CAR T-cell Therapy for Multiple Myeloma

Welcome to the workshop, CAR T-cell therapy for multiple myeloma. My name is Marla and I will be your moderator this afternoon.

Before we begin, I'd like to thank Bristol Myers Squibb, whose support helped make this workshop possible.

It is my pleasure to introduce today's speaker, Dr. Muthalagu Ramanathan. Dr. Ramanathan is the Director of Myeloma Program and Co-Director of the Stem Cell transplant program at UMass Memorial Health.

Her practice includes transplant and CAR T-cell therapy, as well as maintenance strategies with the goal of maximizing survival outcomes, curing patients with hematologic malignancies.

Her research focuses on developing novel transplant and non-transplant therapeutic strategies for hematologic malignancies.

Please join me in welcoming Dr. Ramanathan.

[00:53] Hey, good afternoon, everyone.Thank you for the opportunity to present and welcome everyone to this afternoon's symposium.

We're going to be talking about CAR T-cell therapy for myeloma today.

[01:05] To start with, we'll be talking about what myeloma diagnosis involves, what CAR T is, what are the approved CAR T-cell therapies in myeloma, toxicities, and challenges.

As you all know, myeloma is a diagnosis of a plasma cell neoplasm in the bone marrow, or it could be diagnosed with multiple plasmacytomas. Typically, diagnosed patients have end-organ damage evidence such as hypercalcemia or renal insufficiency or anemia or bone lesions.

Sometimes all of them, sometimes one of them, sometimes none of them if they have other high-risk features like higher involvement in the marrow or MRI evidence of disease.

We talked about how sometimes we see myeloma without end organ damage that we talked about.

[02:11] The reason we use this criterion now without waiting for end organ damage is because we want to try to prevent damage, and these criteria actually predict who's going to develop end organ damage in two years.

This is what we use now. We do diagnose myeloma before end organ damage at this time.

[02:36] The gold standard treatment for myeloma involves currently three to four drug treatment regimens.

We usually do four-drug regimen unless we feel patients are not going to be able to tolerate four-drug for multiple reasons.

After the initial four-drug treatment, we then proceed with auto-transplant as consolidation.That is still considered standard of care in this day and age.

Then after transplant consolidation, we usually do maintenance with one or two drugs, namely lenalidomide with either daratumumab or bortezomib or carfilzomib based on the risk stratification, minimal residual disease at the end of transplant and other factors.

[03:31] The first question that is in everybody's mind is what is CAR T therapy?

CAR T therapy is your own cells that are being modified to be able to recognize cancer and then kill cancer.

The steps involved are taking these immune cells called T cells from the patient.

They are modified in the lab and then they are infused back in the patient which is then leading to cancer cure.

Here you can see that the T cell here is obtained from the patient, and then it is modified in the lab.

[04:24] This is what happens with the manufacturer. Then these cells are now able to detect cancer because they are now armed with receptors.

These receptors, when infused back into the patient, recognize the cancer cell and the cancer cell gets killed.

Here, this is showing what is happening within the patient. These CAR T-cells, once they are infused, they are making their way to the tumor cells because they have those receptors, almost like stickies, which go look for their target.

[05:05] Then the tumor cell, it gets attached to the tumor cell and then causes death of tumor cells.

What is interesting is it's not only the CAR T-cells that are infused. When these tumor cells are killed, they are then presenting antigens to normal T cells, which may be in your body as well.

It's not only the CAR T-cells, whatever other T-cells in the body are also able to now start detecting cancer cells better.

[05:34] Steps involved, the first step is collection of T-cells.

It's called leukapheresis. It's slightly different from autologous stem cell transplant collection in the sense you don't need any preparation for this.

You don't need any growth factor. You don't need to have any stimulation. You basically go to the blood donor center or the place of collection.

Then the cells are taken from you. They are sent to manufacturing. It's usually only a one-day collection because we get what we need within one day.

It is sent to manufacturing to the sponsor. There it undergoes modification. Then it gets expanded.

[06:22] Then once it's manufactured, it is transported back to the center. Patient now undergoes chemotherapy for three days.

