Good morning everybody.

It's a pleasure to be here.

I'm Martha Chesi.

I'm an associate professor in Mayo Clinic, Arizona, and I run a preclinical lab to model multiple myeloma therapy.

Hello. I work very closely with Marta Chesi.

My name is Erin Meermeier, and I'm a research immunologist and assistant professor also at Mayo Clinic, Arizona.

And we're just very grateful to be here to share some of our insights and our new research with you today.

It's been very interesting attending the ASH meeting this year so far and see how much focus and how much discussion there is around the clinical problem of trying to understand why about 40% of myeloma patients unfortunately fail to respond to, in particular, this bispecific antibody therapy that is otherwise very effective.

I like to think that our lab, through the use of very controlled systems and model systems in study, can really figure out the reason for this primary resistance and why patients do not respond to these otherwise effective therapies.

What's the reason they drive the resistance?

And what are the mechanisms that we can use to overcome it?

And so this is where the contribution of Erin comes in, and she can tell us what she has done in the lab so far and what she has discovered.

We have two main stories to share with you today that are new research using our preclinical models in the laboratory.

And for these, we're both trying to address the general question of how to increase the response rates to the bispecific antibodies for myeloma patients.

In our first study, what we really wanted to do was to think about the T-cell as a key driver for mediating the response to bispecific antibodies.

And as this is sort of a live drug therapy that involves T-cells, we know that patients over time can develop exhausted T-cells.

So one way to increase the response rates to this therapy is to decrease the levels of T-cell exhaustion.

And one of the ways we've been testing this in a controlled fashion in the laboratory is by pairing the bispecific antibody with a novel drug called a CELMoD and a very well-established standard of care therapy called dexamethasone.

And what we find is when we pair all three of these agents together in our preclinical models, we find the best response rates and a lower level of T-cell exhaustion developing over time and very good tolerability of these agents.

So we feel like this warrants further study in the future, but it's very promising.

And then on the other hand, we have tried to address the same question of how we can increase response rates to bispecific antibodies for patients through a whole another mechanism.

And in this sense, again, we think about T-cell exhaustion and wanting to decrease it.

But we had a very surprising and unexpected finding in the laboratory a few years ago that we've been working very hard to follow up on since.

What we found is when we pair cytoxin, which is a DNA alkylating agent, with a bispecific antibody.

So cytoxin, we know, works through lymphoid-depleting mechanisms. When we use an optimized dose of this, we actually are just targeting the T-cell populations that are more exhausted over time with a bispecific antibody and just getting rid of them.

And what happens at the same time when you get rid of the exhausted T-cells, it creates space in the immune niches of the body for more refreshed, what we call naive T-cells to come in, and they are actually better at responding to the bispecific antibody therapy.

So in a way, we're refreshing the T-cells over time.

And again, we're doing this in controlled studies in animal models in the laboratory and are very excited to follow up on the very promising results we see so far.

One of the most exciting parts of this study is that getting rid of the exhausted T-cells and reinvigorating a pool of naive T-cells, what we managed to do is actually boost what we call is an endogenous immunological memory.

So not just the combination therapy we have used was effective in depleting the tumor upon initial treatment, but also created this immunological memory so that we created these patrolling T-cells that are ready to be re-engaged in case the tumor cells start growing again and so prevent relapse.

So I think this is really going to be the essential and key element for a cure for myeloma patients is really not just removing the tumor, but actually creating boosts in this endogenous immunity. And that can prevent future relapse.

And then the final aspect of our study that I'll add on to that, as Marta was saying, we feel like we've created this more refreshed population of T-cells that can control the body.

We have taken it a step further and tested the addition of a checkpoint inhibitor in our model system, and found that these T-cells are optimally ready to respond to a checkpoint inhibitor, and that this was completely well tolerated in our model system as well.

And so we know that the checkpoint inhibitors thus far haven't shown single-agent activity in myeloma patients.

But we think that in this setting, they might be optimally combined with a bispecific antibody.