Selection and Sequencing Of Bispecific Antibodies in RRMM and Key Takeaways


Focusing on recent clinical trial data, expert panelists take a broad look at how they might select and sequence bispecific antibody therapies in practice.


Ajai Chari, MD: Wecovered efficacy, safety, CRS [cytokine release syndrome], and all these things. You’ve used the bispecific. Omar, what happens when it stops working? Now what?

Omar Nadeem, MD: We’ve hit on a few of these points already, having newer agents with different targets or mechanisms of action. Thankfully, that pool and development is ongoing and growing very quickly. If you’ve had a BCMA bispecific, could you go on to a different target like cevostamab or talquetamab or other GPRC5D-targeting modalities, such as CAR [chimeric antigen receptor] T-cell therapy? There’s more going on in that space. We have several other investigation agents like iberdomide and CELMoDs [cereblon E3 ligase modulators] in development. You have so much going on in the field that we have to look beyond some of the therapies that we’re talking about now. The big question in that space is, can you give another T-cell redirecting therapy immediately after something like a bispecific? Your group has shown that you can, and you start to see clear benefits using that mechanism. Not necessarily even about the target. That’s something that we need to see going forward. Is T-cell health still adequate at that point to give all these therapies back to back?

Ajai Chari, MD: Keep in mind that these are phase 1 studies. We’re learning so much. Obviously, when we haven’t even gotten to RP2D [recommended phase 2 dose] and figured out all the right doses and schedules. But that theoretical concern of T-cell exhaustion hasn’t been borne out. You can easily go from 1 bispecific to another.

The other thing to mention is that when we talk about these, there are the combination strategies we’ve alluded to as well. We’ve heard about the addition of CD38. We’re waiting for the addition of IMiDS [immunomodulatory drugs]. Cristina, you alluded to dual bispecifics in Spain. There are a lot of interesting strategies that we’re looking forward to.

To close this BCMA category, we have updates on the table…. The number of choices seems to be growing exponentially. But we have, from left to right, a variety of constructs that have been presented, probably the largest with the belantamab and teclistamab. As a whole, some of the differences we see at the top are IV [intravenous] vs subcutaneous, weekly vs every 3 weeks. Those are differences in this administration. But they’re typically 5 to 6 lines of prior therapy, heavily treated triple-class refractory, and very well represented as a class. We’re seeing response rates of 60% to 80%. For the PFS [progression-free survival], the only readout we have is from teclistamab, which is very impressive—over 11 months for an off-the-shelf product, with an encouraging duration of response of 18 months.

In terms of toxicity, CRS [cytokine release syndrome] as a class is 60% to 80%, typically grade 1/2, with very little high-grade CRS. Perhaps there are differences in the treatment of emergent neuropathy and some of the constructs. But infection signals are across the board, and COVID-19–related deaths are also across the board. There a lot of choices. To conclude, what’s going to help us pick these are if the efficacy seems comparable and the safety seems comparable, with that neuropathy signal. The route of administration will differ. One of the biggest differences is who is going to get to market first.

Cristina Gasparetto, MD: I agree.

Ajai Chari, MD: We’re awaiting the approval of teclistamab later this year, with other drugs to follow. Finally, you’ve heard from us lessons learned. I would expand a little about CRS management. What are the things at this point if we’ve treated about 150 patients with bispecifics? It starts when you admit the patient, making the inpatient team. That’s something we’ve been doing. In the era of COVID-19, it’s hard to do outpatient dosing. If you’re going to do that, you’d better train your ER [emergency department] staff to recognize it and give patients bracelets, because you don’t want people going into the COVID-19 rabbit hole for a T-cell redirection fever. We train ER staff, inpatient staff, and frontline nursing to do more frequent vital signs. Sometimes a patient goes from grade 1 to a higher grade very frequently. Maybe we increase vital sign check frequency.

We have order sets. If you’ve never given tocilizumab, don’t waste time looking up that drug. Have the pharmacy mix the drug quickly, get that drug back to the nurse quickly, hang it quickly, and make sure they have an IV. We’ve had some delays for IV infiltration, which have had some adverse sequelae. And then train all the other teams, the neurologists for neurotoxicity, and the infectious disease team for these opportunistic infections that we’ve never seen before. It takes a team effort. The good news is that these patients are getting amazing responses. When done safely with an experienced team, not just physicians, it’s going to be a game changer for patients. But this is a great option for patients. Thanks. Great discussion.

Transcript edited for clarity.

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