Selection and sequencing of bispecific antibodies in the RRMM and key points


Ajai Chari, MD: We’ve covered Efficacy, Safety, SRC [cytokine release syndrome], and all those things. You used the bispecific. Omar, what happens when it stops working? Now what?

Omar Nadeem, MD: We have already touched on a few of these points, having new agents with different targets or mechanisms of action. Luckily, this pool and development is ongoing and growing very quickly. If you had a bispecific BCMA, could you switch to a different target like cevostamab or talquetamab or other GPRC5D targeting modalities, like CAR [chimeric antigen receptor] T cell therapy? More is happening in this space. We have several other investigational agents like iberdomide and CELMoDs [cereblon E3 ligase modulators] in development. There’s so much going on in the field that we need to look beyond some of the therapies we’re talking about now. The big question in this space is, can you give another T cell redirection therapy immediately after something like a bispecific? Your group has shown you can, and you’re starting to see clear benefits from using this mechanism. Not necessarily even on target. This is something we need to see in the future. Is T-cell health still good enough at this point to give all these back-to-back therapies?

Ajai Chari, MD: Keep in mind that these are phase 1 studies. We are learning so much. Of course, when we haven’t even gotten to RP2D [recommended phase 2 dose] and found all the right doses and timings. But this theoretical concern of T cell depletion has not been confirmed. You can easily switch from one bispecific to another.

The other thing to mention is that when we talk about it, there are also the combined strategies that we have alluded to. We heard about the addition of CD38. We are waiting for the addition of IMiDS [immunomodulatory drugs]. Cristina, you alluded to bispecific doubles in Spain. There are a lot of interesting strategies that we are looking forward to.

To close out this BCMA category, we have some updates on the table…. The number of choices seems to grow exponentially. But we have, from left to right, a variety of constructs that have been shown, probably the largest with belantamab and teclistamab. Overall, some of the differences we see at the top are IV [intravenous] vs subcutaneous, weekly vs every 3 weeks. These are differences in this administration. But it is usually 5-6 lines of prior treatment, triple class refractories that are heavily treated and very well represented as a class. We are seeing response rates of 60% to 80%. For the PSF [progression-free survival]the only reading we have is for teclistamab, which is very impressive – over 11 months for a standard product, with an encouraging response time of 18 months.

In terms of toxicity, CRS [cytokine release syndrome] as a class is 60%-80%, usually level 1/2, with very little high level CRS. There may be differences in the treatment of emergent neuropathy and certain constructs. But infection signals are widespread, and COVID-19-related deaths are also widespread. There are many choices. To conclude, what will help us to choose them is if the effectiveness seems comparable and the safety seems comparable, with this signal of neuropathy. The route of administration will be different. One of the biggest differences is who will hit the market first.

Cristina Gasparetto, MD: I agree.

Ajai Chari, MD: We expect approval of teclistamab later this year, with other drugs to follow. Finally, you heard from us the lessons learned. I would develop the management of the CRS a little. What happens at this point if we have treated about 150 bispecific patients? It starts when you admit the patient, doing the hospitalization team. It’s something we did. In the era of COVID-19, it is difficult to do outpatient dosing. If you’re gonna do that, you better train your ER [emergency department] staff to recognize this and give wristbands to patients, because you don’t want people going down the COVID-19 rabbit hole for a T-cell redirect fever. We’re training ER staff, patient staff hospitalized and front-line nursing to take more frequent vital signs. Sometimes a patient goes from grade 1 to a higher grade very frequently. Maybe we’re increasing the frequency of vital signs checks.

We have command sets. If you have never given tocilizumab, do not waste time looking for this drug. Ask the pharmacy to quickly mix the medicine, get it back to the nurse quickly, put it on hold quickly, and make sure it has an IV. We had delays for the intravenous infiltration, which had undesirable 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 teamwork. The good news is that these patients get amazing responses. When done safely with an experienced team, not just doctors, it will be a game changer for patients. But it’s a great option for patients. Thanks. Great discussion.

Transcript edited for clarity.

Martin E. Berry