What does it mean to be triple class refractory?

What does it mean to be triple class refractory? How are triple class refractory patients managed at relapse?

Yeah. So I think the term triple class refractory comes from the use of three major classes of drugs we have for the treatment of myeloma.

So the first one is proteasome inhibitors, and we have three that are FDA approved, one that's BORTEZOMIB, which is the first one. Then there's carfilzomib and then ixasomib. These are the three proteasome inhibitors we have, and there's a second group of drugs called immunomodulatory drugs. And again, here we have three choices as well thalidomide, lenalidomide, pomalidomide. These are all oral drugs belonging to the class of immunomodulatory drugs, and then about a eight, nine years back, we had the third class, a third major class of drug for myeloma, which are the cd38 antibodies.

And again, here we have two choices daratumumab and isatuximab. So those are the three major classes of drugs that are available for our patients. So when you say triple class refractory, it means patients who have received at least one drug from each of these classes and their disease has progressed while on these drugs or has relapsed fairly quickly after treatment on these treatments or triple class refractory patients or patients who have received one or more of these three classes of drugs and the disease is now refractory to one or more of the drugs in each of the classes.

And the reason we talk about triple class refractory so much is these three classes of drugs are very much integrated into treatments of newly diagnosed myeloma, earlier relapses. So when you're talking about patients with two, three, four lines of treatment, that's largely patients with triple class refractory where we need novel choices, novel options, and that's where things like CAR-T cells, bispecific antibodies come into play.

Triple class refractory refers to refractory to the three most common therapies that we use in the initial therapy. Proteasome inhibitors, drugs like VELCADE, Kyprolis and ninlaro, IMiD immunomodulatory drugs like REVLIMID, Thalidomide and Pomalidomide and anti 38 antibodies drugs like Darzalex or daratumumab and or sarclisa isatuximab

And so the three classes of drugs that the patient’s refractory to meaning the myeloma is worse despite being on these drugs, again are proteasome inhibitors, IMiDs and the monoclonal antibodies particularly the anti 38 monoclonal antibodies. And so the question is, is what do we do for patients with triple class refractory? But even before that, why is triple class refractory important?

We know it's important because patients who have triple class refractory historically have had short remissions from subsequent therapy, as well as a shortened overall survival. And so it's really important that we come up with new therapies for these patients.

It depends on where sometimes now with the advent of daratumumab, it's more and more being used in the front line setting as part of quadruplets.

We can see patients being triple refractory after one or two lines. And that leaves a really big challenge, given that the approval to these drugs and treatments that we want, like teclistamab, CAR-T cells are for four plus lines of treatment. So one of the big challenges we have now is what do we do for patients who are triple class refractory but have only had one or two lines of treatment.

And I think that will change. As I mentioned, as new data comes along, some of these treatments will more earlier, but currently I guess the choices would be to use a combination that the patient has not received previously would be one option. A second option would be to use a drug like selinexor which is an oral drug which has activity in triple class refractory myeloma.

It has a mechanism that's distinct from these other three classes. So that would be another choice, or really clinical trials. There are many clinical trials that are being evaluating CAR-T cells, bispecific antibodies, other novel therapies in this space that I think for eligible patients would make a lot of sense if this is a triple class refractory after, say, four lines of treatment.

Then that's the patient that we should consider for CAR-T cells or BISPECIFIC antibody. And we have one of those bispecific antibodies, teclistamab that's approved by the FDA. Now, the common part of all these three drugs are that they target a protein called BCMA. So both the CAR-T cells and teclistamab target, a protein called BCMA that's present on the surface of myeloma cells.

Again, the mechanism that's quite distinct from the three classes of drugs we talked about a little while back.

Since the recording of this video, two additional Bispecific antibodies have been FDA approved for triple class refractory patients who have received four prior lines of therapy. Many more bispecific antibodies are in development.

So the question is how do you manage triple class refractory patients? So that mean they’ve seen a monoclonal antibody, they've seen an immunomodulatory drug, they've seen a proteasome inhibitor like Velcade or Carfilzomib, daratumumab or isatuximab and they are seeing REVLIMID and they are refractory that means they have not responded to it or they are progressing on it.

So how do we manage them? Yeah, so that's a very good, important question.

I think the first way is to put them on a clinical trial because that's how you're going to make a difference is learn what is the best treatment for patients who really have failed these three drugs, a class of drugs. So clinical trials is my favorite answer.

But obviously now the FDA approved other drugs that are available on the market.

the car T cells and also the Bispecific T-cell engager. So they are available. Obviously, we are learning how to administer those to the patients and we have now clinical trials to say after, you know, 1 to 3 line of therapy, you can use, you know, CAR-T cells.