The chemotherapy can be administered outpatient or inpatient based on your treatment center.Then the CAR T-cells are infused.

Again, the infusion can be inpatient or outpatient based on the treatment center.

After infusion of CAR T-cells, if the patient is in the hospital, they are discharged home 10 to 14 days later.

If it is being done as outpatient, they are being seen every day and then discharged to less frequent appointments after 10 to 14 days.

Patients are typically advised to stay close to the clinic for four weeks, though this has been slowly brought down. Typical is two weeks after the initial treatment phase.

[07:26] In myeloma, there are two CAR T-cells that are commercially available.

The first one was approved in March 2021 called ide-cel or Abecma.

The second one, Carvykti, was approved in March 2022.

When they first got approved, they were approved for later lines of treatment, meaning if the patient has had multiple lines of treatment and still had myeloma, they were offered this treatment.

But with the success of this treatment and the safety of this treatment, it started becoming available earlier on.

A little bit brief review of the characteristics of patients who got ide-cel and cilta-cel, because ide-cel was the first one to get approved.

It also looked at really severe disease presentation, most of their patients, 40% of the patients in this study had extramedullary disease, which is kind of plasmacytomas outside the marrow, and 35% or one-third had high-risk cytogenetics.

This population was really, really significantly pre-treated and difficult myeloma to begin with.

Later on, FDA approved these treatments in earlier lines of treatment.

Now, in April 2024, FDA approved Abecma to be used after two or more prior lines of treatment, and cilta-cel or Carvykti was approved after one prior line of treatment.

[09:15] Basically, if a patient had a diagnosis of myeloma, had induction chemotherapy, auto-transplant, and then say lenalidomide maintenance, or if they didn't get transplant, they were on lenalidomide maintenance, and then the myeloma progressed.

At this stage, now CAR T-cell is available, or cilta-cel or Carvykti is available for use in this scenario.

It has moved to after one line of treatment, first relapse, so to speak. The other agent, Abecma, is at second relapse.

[09:54] A little bit about the studies which led to this approval.

KarMMa-3 was the study that led to the approval of Abecma and it compared Abecma or ide-cel to the standard treatments like Dara-Pom-Dex or Elo-Pom-Dex or Carfilzomib-Dex treatments.

What they found was there was improvement in progression-free survival. It was much higher. The one here in orange is the ide-cel.

The one in blue was the standard regimen.

So clear-cut improvement in progression-free survival at this line of treatment.

The other study, which was looking at Carvykti, was the CARTITUDE-4 study.

This looked at patients with myeloma relapsed refractory after one to three lines of treatment.

[10:49] And it compared cilta-cel to Dara-Pom-Dex or Dara-Vd.

Again, here you can see that there is significant improvement in progression-free survival, which was not reached versus 11.8 months.

Again, you cannot really compare head-to-head these two studies, Carvykti and Abecma, because the patient population was different.

[11:19] What you really need to pay attention to is the standard of care versus the CAR T-cell therapy.

So here, the progression-free survival was better. The standard of care group had 11.8 months of progression-free survival.

Whereas if you looked at the Abecma study or ide-cel study, the standard of care patients only had 4.4 months of survival, meaning these patients were significantly pre-treated and had poor survival.

So head-to-head comparison is not possible, but you can clearly see that both the agents which are approved and available for use are significantly better than the standard of care treatment options in the lines that they are approved for.

Now we see how CAR T-cells have had significant improvement in progression-free survival.

[12:10] What about toxicities? Let's talk about toxicities that you can see with CAR T-cells and myeloma.

You can categorize that into three categories, early, delayed, or long-term.

Early toxicities are usually managed at the treatment center. Patients are typically admitted during that time frame or in close follow-up during the time frame.

The physicians and the staff are keeping a close eye on the patient. The main ones that you look for are what we call cytokine release syndrome and ICANS or neurotoxicity.

The next category is delayed. This can happen after the first two weeks.

This can be what we call hemophagocytic lymphohistiocytosis, which is kind of like a delayed version of cytokine release syndrome.

We'll talk about each of these categories in detail.

