What is TECVAYLI? So TECVAYLI is bispecific antibody for multiple myeloma, also known by its generic name teclistamab. It's a class of medications called a bispecific antibody. For those conventional antibodies like daratumumab and elotuzumab, they attract a part of the immune system called the innate immune system. The come and kill the multiple myeloma cells. But bispecific antibodies do is instead of attracting the innate immune system to the myeloma, they attract T cells. So the multiple myeloma, which is another arm of the immune system, and what we've learned through the Car T-cell story, is that T cells seem to have more potency in their ability to kill multiple myeloma cells than the innate immune system.

What is the mechanism of action of TECVAYLI? How does it work? And so in order to engage T cells, these bispecific antibodies are reconfigured so that they don't just recognize the myeloma cell but they also recognize the T cells. So you can think about an and a bispecific antibody is having two arms that are going to inject the bispecific antibody into the body. One arm grabs a myeloma cell one arm grabs and activates a T cell and forces the T cell to recognize the myeloma cell. And then the T cell kills the multiple myeloma cell.

What trial was used to confirm FDA approval? And so that clinical trial, the published trial had 165 patients in it had. And what we found is that most patients respond that I think the exact percentage of patients that would respond with something like 60 to 65% of patients responded. Most of those responses were very good partial responses or complete responses, meaning that patients had at least a 90% reduction in the amount of myeloma in the body, as measured with our blood tests. And those responses lasted a long time. And so if you look 12 months after starting the medication, about 70% of the patients, the medication was still working for them.

What are the major side effects of TECVAYLI? The major side effects are cytokine release syndrome, neurologic toxicity, low blood counts and infection. The clinical trial also told us about some of the risks with the medication. And I would say there are a few risks to be aware of that we learn about in the trial. So one is cytokine release syndrome. And this is an inflammatory reaction that happens in the body as T cells are activated against the myeloma. Most patients have high fevers as part of that cytokine release syndrome. We know from the experience with CAR-T cells and even a little bit with teclistamab, that CRS, cytokine syndrome, has the ability to progressed beyond fevers to include, you know, low blood pressure, difficulty breathing. And even if you look across all patients who have been treated with drugs, like teclistamab and CAR T-cells, there's even potential for cytokine release syndrome to be fatal. So you have to be aware that's a potentially serious toxicity. But in the vast majority of patients on the teclistamab study, that was, a manageable side effect that could be handled either just by watching them closely or providing some supportive care, or in about I think, a third of patients or about half of patients who had cytokines released in them required, a medication called tocilizumab, which calms down that inflammation, and allows you to continue with dosing. So that's one main risk to be aware of that we learned about in the study.

The other is, neurologic toxicity. And so as the immune system gets activated against the myeloma for some reasons we don't totally understand, that can sometimes affect how the brain works. And patients can have something called ICANS, it stands for immune effector cell associated neurotoxicity syndrome. And these are a group of neurologic toxicities that can happen usually in the early period after you start this medication. And the actual manifestations are various. They can be things like tremor, difficulty concentrating, difficulty with motor tasks like writing confusion. In more severe cases, it can it can progress to decrease consciousness, a difficulty arousing, like verbal cues, talking to people and in the most severe cases, coma and swelling of the brain that can be potentially fail. So that's I can it can be seen after all of these T-cell engaging therapies like CAR-T cells and bispecific antibodies. And that happen in the few patients on this trial. But it was but it was most cases low grade and manageable. And but you have to be aware, though, that this is a potentially serious toxicity.

How is ICANS managed? So I ICANS is primarily managed with steroids. And in the case of teclistamab with just holding the medication until it resolves. And because they're happening after the small doses, usually you can kind of, take them a little bit at a time, a small dose, you get a little cytokine release syndrome, let it pass second dose a little bit more. Maybe those side effects tend to happen in the first, you know, couple doses of the drug. As you get further into therapy with the drug, we start worrying a little bit about blood counts. And so most patients on the study had some drop in blood counts after they came on the study. Anemia, thrombocytopenia, low white blood cell count that typically could be managed in some cases with transfusions, with giving medications to boost the white blood cell count like filgrastim or G-CSF. That also, tended to be something that was manageable over time.

