New Myeloma Combinations Using CELMoD’s and Antibody Drug Conjugates | Paul Richardson, MD | #ASH24

My name is Dr. Paul Richardson. I'm the clinical program leader and director of clinical research at the Jerome Lippermilomer Center at Dana-Farber Cancer Institute in Boston, Massachusetts. And I serve as the R.J. Corman Professor of Medicine at Harvard Medical School. At the ASH meeting this year, I think what we've been really excited to see, speaking to specific areas that we're presenting at the meeting, is the success of mesigdomyde, the oral cell mod which has shown such great promise, first as a doublet, as mesigdomyde, dexamethasone, and now in combination. At last year's ASH, we presented data on the combination of mesigdomyde, dexamethasone, and daratumumab, as well as elatuzumab. At this meeting, we're presenting data or updated data on the combination of mesigdomyde, bortezumib, and dexamethasone, and mesigdomyde, carfilzumib, and dexamethasone. Both of these platforms have been very active. We're reporting response rates of over 70% for both, in fact, closer to 80-85% in combination in relapse refractory patients. So to see this kind of combinatorial effect of mesigdomyde with proteosome inhibition is a very strong rationale for the ongoing successor 1 and successor 2 studies, which are comparing mesigdomyde, bortezumib, and dexamethasone, successor 1 to the standard of care, which is pomalidomide, bortezumib, and dexamethasone in that particular trial. That's a global study. And then the second trial, successor 2, is combining mesigdomyde with carfilzumib, and dexamethasone, compared to the standard of care, which is carfilzumib, and dexamethasone. We're very hopeful that both studies will provide a very strong platform, ultimately, for the full approval of mesigdomyde in combination for patients with relapse refractory myeloma. I think what's important to share with you, though, is that at this meeting, we have also reported on a very innovative study in which we combined mesigdomyde with other novel agents, and they're oral agents, in the setting of relapse refractory disease, in which predominantly patients were not only triple class refractory, but above all, bispecific CAR-T type approaches that unfortunately failed them. So this constitutes an area of exquisite unmet medical need. And obviously, we were pleased in our original study to show that mesigdomyde combined with dexamethasone generated response rates in the BCMA-exposed patients of 50%. So this, for an oral combination, was amazing. In this particular trial, we then went a step further and added rationally designed novel oral agents. Now, the two I want to focus on are Tazamizostat, which we'll call TAS for short, and the second one is Trimentinib. Now, both of these drugs are approved and orally bioavailable in different settings. Importantly, they target completely different pathways in myeloma, and on their own, they're not necessarily particularly active against myeloma in themselves. However, what we had was a strong rationale for combining them with mesigdomyde and to see where that landed. The in vitro and preclinical data were really very compelling for both. And in our study, we were able to show that when you combined mesigdomyde with either TAS or with Trimentinib, the combination was very safe and well tolerated, which for an oral regimen is very important. But then remarkably, we saw about a 60% response rate combining mesigdomyde and dexamethasone with Tazamizostat. But then the real sort of pièce de la résistance was the combination of mesigdomyde, dexamethasone with Trimentinib, and their response rates of 75% were overall reported, and in some cohorts, in excess of 80%. So we were really pleased with this, and these combinations proved safe with manageable side effects and very active in patients really in whom all other available classes of therapy have failed them. So a very important step in my view. And we have to recognize that these are relatively small numbers, but I nonetheless think, Cindy, they point to the value of mesigdomyde, dexamethasone as a real backbone for relapsed repatriated patients to which other drugs can be added and really be successful. And even in for that matter, used just as a doublet on their own. And you may say, how does that fit into the therapeutic paradigm? Well, very importantly, we're realizing with immune therapies that you can't just go from one immune therapy to the next. We're realizing with CAR-T therapy that there are lots of potential challenges, and with Bi-Specifics as the real issue of immune exhaustion and infections. So putting that all together, drugs like mesigdomyde provide an opportunity to provide therapeutic windows, if you will, for patients in between these strategies and to dramatically improve outcome, at least potentially. And thus far, all of these data would suggest that that is really what these agents can potentially do. I think another very important positive about mesigdomyde is obviously its oral. And these all oral combinations are increasingly important because they avoid the need to attend clinic, they minimize hospital times, and above all, they're well tolerated. So that provides real value to frail populations and to populations of patients who may be more vulnerable for a variety of reasons. And so I'm very excited to see them coming forward and these results being so consistently favorable. I think the other highlight at this meeting has been to see the success of belantamab mafidotin in combination with other drugs. And I think the DREAM7 data showing a staggering three year, almost three year survival benefit in the randomized trial comparing belantamab bortezomib and dexamethasone to daratumumab bortezomib and dexamethasone really, I think, was a highlight of this meeting. And I think it shows the real value of an antibody drug conjugate in this setting. And it shows the value of combination approaches. And I think what's so interesting as well is the ocular toxicity has become much more understandable, manageable, and less of an issue, especially as we're now able to dose patients with the antibody drug conjugate every 12 to 14 to even 16 weeks. Greatly convenient for patients on the one hand, it's all outpatient. And above all, if we can preserve efficacy in combination, I think this provides a very exciting new platform for BCMA targeted therapy without some of the challenges that we've encountered with other approaches, recognizing their value, but recognizing also that bicsin civics, CAR-Ts are not necessarily feasible for some of our patients, in fact, for particularly older and frailer patient. And therefore, a platform such as belantamab could be particularly useful in that setting.