Bispecific Antibody De-Escalation: Varying Dosing Strategies Aim to Improve Safety, Maintain Efficacy in R/R Myeloma

Rahul Banerjee MD, FACP

Treatment-free intervals may serve as one strategy to enhance long-term outcomes for patients with relapsed/refractory multiple myeloma being treated with bispecific antibodies, according to Rahul Banerjee MD, FACP, who noted that reducing toxicities without compromising efficacy is the goal for de-escalation strategies with these agents.

In an interview with OncLive^®, Banerjee discussed the evolution of bispecific antibody dosing regimens in multiple myeloma and highlighted how additional research could provide additional clarity on the optimal dosing of these agents.

Banerjee, who serves as a physician-researcher and an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center, as well as an assistant professor in the Division of Hematology and Oncology at the University of Washington in Seattle, shared additional insights on the evolution of bispecific antibodies in multiple myeloma in another article.

OncLive: How have past and ongoing studies examined different dosing schedules for bispecific antibodies in multiple myeloma?

Banerjee: Most of our data for teclistamab-cqyv [Tecvayli] were [derived from] the phase 1/2 MajesTEC-1 trial [NCT03145181; NCT04557098]. That trial is complicated because there were various dosing schedules—[the initial schedule] was weekly dosing until disease progression. Data were originally published in the New England Journal of Medicine [in 2022]. There have been [data for] many cohorts published since then [looking at different dosing schedules], including once every 2 weeks and so forth.

For elranatamab-bcmm [Elrexfio], we have mainly been looking at [data from] the phase 2 MagnetisMM-3 trial [NCT04649359]. [Dosing for elranatamab on this study] has also been evolving over time. Instead of giving treatment every week, it's gone to every 2 weeks and now every 4 weeks. They have been modifying the cohort as they go, which makes things tricky [in terms of interpreting data for] progression-free survival, duration of response, or overall response rate [ORR]. [Data] depend a little bit on what cutoff you're looking at.

For linvoseltamab [REGN5458], [data] were published earlier [in 2024] in the Journal of Clinical Oncology. [The phase 1/2 LINKER-MM1 trial (NCT03761108)] also had 2 different dosing cohorts [with full doses at] 50 mg or 200 mg.

Studies [examining reduced dosing schedules for bispecific antibodies] are a work in progress, but the trials on which they're predicated are continuing to evolve. It is like an arms race to give patients less therapy and maintain the same results, and I love that.

Those 3 agents you just mentioned were BCMA-targeted bispecific antibodies. Are dosing schedules of interest for agents in this class with different targets?

Talquetamab-tgvs [Talvey] is a different class entirely. It is a GPRC5D-directed bispecific antibody, and it is the only GPRC5D therapy that we have [currently approved]. In my experience, I have been reserving it primarily for patients following [progression] on a BCMA-directed therapy, such as a BCMA-targeted bispecific antibody, CAR T-cell therapy, or—in the future—an antibody-drug conjugate such as belantamab mafodotin-blmf [Blenrep].

I liked the phase 2 MonumenTAL-1 trial [NCT04634552]—[data from which supported the accelerated approval of talquetamab]—because investigators looked at different dosing regimens, and importantly, more than 1 dosing regimen made it into the FDA package insert. In that study, there was 1 cohort where [patients received] 2 step-up doses, then a full treatment dose, and then once-a-week dosing at 0.4 mg/kg. If you assume that bispecific antibodies are stepped up or started in the inpatient setting, [this dosing schedule] means patients spend approximately 7 days in the hospital [for step-up dosing] and then once a week thereafter. They also had a different dosing schedule that was 3 step-up doses and a bigger dose [of 0.8 mg/kg given] once every 2 weeks. That [translates] to approximately 10 days in the hospital [during step-up dosing], but then only every 2 weeks thereafter.

I like [the different dosing options] because for my patients [who are a] 10-minute drive away, they don't mind the shorter hospitalization and [traveling in for treatment] once a week. Others would prefer treatment every 2 weeks, just from time toxicity alone and the travel distance.

How have recent dose modification studies impacted the way you treat patients with agents such as talquetamab?

What I would argue as one of the most practice-changing studies of 2023 was an extension of MonumenTAL-1 presented by Ajai Chari, MD, [of the University of California, San Francisco], and colleagues at the ASH Annual Meeting. They looked at de-escalating the dosing [of talquetamab] by going from, for example, dosing every 2 weeks to every 4 weeks, or cutting the dose in half and giving it every 2 weeks. They found that most of the toxicities of talquetamab got better with [adjusted dosing].

GPRC5D is one of the oddest proteins in the history of proteins. It is found on myeloma cells, tongue cells, skin cells, and nail cells, comprising an odd constellation of epithelial cells and plasma cell lineage cells. You see good responses [with talquetamab], even in patients who have gotten prior BCMA-directed therapies. You see ORRs of approximately 50% to 70% with talquetamab. However, you can also see dysgeusia in approximately 50% to 70% of patients. Each of my patients who has been on talquetamab has noticed some element of change to their taste. Some have had nail issues or skin issues. [Treatment with talquetamab] can be tricky because [the tongue] is one of the few organs that our other medications don't typically cause that many toxicities to, other than high-dose melphalan during transplant. [Dysgeusia] is hard for patients. I have had patients who lose 10 to 20 pounds as a result of being on therapy. They’re in remission, but [dysgeusia] is hard to manage.

[Chari and colleagues] found that if you de-escalate the dosing [of talquetamab], although weight loss did not [entirely improve], many other toxicities such as dysgeusia got better. This is an important message for the field. In myeloma, it's unfortunate that we have been chasing the maximum tolerated dose [MTD] of different agents for the longest time. Even for our oldest medication, dexamethasone, the dose we give is much too high in myeloma. I don't think anyone doubts that—we're just trying to figure out how far we can back off.

With bispecific antibodies, I like that they're beginning this journey [of determining optimal dosing] early. Even without the FDA nudging, researchers are asking, ‘What if we go down a level? What if we minimize time toxicity?’ You may find that the safety profile gets better in terms of infectious profiles from BCMA-targeted bispecific antibodies and in terms of these tongue, skin, and nail toxicities from GPRC5D-targeted bispecific antibodies.

Aside from safety, are there any other potential benefits from reduced dosing of bispecific antibodies?

What's intriguing—and this isn't totally proven yet—is that there are preclinical data to suggest that bispecific antibodies exhaust T cells. I'm not surprised by that because on one level, a bispecific antibody is an unnatural thing to expose to a T cell. You're taking a T cell that was destined to look for something, and you rip it away to go attack another target instead. That will lead to T-cell exhaustion. There are so many myeloma cells being attacked again and again. There are some intriguing data that a treatment-free interval may help to rejuvenate some of those T cells and prevent T-cell exhaustion [in patients receiving bispecific antibodies].

It's funny to watch this whole house of cards of MTD possibly fall apart. You may find that de-escalating the dose is better, both for safety and time toxicity, and then down the line, it may be better with effectiveness. With talquetamab, we're seeing a little bit of this [with reduced dosing]. It's hard to say whether it's because patients can stay on treatment for longer because it is more tolerable. It [may also be] because these T cells are less exhausted. This is a fascinating idea [that requires further study].

Everything [we know about bispecific antibodies in multiple myeloma] is constantly changing, even what I'm saying right now. That may be annoying, but I could not be happier for it, because everything is changing in the right direction.