And then finally, I would say the big side effect or risk that we learned about with this medication is infection. So teclistamab does seem to increase risk of infection. And at least one way it probably increased risk of infection is by killing the normal plasma cells in your body. So remember myeloma is a cancer of plasma cells. And plasma cells have a normal function in your immune system to help you make antibodies. So plasma cells are the main antibody producing cells of the immune system. And a lot of the drugs that we use to treat multiple myeloma and kill myeloma plasma cells also kill normal plasma cells. And that's especially true of teclistmab and drugs like it. You really do kill off a lot of the normal plasma cells. And as a result of that, patient's normal antibody levels will get very low when they're on teclistamab. And that probably increases the risk of infection.

And so one way we can help with that is to give patients antibody replacement therapy. So just like we can give red cell transfusions when your red blood cell count slow or platelet transfusion when your platelet counts low. We can get antibody transfusions when the antibody levels are low. Then we call that intravenous immunoglobulin. And it's not quite like a red cell or platelet in that it's not from one particular donor. But IVIG is a formulation of antibodies that's collected from many, many different donors purified, down into kind of a drug, and then given as a, as an IV infusion to a patient who needs it. And that can get the antibody levels back up into healthier ranges for our patients. And now it's something we do for regular myeloma therapy with some frequency. But it seems like most patients that get teclistmab will require IVIG or intravenous immunoglobulin to keep their antibody levels up.

Now that we think does reduce the risk of infection but doesn't completely eliminate it. And there's probably other ways that teclistamab affects the immune system that can't be completely remedied just with these antibody, transfusions. And so that's why we have to just be very vigilant about infections. We, we are going to recommend that our patients on teclistamab get some prophylactic antibiotics. And so they should get prophylactic antibiotics against herpes viruses and shingles with a medication like acyclovir or valacyclovir or famcyclovir. And we think patients should also get prophylaxis against a particular type of pneumonia called pneumocystis pneumonia. And the most common way to do that is with the drug called bactrim, which is a conventional antibiotic that's used for a lot of different infections. You can take one dose of that three times a week and get very, very effective prevention of pneumocystis pneumonia.

We recommend that all our patients stay up to date with their vaccines, including their Covid 19 vaccines, following the latest guidance, which tends to change every few months, about which vaccines you should get now, patients on teclistamab will not respond as well to vaccines. Remember, vaccines are to induce your own immune system to recognize a bug, and part of the immune system is going to be disabled by the teclistamab. So patients they get teclistamab are not going to make antibodies in response to vaccines. But there are still other parts of the immune system, like the T-cell part of the immune system that probably can respond to the vaccine. So even though you're not going to make, for example, if you get a Covid vaccine, you're not going to make good Covid antibodies while you're on teclistamab. You might still make good anti-Covid T-cells, and that's still worthwhile. Therefore, to get the vaccines while you're on teclistamab.

Additionally, TECVAYLI can cause liver problems. Increased bilirubin and liver enzymes in your blood are common with TECVAYLI and can also sometimes be severe. These increases in liver enzymes can happen with or without you also having CRS. Your health care provider will monitor you for these problems before you start and during treatment with TECVAYLI, tell your health care provider if you develop any symptoms of a liver problem, including tiredness, loss of appetite, pain in your right upper stomach area, dark urine, yellowing of your skin or white part of your eyes.

Some people taking TECVAYLI can develop symptoms of an allergic reaction that can affect your whole body, and may include fever or a swollen tongue injection site reactions are common with TECVAYLI and can include redness, heat, swelling, bruising, bacterial skin infections, discomfort, blood collection under the skin at the injection site, and rash. The most common side effects of TECVAYLI include fever, pain in your joints and muscles, back and chest muscles, and in your arms and legs. Tiredness and weakness upper respiratory tract infections and pneumonia, nausea, headache, diarrhea the most common severe abnormal lab test results with TECVAYLI include decreased white blood cells, red blood cells, and platelets. These are not all the possible side effects of TECVAYLI.

