ASH 2022 | Identifying immune biomarkers of progression in patients with HR-SMM treated with immunotherapy

So risk stratification models in use today for patients with smoldering myeloma rely primarily on measurements of tumor burden, most recently cytogenetics, too. And here in this study, we hypothesized that the patient’s immune system matters too. And I think it’s kind of an obvious hypothesis, if you will, but one perhaps without a lot of supporting evidence in humans. And so here I presented the final results from our correlative single-cell RNA and TCR sequencing studies on a Phase II trial of elotuzumab, lenalidomide and dexamethasone in patients with high-risk smoldering myeloma.

And we found that we can indeed harness immune cell composition in the bone marrow for prognostication, and that’s true both at diagnosis and post-treatment. In particular, we measured the similarity of a patient’s bone marrow immune cell composition to that of healthy donors and showed that we can identify patients who are more likely to experience a longer progression-free survival in response to therapy.

And then we also showed that a patient’s bone marrow immune microenvironment may actually normalize post-treatment. We termed that post-therapy immune normalization, or PIN. We showed that it also is associated with longer progression-free survival. We also looked at granzyme K expressing cytotoxic T-cells, which is an important T-cell subpopulation that there’s progressively more and more data about it. And so we looked at it. We found that, indeed, if patients who have more of these granzyme K expressing cytotoxic T-cells have longer progression-free survival. And this time we were able to also see that they clonally expand and increase in numbers post-therapy, which of course suggests that they may be a key player in the bone marrow immune microenvironment.

We showed that they’re a major source of PD-1 expression and that they just overall share characteristics of progenitor exhausted T-cells. And so we think that we are helping develop some foundational knowledge about this subpopulation such that we can, in the future, probe it a little bit more and potentially develop therapies that target it, if needed.

And so since we were in the business of developing immune biomarkers, we wanted to make sure that we can, if needed, make due with peripheral blood samples because bone marrow biopsies are difficult to perform. Nobody likes them, they’re painful. There’s some risk that they carry as well and they’re impractical. So we were really excited to see that changes in immune cell composition and T-cell receptor repertoire diversity that we originally detected in the bone marrow were actually also detectable in peripheral blood because it suggests that there’s utility, both diagnostic and prognostic utility, in the peripheral blood-based immune profiling.

And so this study is now out in Cancer Cell and we think it is important in that it, one, serves as a blueprint, if you will, for correlative studies on clinical trials testing early intervention in patients with smoldering myeloma, and perhaps more broadly even, too. And, two, in that it demonstrates the utility of immune profiling, both in the bone marrow and in the peripheral blood for prognostication, which we think may help improve risk stratification for our patients.