An Abundance of Approaches Moves Discussion of Sequencing to the Forefront in MM

During an Oncology Town Hall™ virtual meeting sponsored by Physicians Education Resource® (PER®), 4 investigators in multiple myeloma addressed emerging therapies, optimal sequencing, the role of minimal residual disease (MRD) to inform therapy, and the possibility of storing T cells for use in later chimeric antigen receptor (CAR) T-cell therapy.

IRENE M. GHOBRIAL, MD: [From] the possibility of using CAR T-cell therapy earlier in treatment lines and the approval of bispecific antibodies and next-generation bispecifics, to B-cell maturation antigen [BCMA] or GPRC5D, the question is how are we going to treat our patients with these new and exciting approaches?

SURBHI SIDANA, MD: The emergence and approval of bispecific antibodies in multiple myeloma expands our armamentarium to treat patients…. I think it’s wonderful that we have so many choices with even more approaches on the horizon, including linvoseltamab.1 We anticipate additional FDA approvals in the near future.

That will be the next discussion. How do you choose between one or the other bispecific?

The honest answer is “I don’t think we know.” There are some differences in logistics of dosing or hospitalization. Only time will tell.

My bias, though, is if I can use CAR [T-cell therapy] in a patient, then I’ll use it. But if we can’t use CAR T-cell therapy, I would love to use the combination of teclistamab-cqyv [Tecvayli] and talquetamab.

KRINA PATEL, MD, MSc: I think this is a fantastic time to be a myeloma researcher. You know, [with] these options for my patients, I’ve literally put [patients who] were in hospice into remission, and years later they are still alive.

I mean, that’s what brings us to work every day. I think we’re at that point where [we can ask] how do we treat that patient in the best way possible? My job is to make sure these patients get the best therapy at the time they need it.

I think sequencing is one big question. With all these T-cell engagers and CAR T cells, we can’t just keep using that all the time, because we will kill T cells eventually. That’s not good either.

So [determining] when we give GPRC5D and BCMA, and in which order, [is important]. Then do we take a break and do something else? And then do we go back to a T cell again, when the T cells [have recovered]? It’s phenomenal that we have these amazing responses, and we’re getting them earlier and more [patients] get into that MRD undetectable [stage] and longer PFS [progression-free survival]. Until we can cure [patients], we need to learn how to decrease toxicity and increase overall survival by using the combinations.

It’s impressive that just a few years ago you never heard of immunotherapy. And here we are; not only is it used in relapsed/refractory [disease], it’s [being used] earlier, we’re combining them. It reminds me of the era when [all] we had was chemotherapy, and now we have moved into the novel targeted therapies. It’s not just a fad.

NISHA JOSEPH, MD: First, it’s a good problem to have…to have this abundance of riches. I’m thinking about how do we sequence when we have so many options?

[Another point to make] is about the challenge of infections. I also think about how we can optimize delivering CAR T-cell therapy and making sure we’re standardizing that, particularly in community centers, and developing more clear guidelines. I think the other question is about the fixed duration of some of the bispecifics. I know giving these therapies weekly or every 2 weeks has its innate challenges. [We need to think about] how we can best deliver those therapies and what that rationale would be and how we would define that. I think the last point to make concerns access, the idea of access for our patients to these drugs, and some of it is our access to the drugs and [being] able to use these drugs earlier [in the treatment cycle]. [That would] gives us the freedom to not just use what we can in the moment, which is where we are, that’s what we have to do, even if the patient was rapidly progressing.

IRENE M. GHOBRIAL, MD: I want to ask how you measure MRD in the blood, either by next-generation sequencing or next- generation flow. Do you stop therapy when patients are in deep remission? Should we think of fixed duration or risk adaptive?

KRINA PATEL, MD, MSc: I think MRD is really important, prognostically both early and late line. We’ve had [results of] multiple trials show that for patients who are MRD undetectable, at least a year out from transplant or induction versus even late lines, those patients are going to do much better in terms of PFS.

At some point, quality of life comes into play. If I have patients who are early line, but they’re starting to have toxicity [with laboratory] counts or ongoing diarrhea, if they are MRD undetectable, we stop because my goal is to make sure that their quality of life is good. But I do think that eventually it should be risk adaptive. The more patients who are MRD undetectable after something [such as] bispecifics or CAR T, [the more] I think we are going to get longer remissions.

SURBHI SIDANA, MD: I’m going to be contrarian here. We don’t have enough data to use MRD to guide therapy. For a patient who is suffering from toxicity, of course, you use your best clinical judgment. Even if they were on a trial, you’d stop therapy or de-escalate dosing.

But barring that, whether it’s high risk or standard risk, I am not using MRD to guide therapy. Unless they’re having real toxicity, I’m waiting for the results of lots of randomized studies that are ongoing that are evaluating MRD as a tool for de-escalation or escalation.

IRENE M. GHOBRIAL, MD: Do you collect T cells thinking that they’re better early on? Should I have them stored instead of storing the stem cells? Perhaps you can save them for CAR T in the future? I’d like to hear your practice in your different institutions.

KRINA PATEL, MD, MSc: I would love to [store them], but we don’t have the space that I know of or the insurance approval yet, so I can’t do anything until we get that, and we’ll need evidence that frozen cells will work just as well; I think they will. We just need that data for us to then go to the FDA to say we should be able to do this.

NISHA JOSEPH, MD: Factors that might affect stem cell viability include the patient’s age and other factors for potentially more than 1 transplant. So that’s certainly still an option, even if [the patient has] been in remission for a long period of time. If [they do have] a relapse, that’s something that you might discuss with your patient.

SURBHI SIDANA, MD: I think it’s a great question. For the stem cells, we still like to collect for 2 transplants, knowing that we’ll probably never need a second transplant. But sometimes low blood counts can happen post CAR T; [approximately] 5% of patients, in our experience, are requiring a stem cell boost. So it’s a good idea to have [the extra stem cells] as an insurance policy.

I would love to collect T cells. But currently there is no mechanism or even an FDA-approved pathway to manufacture either cell- or cell-to-cell [CAR] from stored cells and cells that were collected at a center with a different protocol that could then, 5 years later, lead to manufacturing of a product. We just don’t have insurance approval or an approved FDA pathway to use those yet.

REFERENCE

1. Linvoseltamab (Bcmaxcd3) initial pivotal phase 2 data show clinically meaningful responses in patients with heavily pre-treated multiple myeloma. Regeneron. News release. December 12, 2022. Accessed July 29, 2023.https://bit. ly/3KlDy1j