Then there is the concept of immune effector cell enterocolitis. This is unique to the cilta-cel or Carvykti. Delayed neurotoxicity, Parkinsonism, cranial nerve palsy, again more unique to Carvykti.

The third category is long-term toxicities, which happens over a period of months to years. This can be secondary cancers and unknown long-term effects.

[13:35] Cytokine release syndrome, what is this?

Cytokine release syndrome is mainly because of the immune cells activating cytokines in the body. That's kind of how they do their job of killing cancer, but you can also have symptoms from it.

They typically have what we call fever, oxygen drop, blood pressure drop. Again, what is good about these myeloma CAR T-cells is that the grade of toxicity is usually very early in grade, like grade one and two.

Grade greater than three is less than 5% or 4% with both the products. Most of what we see is very manageable and very treatable.

The duration of start of the CRS is one to three days for ide-cel, seven days for cilta-cel. So cilta-cel or Carvykti is a little delayed onset of CRS.

Because of this reason, this is able to be offered more in the outpatient setting so we can keep a close eye on the patient.

[14:58] The early grade toxicities or CRS can be very often, meaning 80 to 90 percent of the time, but like I said, the grade three is less than five percent. Again, very manageable.

What do you do for treatment? Again, grade one is basically fever.

You do symptom monitoring.You can get acetaminophen.

Grade two is associated with a lower blood pressure or a lower oxygen.

Then we give a medication called tocilizumab, which is an IV medication. And we often give it along with dexamethasone, which is, again, to calm these inflammatory cytokines down.

Severe cases are grade three plus where you would need ICU support, high-dose steroids, immunosuppressants.

But like I said, it's less than 5% of the time. In my experience, I haven't really had anybody with grade three.

[15:55] What is ICANS?

It's an immune effector cell, which is the modified T cell associated neurotoxicity.

Again, what can it be? It can be slow speech. It can be patient feeling sleepy; patient complaining of headache, confusion, weakness, seizures, and coma are again higher grades.

We don't see this often. It's very rare.

And what is the time of onset? It's usually within two weeks, which is the 10 to 14 days time frame.

It's very rare beyond that time frame. In abecma or ide-cel, we see it around two days. In cilta-cel, we see it around eight days. Incidence is about 20%.

Grade greater than or equal to three is less than 5%.

[16:50] Not common at all, as opposed to CAR T-cells and lymphoma and other conditions.

In myeloma, neurotoxicity grades are grade one to two.

So in ide-cel, again, you can see here greater than three grades were three percent and in cilta-cel, two percent.  So lower grades. Duration of ICANS, it's usually short if you experience ICANS.

It's usually four to eight days and full recovery is noted.

[17:25] How do you treat ICANS?

The first step when we notice ICANS, which happens in one in five patients or less, we get a neurology consult and we start patients on seizure medications, Keppra prophylaxis.

If they have grade two, which is again based on scoring, there is use of dexamethasone and imaging to look for any changes, MRI and EEG.

If it is grade plus, which is mainly seizures or significant involvement that leads to moving the patient to the ICU.

You use increased steroids. You use a medication called anakinra. We can do a lumbar puncture and give treatment via the CSF as well.

Again, I haven't seen grade three plus. Most of what we've seen, if anything, is grade one.

Now that we've talked about early toxicity, the next topic is going to be delayed toxicities, what to expect.

Delayed toxicities are more unique to cilta-cel.

[18:36] They can be hemophagocytic lymphohistiocytosis, Parkinsonism, cranial nerve palsies, or immune effector cell-associated enterocolitis.

[18:49] IEC-HS, it is very rare. Like I said, it's more or less an overlap with cytokine release syndrome. When I say very rare, less than 1% or so, I haven't seen that happen often.

There is severe inflammatory response, and it can occur weeks to months after infusion. That is why it's important to have follow-up after discharge with the treatment center.

[19:21] You're looking for fever; blood counts are dropping, elevated ferritin, which is again an inflammatory marker.

The treatment is very similar to CRS. You can use high-dose steroids, medications called anakinra and Tocilizumab.

Then what about delayed neurotoxicity?

