marrow biopsy, by sensitive MRD test, by any blood tests, urine tests, et cetera. And so those are the exceptional responders.

- And I'll just add, we're really seeing unprecedented responses to these bispecifics and I'm very, I've been working with myeloma for so many years and really, this is the most excitement I've been since I've started, so we're really excited about this.

- Yeah, you've started the bispecifics before we did. So how long is your longest person out after a bispecific still in remission?

- Oh my God, years, yeah, years. 3, 3-4 years. So and like these are patients with multiple lines of therapy and to see patients get into stringent remissions, it's really exciting.

- Yep and so, and I have some also on BCMA, a BCMA bispecific that are out, just close to three years, that's how long, we've been doing it for about three years here at UCSF. And then with cilta-cel, I have like three or four patients that are still in deep remission after their CAR T-cell therapy. They're just over two years, two and a half years, close to two and a half years. And again, have not had any therapy whatsoever. The average right now for cilta-cel, the average regression free survival seems to be, it's gonna be somewhere between 27 and 30 months.

So two and a half years after they get that CAR T-cell therapy. And we hope if we move it and this is in really relapse or refractory patients, a tough late line of therapy. If we move it in earlier lines, we hope that the remission duration is gonna last longer, that's what the hope is. But, and what my final note is that I think we're gonna do a CAR T-cell and then we're gonna do maintenance with one of these bispecifics and then we're really gonna push the remission duration out a lot longer, but have limited duration of therapy. Donna, what is your last hope?

- I agree with you and I think, like I said, I'm very excited, this is unprecedented, and I've been doing myeloma for 20 years and I just haven't seen responses like this. So it's just so exciting and there's hope, just know that there's hope on the horizon and we're like almost there.

- Awesome. Well, thank you everybody for writing in all those questions, the questions are great. Hopefully, we got to a lot of them, some maybe we didn't and you can come see us in consult, et cetera, which is fine. And Robin, do you wanna close out the session?

- [Robin] Yeah, absolutely. The two of you always bring us hope and in such an easy to understand way, I just feel so invigorated and positive for our future in the myeloma world. And I really, really thank you for your time and for this really excellent information.

It was a lot to absorb, so I'm so glad that we've also recorded this webinar, like we do all of our webinars. So the replay will be available early next week and folks can access it, as well as all the previous webinars, on myeloma.org and just click on IMF Videos at the top of the bar. Some really quick reminders, I'm really grateful to all the support groups that are continuously meeting, some are virtual, some are in person, some are hybrid doing a little bit of both, whatever their members are comfortable with.

And I just wanna remind everyone that with all the good questions we had today and great summaries, both Donna and Dr. Martin. You were reading that chat box and I think we had over a hundred questions easily in there. So thanks for your eagle eyes and summarizing that. But don't forget folks about the IMF info line, that toll free number is 800-452-2873, which by the way is cure C-U-R-E, isn't that a great number? And Missy, Judy, Paul and Deborah are happy to take your call, so don't forget about them. And last but not least, you're looking at this feedback survey slide. We really do value your thoughts about our program. So take a minute, it's really short, fill it out, we listen to it.

And thank you again, everyone, for taking the time to join us to learn about bispecifics. Hopefully everyone feels as invigorated as Dr. Martin and Donna do, they're looking so positive there. It's certainly a promising time for treating myeloma. So thank you again for this excellent and much appreciated information. And once again, you can see our sponsors here, Bristol Myers Squibb, Janssen, and Takeda Oncology.

We thank you for bringing this excellent educational program to all of us. So I wish you a wonderful rest of your day or evening. Good night.

- [Donna] Thank you.

Webinar Sponsors:

The IMF thanks the following event sponsors for their generous support:
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