Time-Limited Bispecific Antibodies Could Represent Next Shift in Myeloma Treatment

As bispecific antibodies have become more engrained in the treatment armamentarium for patients with relapsed/refractory multiple myeloma, ongoing research could help shift how these agents are used, including work looking at time-limited treatment, according to Rahul Banerjee MD, FACP.

“Everything that I'm saying right now [could] be wrong 2 years from now, and I could not be happier for that. The caveat is that the field is rapidly evolving,” Banerjee explained.

In an interview with OncLive^®, Banerjee discussed the rapidly evolving therapeutic landscape of bispecific antibodies in the treatment of patients with multiple myeloma, expanded on the importance of acknowledging the time toxicity associated with these agents, and highlighted the evolving use of the class of treatment.

Banerjee serves as a physician-researcher and an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center; he is also an assistant professor in the Division of Hematology and Oncology at the University of Washington in Seattle.

OncLive: How have bispecific antibodies morphed the treatment paradigm for multiple myeloma?

Banerjee: I presented some of the updates from the 2024 ASCO Annual Meeting and 2024 EHA Congress, in terms of the big BCMA-targeted bispecific antibodies, as well as [the GPRC5D x CD3 bispecific antibody] talquetamab-tgvs [Talvey]. A bispecific antibody means different things to different people. In my world of multiple myeloma and lymphoma, I would define a bispecific antibody define as something that binds CD3 in a T cell and a cancer cell antigen. For example, tarlatamab-dlle [Imdelltra] would count, but amivantamab-vmjw [Rybrevant] in small cell lung cancer would not count because it's not binding CD3 and redirecting T cells.

We are lucky to have several [bispecific antibodies] in multiple myeloma. In terms of a BCMA-targeted agents, as of August 2024, [we have 2 approved]: teclistamab-cqyv [Tecvayli] and elranatamab-bcmm [Elrexfio]. We have others that are in late-stage development, such as linvoseltamab [REGN5458] , which will hopefully be approved soon—[the FDA issued a complete response letter to the biologics license application for linvoseltamab in August 2024]. ABBV-383 is also being investigated. We have 1 approved GPRC5D-targeted bispecific antibody, talquetamab. We have others, including some targeting different antigens, that are also under investigation.

Although none of these agents have been compared in head-to-head trials, how do currently available bispecific antibodies compare with each other in terms of efficacy?

Bispecific antibodies, clinically, are probably more similar than they are different. The overall response rates [ORRs] for them are relatively similar in the 60% to 75% range. One of the interesting things about bispecific antibodies is that the time to first response is typically between 1 to 2 months for everybody. In my experience, you can rapidly differentiate patients who are having a response because they have good T cells and the antigens being expressed and are blocking it.

Normally in cancer, we care about progression-free survival [PFS]. It’s not as helpful [with bispecific antibodies] because you see these 2 populations [of responders vs non-responders] diverge quickly. For some patients, after a month or 2 of a bispecific antibody, if it doesn't work, we move on to something different. Duration of response [DOR] ends up being more important, because after that first month, if the patient is having a response, they ask me, ‘How long can I maintain a response? Do I go on to CAR T-cell therapy or do I stay on this bispecific?’ That is where things get interesting.

I talked about how the ORRs are similar between [bispecific antibodies]; the DOR depends from study to study, but [the median DOR] is probably at the 2- or 3-year mark for most of them, based on what we're seeing right now, depending on variations and the dosing for these different phase 1 and 2 trials. The efficacy [between the agents] is similar.

What toxicities should oncologists and patients be aware of for bispecific antibodies in multiple myeloma?

The toxicities are similar [across bispecific antibodies] in terms of cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome. Infections are a big problem across the board with BCMA-targeted bispecific antibodies. I recommend intravenous immunoglobulin [IVIg] for these patients to help prevent infections.

What's different between these bispecific antibodies are the logistics. The idea of time toxicity in multiple myeloma is real. Our patients, particularly in the relapse setting, spend much more time in clinic than even they might expect and certainly more than we realize, if you include time spent scheduling, coming in, getting blood work, getting IVIg, etc.

[One of the reasons I think] that what I am saying right now will be outdated 2 years from now is [that we are looking at ways to] deescalate treatment. How do we get the drug started more quickly for patients and spend less time in the hospital? We are investigating that. You will see different variations between the [agents] in terms of how many hours of inpatient observation have historically been required after each step-up dose. The step-up dose is the priming dose to mitigate the risk of CRS, and that varies between the drugs. How quickly you can get to dosing of once every 2 weeks for the trials varies between the drugs. For teclistamab, right now, it's 6 months sustaining a complete response. For other drugs, it's more like every after 4 months or 6 months. Linvoseltamab and elranatamab have evidence for [shifting dosing to once] every 4 weeks. The field is rapidly evolving.

We've also published data in the real-world setting; people de-escalate bispecific antibodies much faster than the 6-month mark. I certainly do the same in my practice because patients have time toxicity and infections, and it makes sense to de-escalate their treatment to once a month so they don't have as many adverse effects or time in clinic. We are seeing this evolve across all bispecific antibodies, and that will continue to evolve.

How are you hoping that treatment with these agents will evolve in coming years to combat time toxicities?

Everything I've said is still predicated on the idea that patients stay on bispecific antibodies forever, basically until progression. The DOR can be 2 years. By the book, that would be 2 years of coming in every single week for therapy, which sounds crazy. Therefore, we're de-escalating to once-a-month [dosing], and there are studies ongoing of quarterly dosing once every 3 months.

The phase 2 LimiTec trial [NCT05932680] being run out of the Abramson Cancer Center at Penn Medicine [is evaluating] time-limited [teclistamab] at 6 to 9 months of treatment before patients stop and are observed carefully. I believe that's where the future is headed. If we can [offer time-limited therapy with bispecific antibodies], that will be fascinating in terms of the broader discussion of bispecific antibodies vs CAR T-cell therapy.

CAR T-cell therapy is a little bit tougher logistically on the front end to get situated, but on the back end, it's a one-time infusion, and patients typically don't need to come in more than once a month for blood work or perhaps IVIg. Bispecific antibodies are a little bit tougher in terms of time toxicity, but if it's 6 to 9 months of therapy before patients are done, that might equalize the playing field here. You may see some patients say, ‘CAR T-cell therapy has some scary toxicities or is too impractical for me; let's go with a bispecific antibody instead.’