[19:43] Delayed neurotoxicity can be Parkinsonism, can be cranial nerve palsy like Bell's palsy, can be peripheral neuropathy like sensory loss in the feet, things like that you would see with Velcade or Bortezomib for example.

What we find is it's again not very common, but we have to be aware and keep an eye for it. It's about 12 to 15%.

Median onset is close to about a month, anywhere from 21 days to 30 days.

Parkinsonism is actually much lesser than what was reported in the first study, which was after multiple lines of treatment. it's about 0.5%, meaning one in 200 patients who get this treatment or less.

Cranial nerve palsies happen in about six to nine percent, but it's very treatable and reversible.

Parkinsonism with cilta-cel, I know this is something that is concerning, but like I said, it's very rare.

The risk factors for this is high tumor burden.

[20:48] If the patient developed CRS or ICANS during the hospitalization, it is related to very robust CAR T expansion.

The mechanism is, it is actually the same target as the cancer cell, but you have these antigens expressed also in the brain and the thalamus.

Even though it is technically doing what it's targeting. Usually it happens about three months after cilta-cel infusion. It is due to the fact that these CAR T-cells are persistent longer, meaning they are continuing to proliferate and persist in the blood and brain.

[21:43] Again, very rare. I wouldn't necessarily be worried because of this. It's unique to cilta-cel.

If there is a patient with neurological comorbidities to begin with, then maybe the other CAR T-cell, such as ide-cel, should be considered.

[22:08] So how do you treat and what's the duration? Usually the symptoms are there for a few months and the recovery can be incomplete.

Treatment is treatment very similar to Parkinson's with carbidopa, levodopa, ropinirole, and there is rapid resolution of symptoms. Sometimes we can use ruxolitinib, which is used for other diseases such as myelofibrosis, and then sometimes cyclophosphamide.

[22:40]I haven't seen this happen in a regular practice, but something to be aware of. Like I said, it is much lesser than what it was having been using it earlier on in treatment lines.

[22:58] Cranial nerve palsies with cilta-cel. You have mostly, like I said, Bell's palsy, which involves the seventh nerve.

Median time to onset is about 22 days and treatment is steroids and resolution in pretty much 90% of the patients.

The key would be early detection and early treatment before permanent damage occurs. Other cranial nerve palsies, they're usually low grade and one-sided meaning like you can have just foot drop in one foot something like that MRI imaging and it is reversible in 90% of the patients median duration about two months and how do you treat you treat it with steroids for two weeks and because you're using steroids and with CAR T-cells, we do antiviral prophylaxis for up to six months at least.

[24:01] There is this concept, which is again unique to cilta-cel, which has been identified.

It's called enterocolitis. It seems to occur one to three months after infusion. It is associated with diarrhea, abdominal pain, and weight loss. It is usually mild, and then the treatment is just steroids.

For moderate, you get GI and ID consult because you also want to rule out infection. You do an endoscopy and biopsy.

You can treat it with infliximab and vedolizumab, which is kind of used in GI for other GI issues like ulcerative colitis and things like that.

Again, very rare, but something to be aware of.

[24:40] What about long-term toxicities?

Secondary cancers are something to be aware of. You notice this with just lenalidomide use and myeloma, for example.

In CAR T-cell treatment, again, because it is immune treatment, the immune system gets altered.

There is a risk of developing this in one to three years after treatment. It's about one to two percent incidence.

[25:11] Patients who've had heavy pretreatment, like autotransplants, significant lines of treatment, tend to have more likelihood of developing secondary cancers, tends to be leukemia or MDS.

[25:26] Rarely it can be solid tumors and skin cancers. T-cell malignancy because of the modified T-cell is very rare. It is 0.09% or 1% and it is due to the fact that patients have immunosuppression from this treatment.

[25:55] Relapse after CAR T-cells does it happen? What do you do so CAR T-cell gives you the best chance of disease-free survival?

It's not a hundred percent guarantee so if you relapse even after CAR T-cells what can you do there are several treatment options available for relapse after CAR T there is more promise with agents that are used in multiple myeloma treatments such as selinexor which is an oral drug pomalidomide another oral drug carfilzomib which is IV or there are bispecific antibodies which are alternatives to CAR T but you use antibodies which are different from the target that the CAR T utilizes.