So clinical trials, bispecific, T-cell engager, novel therapy, new things that we have not used upfront

So what do we do with patients who have triple class refractory? We have we have treatment options available

where we have xpovio or selinexor, which is an oral agent also being looked at at earlier lines. That's available.

That can in certain situations overcome resistance to prior refractoriness, to things like Pomalidomide or Kyprolis.

And then the other therapies that we have in the triple class refractory setting are the new BCMA targeted therapies, CAR-T cells and BISPECIFIC antibodies.

How do you manage triple class refractory patients who have had subsequent relapses

Yeah. So that becomes more and more challenging.

And I think that's really where we should be considering clinical trials. So again, one of the we've been doing BCMA directed CAR-T cells and Bispecific antibodies now for seven or eight years. So I have some patients who got their first CAR-T cell more than six, seven years back and unfortunately some of them eventually relapsed. And it is another area of significant unmet need.

My to my mind, what do you do after you get a car T-cell? And unfortunately, it stops working after a little while. The good news, I guess, is in clinical trials, we have several other treatments that look promising. Drugs that target, for instance, GPRC5D, another protein that's present on myeloma cells, or treatments that target FcRH5, a third antigen, the protein that's present on the myeloma cells.

Since the recording of this video, talquetamab, a Bispecific antibody targeting GPRC5D received accelerated approval from the FDA.

Unfortunately for now they're available in the context of clinical trials. And so this is really where I would encourage patients and their doctors to be proactive about looking for clinical trials within their center or outside. For instance, we now have patients here who have gotten more than one car t cell, so they've gotten a BCMA, CAR-T cell that worked well for a while.

And then unfortunately, when it stopped working, we were able to go on another clinical trial targeting a different protein and still benefit from that treatment. So there are several options, but some of which might require, you know, more investigation into trial options, availability, etc. Clinical trials is really critical.

in the triple class refractory in the triple class refractory patient population, especially in that space where they the patient can't get approved for these fourth and fifth line therapies and using a clinical trial is would be really important for two reasons. One is that the clinical the reason where we place a patient, a recommended clinical trial is because we think that's the best option for the patient.

And and even phase one studies whose design is to try to figure out the right dose and schedule of the drug. The reason we're recommending a Phase one study is that we are all hopeful that that drug will help the patient with myeloma.

In the triple class refractory population, would using a different agent in the same class of drugs work? Or is it best to look for treatments that have new mechanisms of action?

So typically, we would like to use in triple class refractory patients. You know, even if you try a drug from a different class, the likelihood of long lasting success is relatively lower. We can utilize those drugs, but they have to be combined with, you know, a new mechanism of action.

So that's kind of like the general concept. But it also has to do with how much time you have. You know, is this disease moving rapidly? Do you need to see a response yesterday or can you try, um, you know, some easier treatments before patients actually, you know, become symptomatic? So so it also has to do with how quickly you want that response and which treatment option will give you that likelihood.

Are CELMoDs used in triple class refractory?

I think it's too early to say and it's also too early to say, you know, which cell model will be positioned and, you know, for what kind of patients. But it looks like the CELMoDs that are active in patients who are len and pomalidomide refractory.

So, you know, they're certainly more active. And if they do come along, especially in combination with other mechanisms of action, then then, yes, we'd use them too.

Do all triple class refractory patients have the same outcomes?

So the meaning of triple classic refractory or exposed and resistant triple class exposed and resistant to one is variable, I think. And it means different things to different people. But importantly, a number of studies, such as the mammoth study, looked at that group of patients and found that the prognosis was not good.

And so it's a group of patients where novel treatments have been tried. It's been an important group because it's allowed us to move forward rapidly with new therapies. The issue with the group is it's diverse and so not all patients that are triple class refractory have a poor outcome. There's a lot of variability between individuals and the genetic makeup of the group is not homogeneous.

So comparing between groups done in different studies is ill advised and probably shouldn't be done. So you might get some idea about the efficacy of a drug. But to say one drug is better than another drug based on its activity in relapsed refractory cases is fraught with dangers. However, like I say, we've been very successful evaluating the CAR-T's and the Bispecific therapies in this group of patients because we've seen remarkable response rates with, you know, 90% plus of people responding and durable responses where we saw improvements of just 2 to 3 months.

We've now seen people treated with CAR-Ts and Bispecifics that are alive and well out to 30 months and beyond, which is why there's so much excitement about the efficacy of these drugs and how they're going to behave in an earlier line of therapy.

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