ASH 2025 | The evolving role of T-cell engagers in myeloma: the MagnetisMM-6 and MELT-MM trials

Thank you for this opportunity to share some of the works we’ve been doing in the field of multiple myeloma, specifically on the evolving role of the T-cell engagers and how to incorporate them in both frontline and the relapsed/refractory setting. So I would like to start off with the Magnetis-MM6 trial because it really represents an inflection point in how we think about the treatment of the front line for the newly diagnosed transplant ineligible multiple myeloma patients. So as many know, MM6 trial consists of two parts. Part one is the safety run-in for testing the feasibility of using elranatamab in combination with lenalidomide, and part two is the randomized phase, originally conceived to compare Elra-DR versus DRd. So with the promising results out from the part one, both the safety and efficacy data that was made available earlier this year, the study was set to proceed to part two. 

We saw some major advancements come about in the treatment landscape for the newly diagnosed transplant ineligible multiple myeloma this year. So now we have the quadruplet, based on the anti-CD38 antibody, consolidating their position as a new standard of care for those under the age of 80 and fit patients. So as such, we figured that the current control arm of DRd might not be sufficient, so we made the rather radical but important decision to update the study design to really align with where the field is today. So now, part two, we’ll compare Elra-DR versus DVRd, the quadruplet. So this change really ensures that we are answering the right questions for 2025 and beyond. For example, what is the role of a proteasome inhibitor in the frontline setting? And can we use the T-cell engagers for everybody? And of course, it also ensures that the clinical trial stays relevant to the physicians and patients alike. Also, there is a strong biological relevance or rationale for using elranatamab early. So T-cell engagers obviously or inevitably depend on the functional T-cells for the maximum benefit. The newly diagnosed patients, they have far less immune exhaustion and they have more profound T-cell activity. So by introducing BCMA targeting T-cell engagers, for example, elranatamab early on, especially in combination with a potent antibody backbone, we’re really giving these patients the chance for deeper responses and sustained MRD negativity, and hopefully a chance at a treatment-free survival, which never really happened in these populations of patients before. 

MM6 really is about optimizing the use of elranatamab in the earliest phase of the disease. I also have another program that is very exciting, but focuses on the later stages of the disease course, the relapsed/refractory setting. So in this setting, we are testing the combination of elranatamab plus mezigdomide, which is a new CELMoD with a strong immunomodulatory effect. So what mezigdomide does, among many other things, is that it can enhance cytokine release, and it can also improve immune synapse formation, and it can potentiate T-cell proliferation. So basically, mezigdomide essentially reconditions T-cells to fight better. So there has been a long speculation or scientific hypothesis that if we pair the two together then it’s going to lead to a more durable and deeper responses and perhaps overcome the resistance mechanism. I’m happy to share that our MELT-MM study is the first ever clinical trial to test the combination and actualize this concept, and the preliminary results look very promising.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.