CAR T is primarily BCMA targeted, but there are other targets that are in development. GPRC5D is a target. There is actually a CAR T which is targeting GPRC5D.

Then there are dual targeted CAR T-cells which are targeting two antigens. So it is making it difficult for the cancer cell to escape the treatment.

[27:06] There are bispecific antibodies which aim different targets like talquetamab, which is available commercially, or even if it's a longer duration after CAR T that the patient relapses, you can use the BCMA targeted bispecific antibodies because it worked. It's just that it has gone away and now you want to re-trigger it.

[27:25] There is teclistamab, elranatamab, and linvoseltamab, all of which are already approved and available in clinical use.

Then there is cevostamab, which is another target, FcRH5, which is on a clinical trial.

There is belantamab, which is a BCMA target, but with a molecule that helps kill cancer.  So that is an option.

Then there are other clinical trials with cell mods like iberdamide and mezigdomide, which are probably going to be available as standard of care soon. But in the meantime, you have clinical trials.

So there is no shortage of options if you were to relapse after CAR T.

We've come to the end of our presentation today. Most of what we've discussed, I'm going to kind of give you a summary of what we talked about today.

[28:20] We talked about the fact that CAR T-cells are our own immune cells. They're not gotten from anybody else.

It is our own cells that get modified in the manufacturer and then get given back to us after manufacturing.

This is kind of like a 2.0 or a 3.0 immune system. Our own immune system is modified so that it can recognize cancer cells better. Because it's our own cells, there is no risk of rejection.

[28:54] There is no risk of having to be on immunosuppression for longer like if you were to do a donor transplant which is again very risky so this is very scientific in the sense that this is almost like science fiction where we are able to modify our immune system to do a better job of getting rid of the cancer.

Then CAR T-cells get rid of the cancer cells and there is actually data to support that one third of cancer patients who get these CAR T-cell treatments are cured, meaning they are in long-term remission and they die of something else.

[29:39] We never use the word cure in cancer, but CAR T-cells have made that possible, short of allogeneic transplant or donor transplant, but that comes with a higher risk.

Carvykti or cilta-cel is used in first relapse. Abecma or ide-cel is approved in second relapse.

You need to stay close to the treatment center for two to four weeks after infusion. You can drive after two to four weeks after infusion, provided you're not running into any toxicities or complications.

As we discussed, there is progression-free survival benefit, possibility of a cure, efficacy is very good. The higher-grade toxicities like CRS or ICANS are less than 5%. So it's very safe.

[30:34] Delayed neurotoxicity and enterocolitis are something that we need to keep an eye on when we use cilta-cel.

[30:41] This is more for awareness rather than any concern.That brings us to the end of our presentation. Thank you, everyone, for listening. I'm happy to answer any questions.

Questions & Answers

[30:56]  Moderator: Thank you, Dr. Ramanathan, for this excellent and timely presentation.

[31:01] I think there's a lot going on in the world of CAR T, and we know we're going to see more in the future. So let's get to some questions. If you have a question, please use the question box on the lower left side of the screen and we will answer as many as possible.

First we've got, what are the average periods of remission for cilta-cel and CAR T-cell?

[31:24] Dr. Ramanathan: The average period of remission varies depending on your risk category. For patients who are standard risk and early lines of treatment, it can be a long-term remission that can last years and years. For patients with high-risk disease, what happens is there can be early relapse.

It truly depends on your risk stratification and in what line of treatment you are using CAR T-cells.

[32:01] We had shown actually I can go back to the slide on progression free survival benefit for cilta-cel okay so here you can see that this is going median progression free survival not reached and they've looked at it for about three years or so patients are still surviving in this and then the study that I talked about where 30% were cured looked at it at five years and they were still doing well at that time.

[32:31] Moderator: Great. Thank you. When can we expect anito-cel therapy to be available?

[32:43] Dr. Ramanathan: I'm equally looking forward to it. It was supposed to be approved this year and I still think that is going to be the case.