What is step up dosing and why is it needed. So there's toxicities I mentioned before like cytokine release syndrome and neurotoxicity. These are generally toxicity that are seen just with the first couple doses. And as a result of that risk with those first couple doses, the study implemented some measures and the FDA approval implements some measures to reduce the risk of severe complications. And so one of them is step up dosing. We think that by giving a little the dose initially as a small dose and then a couple of days later a medium dose, and then a couple days later the full dose, we can kind of ease in to that. So that risk of toxicity, instead of kind of activating the immune system all at once with one big dose and those initial will be called step up doses are recommended to occur in the hospital because some of those toxicities that develop the high fevers, the low blood pressure, the difficulty breathing, they can sometimes happen in the middle of the night. And the best way to handle those if they develop is to have kind of the resources of a hospital around.

But if things go smoothly, you know, you can get in and out of the hospital. And about a week after getting this medication and then resume the rest of the treatment in the outpatient setting in terms of the types of centers that are going to be able to do this. So, because of these particular risks of cytokine release syndrome and neurologic toxicity the FDA has instituted for this drug, what's called a REMS program, which is a special set of trainings that prescribers and institutions have to go through in order to be able to legally prescribe the medication. And so the physicians ordering the medication have to be certified in this REMS program. The hospital and the institution that's giving the medication in the pharmacy has to be credentialed in the ceramics program to be able to give them medication. So it's a little bit of paperwork and bureaucracy and a little bit of training. But I do believe, though, that this is well within the capability of community hospitals and practices to handle, most of the toxicity was low grade, and it's manageable. There just has to be that, that process has to go forward before those places are going to be able to start the medication, at least in our network here.

I think what will happen a lot is that, we'll maybe start the patient on the medication at the subspecialty center. But then once you get beyond those that first month or two of dosing transition patients back to their, local oncology offices to get the continuation dose dosing that they can just do in their office without necessarily having to link with the hospital that's been set up to give those initial doses.

What is the schedule of TECVAYLI after step up dosing is completed? So the way it's dosed, after you get through those first couple doses that are in the hospital is once weekly subcutaneous injections. And the way the FDA instructions are written is once weekly subcutaneous injections indefinitely until the disease starts progressing. And I think in reality, we will probably experiment with less frequent dosing for patients who get into very good responses. And a little bit of that was done in the clinical trials as well. And I think we'll learn more about that over time. How what how long we need to continue that once weekly dosing can be back off to less frequent dosing. Can we even stop the drug in some patients? But we don't know all that yet. That takes will take some work to figure out. But but once the. But the simple answer to the question is once weekly subcutaneous injections.

On February 20th, 2024, the US Food and Drug Administration has approved a Supplemental Biologics License Application for TECVAYLI for a reduced dosing frequency of 1.5mg per kilo every two weeks, and patients with relapsed or refractory multiple myeloma who have achieved and maintained a complete response were better for a minimum of six months. There is a continued unmet need for patients with multiple myeloma, and this approval allows increased flexibility in dosing schedule for appropriate patients with a weight based regimen.

Are medications given before TECVAYLI administration? The pre medication is really restricted to those first couple doses. And so there's some dexamethasone free medication I believe there's also some Tylenol and perhaps Benadryl pre medication. But it's really around those first few doses. And so this is not a drug where you're going to be getting weekly dexamethasone forever. It's really just around those first few doses. And that's to reduce the risk of allergic reactions and cytokine release syndrome.

How long will it take to see if I'm responding to TECVAYLI? The responses, I think, apparent in most patients within the first couple of months, even if they don't meet that formal criteria for having a 50% reduction in the M-spike or the light chains, it's kind of clear what direction they're headed very early, if you check the numbers. For some patient in the hospital where we were very curious and kind of checking, you know, labs, even in between those step up doses, we saw some patients, even respond to that first tiny dose that they got. There are some people, even at these very low doses that respond just to that very low dose.

Can an individual with previous BCMA directed therapy respond to TECVAYLI? If you've received prior therapies at targeted BCMA, you can still respond the TECVAYLI or teclistamab. There are reports it's basically a smaller number of patients that have been tested in this way that in clinical trials. But it does seem like a good portion of them responded. At the time of this recording teclistamab is approved for relapsed or refractory myeloma, but studies are exploring its use earlier in treatment. For the latest updates, please check the manufacturer's website. The link is in the description below, or talk with your health care team.

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