ASH 2023 | Immunotherapeutic approaches to overcoming drug resistance in venetoclax-exposed patients with MM

So this is a very interesting work. We know venetoclax is an important drug in t(11;14) myeloma, and in combination with bortezomib, it works beautifully well, even in non-t(11;14) patients who have overexpressed BCL2. However, there has been data that has not been as clear in regards to overall survival in the BELLINI study. So, we have investigated in this particular research work what the resistance to venetoclax means, why do patients not do so well afterwards possibly, and what can we do to improve the outcome? 

And if I give a very brief rundown on what we did, was that we developed a venetoclax resistance cell line and we developed multiple clones of a single clone. And what we found was that when cells develop venetoclax resistance, they are also resistant to a number of traditional myeloma drugs, including proteasome inhibitors bortezomib and carfilzomib. It includes immunomodulators pomalidomide and lenalidomide. It includes all the cytotoxic drugs, melphalan, bendamustine, and cyclophosphamide. So, it’s a possibility that when you develop venetoclax resistance, you may not respond much to the subsequent treatment. So that’s one part of the story. 

The second part, and a very exciting part, is that even though the response to this agent is not good, when we use immune targeting treatment… And why did we look at those? It is because immune targeting treatment goes through a different pathway in killing the cells, not through the BCL2, the typical apoptosis pathway. So we reasoned that if you use a different pathway maybe we can kill, and that’s exactly what we saw. If you look at the ADCC daratumumab-mediated killing, that’s very good. If you look at a CAR T-cell mediated killing, it’s excellent. And we even had a patient who was venetoclax resistant, we took his bone marrow, it was sensitive to CAR T-cells, the patient actually got CAR-T and had a beautiful response. So, the bottom line is that if you are resistant to venetoclax, there is a chance that you will be resistant to other traditional myeloma drugs, but your immune treatments, including daratumumab and other antibodies, may still be effective. And that’s how we may need to sequence them to get the optimum response.