We are very excited about this because it does seem to be as efficacious as cilta-cel with less toxicity given the delayed neurotoxicities and enterocolitis and hemophagocytic lymphohistiocytosis. We are looking forward to anito-cel becoming available.I hear it's any time at this time.

[33:13] Moderator: Thank you. This person had a transplant and more recently CAR T. Do you know if there's any correlation between weaning off of an antidepressant, they were on something for 30 years, and neuropathy from Velcade worsening?

Dr. Ramanathan: Weaning off from an antidepressant shouldn't necessarily make neuropathy worsen, but if you're about medications like Cymbalta, which have efficacy in neurotoxicity, you can continue to do very, very slow taper to see if it gets worse; obviously, you go back on it.

[33:59] Moderator: Why do multiple myeloma patients have a transplant before CAR T?

[34:05] Dr. Ramanathan: As we know, at this time, CAR T is approved after first relapse.

So autologous transplant in myeloma is considered what we call consolidation, meaning you get initial treatment for your myeloma and then you consolidate the treatment response with the autologous transplant.

It's considered first-line treatment. The nice thing about autologous transplant is that because most of our treatment nowadays for myeloma is very targeted.

This autologous transplant gives you the option of getting chemotherapy to get rid of the cancer cells deeper and longer. You may not ever need CAR T-cells. Your idea is to decrease relapse and prevent relapse.

When you do autologous transplant as part of your treatment regimen with induction treatment, what happens is you are increasing your progression-free survival and consolidating your treatment response.

Our goal as we move forward with newer, newer regimens is to prevent relapse, that we don't even have to get to the point of CAR T-cells, which is approved at first relapse and second relapse at this time.

[35:26] Moderator:Thank you.Okay. I'm going to try to read this here.

This person wants to know what your professional opinion is on butyrate supplementation. They are saying that it has shown in phase one clinical trials as an effective treatment for reducing disease severity in acute ulcerative colitis?

[35:49] Dr. Ramanathan: Again, this is more of a general maintenance kind of setting. Most of these supplements, unfortunately, are not rigorously studied like our clinical trials.

It's hard for me to comment on it. But if it is a diet that is helping you, that is totally fine. It's going to be patient-dependent. If you feel good on it and you're doing well on it, it's okay.

[36:26] Moderator: Thank you. Do patients who have plasma cell leukemia have the same or shorter periods of response to Carvykti and would they relapse sooner? Is there any data on that?

Dr. Ramanathan: We don't have robust data on this. Plasma cell leukemia, as you know, is a very aggressive version of plasma cell neoplasm.When patients present, they are presenting with plasma cells in the blood. It is harder to get rid of.

And because of that, all our treatment options are slightly less effective in plasma cell leukemia scenario compared to patients without plasma cell leukemia. But plasma cell leukemia tends to respond better to chemotherapy options, auto transplant, and CAR T-cells. It's still effective but may not be as effective as somebody without plasma cell leukemia, just standard myeloma. 

[37:30] Moderator: Thank you. This kind of goes back to the anito-cel. Are there any requirements to be able to have this yet, or is it still kind of too soon?

Dr. Ramanathan:You mean why anito-cel is not approved yet? Yes. I don't know the answer to that question.

I think it's just going through the FDA approval process at this time and data gathering and support to get it approved. The last I heard, it's still on track. They haven't had any setbacks, so to speak.

Moderator: Great. This person was on a GPRC5D clinical trial two years ago, and they're having trouble with poor balance. Do you have any suggestions for that?

[38:23] Dr. Ramanathan: Again, it is likely from neurotoxicity, which can be a side effect of all the treatments that the patient has had over the years.

It's standard neurological support with diet medications, magnesium supplements, gabapentin, and other neurological supportive medications, physical therapy, but nothing specifically targeted towards talquetamab per se.

It is with neurology consult and nutrition consult what we can do to provide supportive care for this.

[39:07] Moderator: Thank you. Someone wants to know if you can talk about CAR T-cell being administered via a virus in research, when that might be available, and are there benefits to this?

Dr. Ramanathan:The interesting thing is what, remember how we are currently waiting four to six weeks for manufacturing to happen before we can infuse the patient.

