Preventing Myeloma Relapse Using a Response Adaptive Dosing Approach | Erin Meermeier, PhD

I’m Erin Meermeier and I’m from Scottsdale, Arizona. I work at Mayo Clinic at the Arizona site. My team has been doing research on BCMA bispecific antibodies for multiple myeloma patients.

As you know, these FDA approved antibodies already have outstanding efficacy in the relapsed and refractory myeloma setting. However, there are some drawbacks that we’re considering in our research. One of them is the durability of these antibodies. We would love for them to work longer in our patients.

This durability has been shown through research to correspond with relapse in these patients through a mechanism called immune evasion. And this is where the tumor learns how to not be recognized by the drug anymore. And this limits the durability of the drug.

So in our lab, we are investigating the hypothesis that different dosing regimens of the drug might extend the durability, or cause different pathways of relapse of the tumor. And to do this in the laboratory setting, we’re using a controlled animal model system that recapitulates the relapsed refractory multiple myeloma setting.

But it’s in a controlled way that we can test many different test subjects with the same drug and test different dosing regimens before it’s tested in patients at the clinical level. And we can learn from these test subjects in a more detailed fashion.

So what we’ve done specifically in this study that we’ve presented here at ASH is to recapitulate the continual dosing cycles with a BCMA bispecific antibody, which is the current standard of care for patients. And that’s our control arm.

And then we varied this by testing an intermittent or response adapted dosing mechanism where our animal model is dosed initially with the drug and the tumor goes away. And then we do very regular and detailed monitoring for when the tumor is ever going to come back in these test cases.

And as soon as there’s a first instance the tumor is coming back, we dose it again with the drug. So it’s less drug given to these test cases.

And so the results of this study, number one, interestingly the progression free survival in both of these test cases were the same. So in the arm that is response adaptive dosing, we see a similar efficacy of the BCMA bispecific antibody, which was encouraging and surprising to us.

Secondly, we also interrogated when the animal test cases from either model relapsed, what are the pathways that are causing the tumor to not respond to the drug anymore, and is that difference different between the two dosing mechanisms?

Clinically, we know that immune evasion by the tumor not expressing the target BCMA anymore is responsible for relapse after continual therapy in many cases. And in fact, we did find that recapitulated in our animal model where the actual DNA of the tumor changed, so that BCMA was not displayed on the tumor cell surface anymore, allowing it to hide.

As a second, different pathway, that the tumor was able to evade the therapy and relapsed, we found that there was a mechanism where the tumor was able to decrease the level of BCMA on its surface, not deleted, but just below a threshold that’s needed for detection.

So we call this a transient downregulation of BCMA. And importantly, this was transient, where we saw that when we took the drug away, the BCMA came back on the surface. So this is sort of a rheostat in a way that the tumor is able to hide for a period of time when necessary and then resume its normal biology.

When we dissected down to what details might be occurring in this tumor that allows a transient BCMA downregulation, we found that this was associated with the tumor cell reducing different genetic programs associated with the actual plasma cell biology in some cases. In other cases, we weren’t able to find the reason yet, and that’s a hot topic of future research for us.

And then finally, we focused on trying to understand how the tumor was relapsing in the dosing regimen arm that was treated intermittently or response adapted. Because the most interesting finding here was that those tumors maintained BCMA expression and that T cells were able to be activated by the drug.

So these conventional mechanisms that we think might cause resistance to BCMA bispecific antibody weren’t happening in this dosing regimen with less drug. So how has the tumor in these cases been able to evade the therapy?

And to dig more deeply into this, we took a multiplex approach where we are able to interrogate what are the individual immune cell types that are around the environment of the tumor at the time of relapse compared to the controls.

And when we do that, we found that strikingly, in all of the cases treated with a bispecific antibody that then relapsed, there was a network of immune cells called macrophages and immune cells called fibroblasts and immune cells called neutrophils in a triangle format.

They formed an inflammatory circuit that deposited, or that are predicted to deposit, barrier-like proteins, one of them called vimentin. These barrier-like proteins have been associated with immune exclusion of T cells and other lymphocytes that are important for the killing activity of the bispecific antibody.

So our working hypothesis is that even though in our preclinical laboratory model we were able to use less BCMA bispecific antibody to achieve the same efficacy, those animal models, when they relapsed, they maintained BCMA expression but had an inflammatory immune environment around the tumor that might exclude those important T cells from performing their job.

But in summary, we think that it may still be beneficial to explore clinically using response adapted bispecific therapy to maintain BCMA expression, because for patients that would allow them to continue using BCMA directed immunotherapies even if the bispecific antibody might not work for them anymore.

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