Bispecific Antibodies and CAR T-Cell Therapies Continue to Reshape Myeloma Treatment Landscape

The emergence of CAR T-cell therapies and bispecific antibodies has redefined the treatment landscape for relapsed/refractory multiple myeloma, providing new options for heavily pretreated patients, according to Syed Abbas Ali, MBBS, who emphasized the importance of sequencing strategies and patient-specific considerations in this evolving paradigm.

“These are very exciting times for our patients and for ourselves as clinicians. There's a lot of discovery to be made,” Ali said.

In an interview with OncLive®, Ali discussed how CAR T-cell therapies and bispecific antibodies have affected the multiple myeloma treatment paradigm, sequencing considerations for BCMA-targeted agents, and the need to continue developing these types of therapies with novel targets.

Ali is a medical oncologist and assistant professor of oncology at Johns Hopkins School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

OncLive: How have the emergence of bispecific antibodies and CAR T-cell therapies impacted the treatment paradigm for multiple myeloma?

Ali: CAR T-cell [therapies] and bispecific antibodies have revolutionized the late-relapse [treatment] landscape in multiple myeloma. Previously, this was a situation where we had a paucity of drugs, and in the absence of a clinical trial, there would be a point where patients did not have many options at all—certainly not any good options.

[The emergence of CAR T-cell therapies and bispecific antibodies] has allowed us to [have other options for] a particular population of patients who were penta-drug refractory or triple-class refractory. At the time CAR T-cell therapies and bispecific antibodies were introduced, [identifying treatments for these patients] was an unmet need. Our patients in that setting now have access to drugs that aren't salvage efforts. These are treatment modalities that work well, including in patients who are heavily relapsed or may have a very aggressive myeloma. This has changed the field entirely. Every few years or so, we get big leaps [in treatment], and CAR T-cell therapies and bispecific antibodies have changed things.

The next leap within that same paradigm happened when CAR T-cell therapies moved into the earlier-line settings with the FDA approval at first relapse and second relapse for ciltacabtagene autoleucel [Carvykti] and idecabtagene vicleucel [Abecma], respectively.

At any given time, you had a certain number of patients who had a late relapse and were eligible for CAR T-cell therapy. By moving these [agents into earlier settings], that number has increased a lot. The earlier indications have allowed our patients access to drugs that they may not have otherwise been able to get and have been shown to have better overall survival.

However, [increasing the number of patients eligible for CAR T-cell therapy] has implications for infrastructure, the size of institutions, access to therapy, and delivering that care.

When CAR T-cell therapies and bispecific antibodies are both viable options for patients in the late-relapse setting, what factors do you consider when selecting between these treatments?

There have been numerous attempts to look at the data on T-cell–engaging therapies to see how patients who meet certain criteria respond. For example, you may have patients who are BCMA-exposed because BCMA is the target for [the 2 approved] CAR T-cell therapies and [most] bispecific antibodies. [Prior exposure to a] BCMA-directed agent could include an antibody-drug conjugate, CAR T-cell therapy, or bispecific antibody. What effect does that have when you give another BCMA-targeted agent downstream?

In general, looking at how things have gone, if you are targeting BCMA, then it's usually better to try to give your CAR T-cell therapy first, followed by a BCMA-targeting T-cell engager or bispecific antibody [in a subsequent line]. It seems that the CAR T-cell therapies are disadvantaged if [a patient has already received] an anti-BCMA therapy.

It's a bit different when you do it the other way around if you give the CAR T-cell therapy first and then the BCMA-targeting bispecific antibody later. Although there is a reduction in response, the hit [in the efficacy of the bispecific antibody] is not as large. CAR T-cell therapy seems to be disadvantaged if you've had BCMA-targeted therapy prior to the CAR T-cell therapy, particularly if [a patient] had that anti-BCMA therapy for a longer period of time or very recently prior to CAR T-cell therapy.

If one has to go with BCMA-directing therapies in sequence, then ideally, it's nice to have a gap between them of longer than 3 to 6 months. It's [also] nice to have a situation where a patient was not exposed to the prior anti-BCMA therapy for a long period of time. If a patient had a great response to a prior BCMA-targeted therapy, then [received a non–BCMA-targeted] therapy in between [before] another anti-BCMA therapy months later, then there's a higher degree of confidence that the subsequent anti-BCMA therapy will work because you've shown on at least 1 occasion that anti-BCMA therapies work for this patient.

By and large, for patients who are able to get a CAR T-cell therapy, [clinicians should] go with a CAR T-cell therapy first. If you can't go with CAR T-cell therapy and you have to go with another anti-BCMA agent, then [clinicians should] try to see if there is an alternative. Alternatives include other treatment modalities such as bispecific antibodies in clinical trials or CAR T-cell therapies with other targets, such as GPRC5D. The FDA has already approved [the GPRC5D-targeted bispecific antibody] talquetamab-tgvs [(Talvey) for patients who received at least 4 prior lines of therapy].

[Using an alternative treatment] does [leave the door open for] anti-BCMA therapy, whether it's CAR T-cell therapy or so on. More drugs [being approved] will also give us a greater degree of flexibility.

How could identifying novel targets beyond BCMA help address sequencing challenges in patients previously treated with BCMA-targeted agents?

We lucked out in the very beginning with BCMA as a target because it's a great target. It's almost universally expressed on plasma cells, and it's restricted in its expression, [meaning] that [it isn’t] typically [expressed] on anything other than plasma cells. [BCMA-targeted therapies] will typically give patients an on-target effect but not off-tumor effects, which is an issue with a lot of other targets.

By comparison, a target like GPRC5D is [highly] expressed on myeloma cells, but it is also present in cells in the mucosa, which can lead to taste changes and changes in the skin and nails [with GPRC5D-directed therapies]

[BCMA and GPRC5D] are great [targets], but we need to increase the repertoire. The challenge is finding targets often expressed on myeloma cells, expressed in a high density, and don't disappear when you put them under pressure with treatment. Numerous [novel] targets are being studied, and we'll have to see how the early- and later-phase trials pan out with those.

It's easier said than done to find something that's only present on one particular kind of tissue and not present anywhere else because the body likes to reuse things in many different ways.