What is being studied in clinical trials now is instead of having it sent elsewhere for manufacturing. Can we do that process within the patient itself? So this way, one, it's quicker. You can immediately get this treatment started.

You don't have to wait four to six weeks and worry about disease progression or bridging therapy in the meantime.

And two, because it's happening within the patient, they tend to be younger, more memory, more naive cells, which can possibly last longer.

The potential benefits can be one, less wait time. Two, they could be more efficacious. Three, most importantly, they could be longer lasting.

 Because it's happening within the patient, maybe the patient can have this benefit lasting for an extended period of time compared to the external manufacturing and expansion.

[40:36] With this, probably it's going to be much easier to administer when it becomes available. Again, it's still in clinical trials at this time. It is very promising.

We don't know toxicities and other concerns at this time, but it is something which we are looking forward to.

[41:02] Moderator: Let's see what we've got here. My doctor mentioned tri-specific in trials. When will tri-specific be available? Is it much more beneficial than bispecific?

Dr. Ramanathan: The interesting, again, right now, bispecific antibodies are one side targeting the cancer cell and the other side binding to the immune cell or the T cell.

That's your standard bispecific antibodies, which are drugs, not CAR T-cells, but drugs. When you have tri-specific, you can have two antigens that you're targeting with one drug, so to speak.

The benefit or advantage to doing that would be the escape of the cancer cell, because what happens is when you target one antigen, the cancer cell can stop expressing that antigen and then escape the treatment.

When you have two antigens that you're targeting, then if you escape one, you're getting killed by the other antigen target.

[42:08] It has a better efficacy of getting rid of the cancer cell. And this is true of CAR T-cells as well. Instead of one antigen, they are targeting two antigens. Sometimes they are targeting the same antigen, but double.

It's kind of like double strong attacking the same antigen or attacking two different antigens. The hope is you're going to have better efficacy and less relapse.

That's the hope. Again, it's in clinical trials. I don't know of any immediate approval yet.

[42:45] Moderator: Got some great questions here.Thank you.

Next one is, does lenalidomide play any role in treatment if a patient relapses and has CAR T-cell?

[42:58] Dr. Ramanathan: Yes, it is possible.

Again, when you have CAR T-cell, say you have lenalidomide refractory and you got CAR T-cells.CAR T-cells are now rejuvenated immune cells.When they start waning, because after some time, those T cells are disappearing.

And when you give lenalidomide again, or pomalidomide or any of the immunomodulators, what happens is these immune cells can be re-stimulated to recognize cancer and clear cancer.

There is potential for use of lenalidomide or pomalidomide after CAR T-cells, especially if you believe it worked, but it stopped working and the response is starting to wane.

[43:49] Moderator: Can you speak a little bit to caregivers that are needed for CAR T for myeloma patients? Are there differences of roles versus an autologous transplant?

Dr. Ramanathan: Absolutely.

So the thing about autologous transplant is because it's high intensity chemotherapy they have what we call loss of appetite nausea diarrhea and things like that for an extended period of time and because of that they may take longer to fully recover again it can be anywhere from 30 days to 90 days for full recovery from an autologous transplant.

In CAR T-cells, it's different in that the chemotherapy that we give for conditioning prior to the infusion is not heavy-duty chemo at all. It is very low intensity chemo. The goal is basically immunosuppression.

[44:38] They don't have that same toxicity like nausea or diarrhea or hair loss or anything like that with CAR T-cells. But they can have other toxicities we didn't talk in depth about cytopenias meaning the blood counts can take longer to recover and they may need transfusion support they may develop any of these delayed toxicities so you want to keep a close eye on them so to speak but it is much easier.  

Patients are allowed to drive two to four weeks after the infusion if they didn't have any problems So again, if they had a pretty non-toxic kind of infusion, they are back to doing everything very quickly. The other nice thing about CAR T-cells is there is no requirement for maintenance after CAR T-cells as it is for auto transplant.

There is potential that patients are off all treatment and free, so to speak. So the CAR T-cell caregiver role is not very well defined or required as we do for auto transplant.

[46:01] Moderator: This person wants to know, can you get Carvykti again after relapse or is it not as effective?

