IMS 2023 | Addressing proteasome inhibitor resistance in multiple myeloma in the immunotherapy era

One of main things that we’re interested in in my lab is thinking about: how does myeloma become resistant to proteasome inhibitors? What else changes in the cell? How does that create new therapeutic vulnerabilities, that we can then go after specifically in the context of disease resistance? One thing we found that we published last year is that the myeloma surface proteome in the context of proteasome inhibitor resistance, does change quite dramatically. Unfortunately, we didn’t find any highly specific immunotherapy targets in that context. One thing we’re really focused on now, in terms of overcoming proteosome inhibitor resistance, what are other intracellular targets that we need to go after, inside the plasma cell, that could be changed as a result of proteosome inhibitor resistance? Now we’re much more focused on thinking about, for example, BCMA CAR-T – it appears to be highly efficacious versus proteasome inhibitor resistant disease. We recently published a review where we discussed this concept of, do we need to focus on that very specific biology of proteasome inhibitor resistance anymore, or is the question a bit moot? Do we just want to find therapies that are effective against this disease context? Also, we’re moving to focus on, once you become resistant to an immunotherapy, then what are your next angles? Because we know the existing immunotherapies are very effective against proteasome inhibitor refractory disease.