ASH 2023 | Investigating immune dynamics in multiple myeloma treated with talquetamab monotherapy

As you probably know, myeloma right now has a couple of new drugs, including bispecific antibodies, that have really revolutionized the treatment landscape. And there are multiple targets for it and using them as monotherapy is leading to very durable responses and very deep responses. However, we are still not entirely sure what dictates the response in terms of how deep you go and for how long you sustain that response. So, the aim of our study was to actually try to identify some factors that could be predictive of that and to see if we identify any mechanisms of resistance so we can probably find ways to overcome them. 

So there are basically two ways to have resistance to therapy, either it’s the tumor itself or the immune system, in the case of bispecific antibodies. So, the drug we were studying was talquetamab, which targets GPRC5D, one of the myeloma antigens, and some reports so far have started coming out to say that GPRC5D can be altered, whether it’s loss or mutation, and that could lead to treatment failure. So we looked at our patient cohort at Mount Sinai, and we had 84 patients who received talquetamab as part of the MonumenTAL-1 trial. And so far we’ve looked at 30 patients, and we’re extending that to to reach 84. And interestingly, none of those patients had any alterations in GPRC5D, so the tumor compartment, so we started looking into the immune compartment to see if we can see reasons of resistance or therapy failure there. 

So we actually utilized a relatively new methodology called CITE-Seq, and CITE-Seq is a way of studying cells in a single-cell manner, whereby we can look at both the proteomic epitope as well as the RNA transcriptomics within the cells, which can basically provide us with even more information about each cell type and we will be better able to characterize the cells that we’re looking at. And we looked at both the peripheral blood and the bone marrow of patients, at baseline right before they began therapy, and we also looked at the peripheral blood at cycle three, day one of all the patients. And definitely we had a mix of responses within these patients, some who had a very short PFS, progression-free survival, or a long progression-free survival. And we were able to basically use 150 days as the cutoff between what we call short PFS and long PFS. And we found that patients who had a longer PFS had a different immune makeup within the bone marrow, particularly having higher different subsets of CD8-positive T-cells, and that included the central memory, effector memory, and TEMRA T-cells. 

And in terms of those who responded well, they were associated with having lower exhaustion markers at cycle three, day one. So basically after starting therapy, the amount of exhausted T-cells we observed at cycle three was much less. And those exhaustion markers that we chose were according to the literature, where a lot of study studies are coming out to look at them. And those included TIGIT, as an exhaustion marker, as well as PD-1, TIM-3, and LAG-3. So we see a significant increase in patients who don’t have as much of a good response compared to those who did. 

And this is providing basically the framework for our next steps and other studies that are ongoing right now, whereby we’re trying to see if we can target any of those exhaustion markers to see if we can reverse this resistance to bispecific antibodies. And so far, we’re still early on in this, but it seems like not every exhaustion marker should be targeted. There are specific exhaustion markers that can be targeted and actually help. So, I would say the conclusion so far from preliminary data is that not every checkpoint inhibitor will help. So it might be patient-dependent, and that’s what we’re working on right now, and hopefully, we’ll have more data in the next few months.