Dr. Ramanathan: Yeah, so very good question.

Typically, when we collect once and manufacture, it's not like we get products saved for future use. So it's one and done.

If patient relapses after CAR T-cells, it's unlikely that they're going to respond to the same CAR T-cell again. Especially if they relapse really early, it's unlikely to be responsive.

What we typically do if somebody relapses after CAR T-cell, we use a different CAR T-cell if it's available. Again, both the ones available are BCMA targeted.

[46:50] So if they relapse after that, we do CAR T-cells on a clinical trial with GPRC5D, or other targets, or bispecific antibodies with a different target, like talquetamab or belantamab, which has the same target, but an additional molecule to kill cancer.

Even bispecifics with BCMA target, but to kind of amplify the response.

But no, we don't use the same CAR T-cell again, because it may be a lot of work for minimal benefit.

[47:25] Moderator: Thank you. Okay, this person wants to, they're in a multiple myeloma group, and they have a person that had first-line CAR T and relapsed after eight months, and now they are considering a stem cell transplant. Why would that work if CAR T did not?

[47:43] Dr. Ramanathan: It can work. Again, this patient didn't have autotransplant as first line, and I'm assuming it's because they had pretty refractory disease that they decided to pursue CAR T-cell.

Because they haven't seen chemotherapy, doing an autotransplant afterward gives you the benefit of chemotherapy in getting rid of the cancer cell.

It's not a permanent fix, so to speak.

There is still going to be the chance of relapse after autologous transplant, but it'll buy you some time to either get on to other newer agents that may become available or clinical trials, but it will be effective.

It can still be effective because you're counting on the chemotherapy to give you the benefit and they didn't get that upfront.

[48:35] Moderator: This person had an autologous transplant in 2019, and then developed AML. Now 120 days post-allo transplant in remission, now the myeloma is coming back.

Once they've relapsed for the myeloma and no AML is back, would it be possible for them to have CAR T as a following line of treatment?

Dr. Ramanathan: It is possible, except again, now it's likely going to be the allogeneic donor T-cells that we are trying to collect and manufacture and give.

So yes, it is possible as long as the patient doesn't have graft-versus-host disease, which is requiring immunosuppression or steroid use or things like that.

It is possible to use CAR T-cells.

But I would first start with trying to get the disease under control with standard regimens, like whether it's lenalidomide-based or pomalidomide-based, and then consider CAR T-cells.

[49:40] Moderator: Can you speak to any other CAR T treatments that are on the horizon for multiple myeloma that we haven't talked about yet?

Dr. Ramanathan: We did cover most of the options that are coming up, but there are newer targets coming up.

The ones that we talked about how we need four to six weeks for manufacturing, even if the manufacturing is done outside, there is rapid manufacturing.

This can be done within like one week or so. Again, the thought process is they're going to be much younger. They are probably not as exhausted, so they're going to last longer.

That is something which is also coming up. We talked about multiple targets, different targets of CAR T-cell, like the GPRC5D CAR T-cell.

[There is also the bispecific and the trispecifics, all of that coming up.

So yeah, the clinical trials are looking at several options, and there is also clinical trials looking at CAR T-cells earlier on, not in first relapse, but maybe for high-risk patients who have a partial response or patients with minimal residual disease.

[51:06] There is CAR T-cells being studied even before relapse. That is also coming up in the pipeline. It is very exciting that we have all of these options available.

We didn't talk about allo CAR T-cells, which are off the shelf. There that is also being studied in clinical trials.

This is basically T-cells from a donor, but that won't get rejected by the patient because they've removed the receptors that will cause rejection.

They are used to target myeloma cells. Several different spectrum of CAR T-cell therapies are being developed and explored in terms of safety, in terms of efficacy.

So the 2.0 and the 3.0 CAR T-cells are probably going to be more efficacious and less toxic.

[52:06] Moderator: And on that note, we have come to the end. We had some great questions.

On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Ramanathan for an extremely informative presentation and you, the audience, for your excellent questions.Thank you.

[52:31] Dr. Ramanathan Thank you. I'm very impressed by the questions asked by the audience. You are all up to date and working on this. Thank you so much.