Paula Rodríguez-Otero, MD, PhD, and Amrita Y. Krishnan, MD, on Multiple Myeloma: Moving BCMA-Directed Therapies to Earlier Use

Paula: Hello, Amrita. So happy to be with you today. Can you discuss a little bit the data that is going to be presented about CARTITUDE-4? Amrita: Paula, I'm really excited. The CARTITUDE-4 subgroup analysis, and the FDA approval of cilta-cel in an earlier line of therapy, really has changed our paradigm for patients with early relapse. And CARTITUDE-4, in this functionally high-risk group of patients, shows that there's a significant benefit to using a BCMA-directed therapy early, in comparison to a CD38-directed therapy. So it could be very paradigm-shifting. Having said that, obviously, the toxicity still becomes a part of our balance of equation. The delayed neurotox is very low, 1%. You could argue, if you're that 1%, that's all that matters to you. Paula: Exactly. This is your 100%. Amrita: Exactly. So I think that is a challenge when we talk to patients. But certainly, for these functionally high-risk, so dynamically early relapsers, len-refractory, aggressive tumor burden, it really represents an option that hopefully will give them really prolonged remissions, assuming also that those functionally high-risk patients can actually make it to CAR-T. Paula: CAR-T infusion. So, I think that you raised this very important point about balance between efficacy and toxicity with these so-active BCMA-directed therapies. Take it into consideration that only one quarter of the patients that were enrolled in the CARTITUDE-4 were anti-CD38 exposed. So the majority were naive to anti-CD38 monoclonal antibodies. One of, I think, the biggest questions in the field is whether you're going to use CAR-T before even exposing the patient to anti-CD38 monoclonal antibodies. So what will be your impression? For sure, functional high-risk, these patients that may not have good experience or good outcomes with anti-CD38, is different. But all early-relapse patients? So what is your impression? Amrita: The criticism of CARTITUDE-4 has always been the control arm being dara-pom-dex or dara-vel-dex, versus a carfilzomib-based combination, right, based on the CANDOR trial or IKEMA trial. But even looking at that, in terms of, again, functionally high-risk patients, I do think we have to look at risk of disease to help drive our decision. And it's obviously still shared decision making, but one can safely say, for those truly high-risk patients, even the most potent CD38 combination is unlikely to provide progression-free survival beyond about two years. Paula: And what else do you want to see regarding safety? Because you discussed the delayed neurotoxicity, which is a concern with BCMA CARs. Any other particular aspects of toxicity that will prevent you or caution you for using so early? Amrita: One would expect, and certainly in earlier lines of therapy, less of the issues of cytopenias- Paula: Yeah, definitely. Amrita: ...and tumor burdens less. So CRS, early neurotox, much less. So I think, really, not so much. It's really just the cranial neuropalsies and the delayed MNTs. And if we can have a better model to predict who is going to get that- Paula: Exactly. Yeah, exactly. I think that this is the key, that we do not know who is going to have this delayed neurotoxicity. Cranial nerve palsies eventually are not that relevant, because normally they will recover, but definitely the Parkinson's-like phenomenon is something that is more relevant. So, in the congress, there were also presentations about belantamab-based combinations, so DREAMM-7 with belantamab-Vd and DREAMM-8 with belantamab-pom-dex. So how do you see this fitting in the treatment landscape, with cilta-cel being available? In the future, bispecific antibodies...? Amrita: Have you heard of the actor Robert Downey Jr.? I always use the analogy, right... His career went downhill, right? He was written off, and then he resurrected- Paula: Yeah, definitely! Yeah, yeah, yeah. Amrita: ...and won an Academy Award! So, well, DREAMM-7 and DREAMM-8 won two Academy Awards, right? In terms of two New England Journal papers. So clearly there's a space. I think DREAMM-7, which is the abstract I'm discussing, is to be commended. It's a triplet-versus-triplet combination. How many face-to-face- Paula: Yeah. Head-to-head, bela/dara combo. Exactly. Amrita: And so, results are really impressive in that functionally high-risk group. Of course, the toxicity... Which I think is much, in a way, easier to fix than in CAR-T, right? Because no one's going to give bela in the real world every three weeks. Paula: Exactly. And then, we know ocular toxicity is reversible, so all patients will recover sooner or later, by holding the drug and so on. And bela-Pd I think is also a very interesting combo, eventually, for those patients that may relapse after DRd, for example, those from PERSEUS or even from MAIA combo. That will also be a very interesting combination. Amrita: I agree, because I think, ironically, more of our elderly, frail patients are going to be CD38-refractory. Paula: Exactly. Yeah. Completely agree. So, thank you very much, Amrita. It's been great. Amrita: My pleasure, Paula.