Closing out their discussion on novel agents in multiple myeloma, expert panelists consider remaining unmet needs and future evolutions in the treatment paradigm.
Ajai Chari, MD: I think we should also mention that we’re just in this first generation of CAR [chimeric antigen receptor] T-cell therapy.
Cristina Gasparetto, MD: They are still improving.
Ajai Chari, MD: We can improve the manufacturing process, the targets, and the T-cell ratios. There’s a lot. We’ve heard about bb21217.
Cristina Gasparetto, MD: The manufacturer, they took 2 days to manufacture, which is incredible because we don’t have time to wait. They are definitely improving and there are amazing different targets.
Ajai Chari, MD: I know we heard about bb21217 at the prior ASH [American Society of Hematology annual meeting], and then also we’ve heard about several different GPRC5D constructs. Are you all excited about having these newer therapies? Is there one that particularly stands out, or do you want everything as always?
Krina Patel MD: GPRC5D I’m excited about, and because we don’t—it’s a small group of patients, I know—but we don’t see those same adverse effects, which to me is a little strange. I thought you’d probably get it, the toxicity. But I’m really excited to see that. I think even the CART-ddBCMA [synthetic binding domain targeting B-cell maturation antigen] that was presented had 100% response rate in 30-something patients.
Ajai Chari, MD: One hundred percent is the new 20%, right?
Krina Patel MD: Yes, exactly. I think even the allo [allogeneic] CAR Ts, which haven’t been presented yet, but I think they have potential, and hopefully we’ll see some of that in the next few meetings.
Ajai Chari, MD: Omar, we’ve heard a lot about T-cell redirections, bispecifics, CAR Ts; anything else up your sleeve for us?
Omar Nadeem, MD: These therapies are obviously amazing, but there are other agents with different mechanisms of action still in development. We need all these therapies to make a big difference and then figure out how to deploy these in the right patients. There are a few things ongoing now about CELMoDs [cereblon E3 ligase modulators]. They’ve been presented over several meetings, particularly iberdomide, which is studied in combination with dexamethasone and also in other combinations in various phases of myeloma therapy. That’s a CELMoD drug. We saw a response rate that was exciting at about 25%, 26% with dexamethasone. But now I think in combinations, we’ll see hopefully that agent evolve more, and more data on that to come.
We have another agent called modakafusp alfa. This is a way to deliver interferon to the myeloma cells and use CD38 as a target, and like we talked about before, all CD38-directed therapy may not be the same. It’s all about the mechanism. This is showing a response rate as a single agent of about 40%. And some of these patients’ responses are quite similar in patients who are dara [daratumumab] refractory or CD38 refractory, which is a growing population we now have. It’s good to have some of these agents. We’re going to have to sequence all these therapies. Unless we start seeing big tails in the curve with CAR T, we still need new therapies for these patients. Those are some examples of what’s being studied.
Ajai Chari, MD: Great. I think we’ve heard so many exciting things. I’d like to hear from each of you, some closing thoughts, what are the unmet needs? Has Omar satisfied all who want everything for everyone, and he’s giving you more tools? But are there unmet needs? What are you excited about?
Krina Patel MD: I think to be a myeloma doctor right now, I don’t want anyone to ever have myeloma, but I get to see patients do better. Every day I get to go to work and actually say, “you’re in remission.” We didn’t get to do that before with these really relapsed/refractory patients. We’re seeing these earlier lines and hopefully making even more improvements for our patient outcomes. I think the need still is for our end-stage renal patients. We have some drugs that work there, but I get through everything really fast with my patients on dialysis. CNS [central nervous system] myeloma, I’ve actually had a couple of patients at diagnosis with CNS myeloma. But once they really get relapsed/refractory…I don’t know, it was crazy. And during COVID-19, people waited to see doctors, so then we saw disease everywhere, right? I think access, not just CAR T, but access to care [needs to improve]. Because we always see that patients with socioeconomic disadvantages don’t get the treatments they need. And I think that’s something we really need to monitor and look at and figure out a way to do better.
Ajai Chari, MD: Rafael?
Rafael Fonseca, MD: We’ve talked about so many exciting tools that I don’t think we are a drug away from curing a significant fraction of myeloma, I think we’re a strategy away from that. To try to contribute something different, I’m going to say a lot of what we see are missing are good biomarkers, predictive biomarkers. I love to make the call of MRD [minimal residual disease] at negative at 10-6 to my patients. It comes with all the footnotes, but I can tell you, it comes with a lot of hope and joy, and people love to get that call. “You’re negative at 10-6.” I do it on Saturday night if the result comes in on Saturday night because I think it’s that important. But I think we need similar markers to know about all the drugs. I always say, for instance, we don’t have any markers to know who’s going to respond to an IMiD [immunomodulatory imide drug] or not. And the IMiDs are so ubiquitous in what we do that I wish we did have those markers. We do have that, we didn’t talk about it today, for venetoclaxnow, which is a great addition to our toolbox. But I think we’re one strategy away, more than several drugs away, from curing a significant fraction of patients with myeloma.
Cristina Gasparetto, MD: I totally agree. Understanding the biology of myeloma and treating patients differently, like other cancers. With breast cancer, you treat it based on the tumor type. It would be fantastic to have that tool for myeloma because we talk about everything when we achieve the MRD, the sustainability, how long, and how much we have to push transplant on transplant. And now we treat everybody the same way. It would be fantastic to individualize and say, “You are OK with this therapy for a prolonged period, and your risk of recurrence is…vs you need the real deal.
Ajai Chari, MD: Great. Thank you. Omar?
Omar Nadeem, MD: Yes, I think similar theme. For me, I think defining the high-risk patient population even better is important, and then finding the right therapies for them. Because talking in all these panels, talking about all these beautiful data being presented at all these meetings, I still have patients in my clinic who unfortunately progress so fast on these therapies, so quickly. That’s a real population that I think we need to do a better job treating and figuring out exactly what’s different about them. I think that needs to be a bigger focus going forward.
Ajai Chari, MD: I agree with everything you’ve said. I would just throw in the frail, elderly, and the multidrug refractory, now with the post T-cell redirection therapies. That’s the new unmet need. There are a lot of areas of opportunity, but a lot of excitement too.
With that, I want to thank our entire esteemed panel for this really enlightening and informative discussion today. I think it’s been great to hear all of these developments, and we hope you found this informative. Thank you for joining us on this OncLive® Peer Exchange, and we welcome your feedback.
Rafael Fonseca, MD: Thank you.
Omar Nadeem, MD: Thank you, guys.
Transcript edited for clarity.