Teclistamab, Other BCMA-Targeted Agents Represent New Options in Relapsed/Refractory Myeloma

The bispecific antibody teclistamab-cqyv (Tecvayli) joined the CAR T-cell therapies ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma) as FDA-approved BCMA-targeted therapies for patients with relapsed/refractory multiple myeloma. According to Andrew Kin, MD, the development of other novel agents directed at BCMA could continue to shift the multiple myeloma treatment landscape.¹

“BCMA-targeted therapy in one form or another is extremely effective. All [patients with] multiple myeloma patients should be considered for at least one BCMA-targeted therapy, if it is available and if they can get access to it,” said Kin, who participated in an OncLive^® State of the Science Summit™ on multiple myeloma.

In an interview with OncLive^®, Kin expanded on the ways BCMA-targeted therapies that are currently available and under development have shifted the treatment landscape for relapsed/refractory multiple myeloma, the implications of the approval of teclistamab, and the limitations that still exist for using BCMA-targeted agents. Kin is a medical oncologist from the Barbara Ann Karmanos Cancer Institute, in Detroit, Michigan.

OncLive^®: What message were you hoping to convey to colleagues in your presentation on the development and emergence of BCMA-targeted agents in multiple myeloma?

Kin: The key takeaway was how much of an impact the BCMA-targeted agents have had in what has historically been a difficult [treatment setting]. Once patients with myeloma have reached the end of recent novel therapies with proteasome inhibitors, immunomodulatory drugs, and CD38-targeted monoclonal antibodies, patients are very refractory and have poor overall survival. Almost regardless of the choice of agent, the BCMA target is a phenomenal target that patients now have access to.

What led to the FDA withdrawal of the BCMA-targeted antibody-drug conjugate (ADC) belantamab mafodotin-blmf (Blenrep), and could this agent have a different role in the future?

[Belantamab mafodotin] was the first [BCMA-targeted agent] approved. It is an ADC linking a microtubule-disrupting chemotherapy agent to monoclonal antibody targeting BCMA. [Belantamab mafodotin] had similar response rates from what you would expect for other drugs in the penta-refractory space.

Belantamab mafodotin has some unique toxicities, particularly with the corneal involvement, which is on-target, off-tumor effects of the microtubule agent that is used. What got [the agent] withdrawn from the market was data from the [phase 3] DREAMM-3 trial [NCT04162210], where they tried to compare it head-to-head as a superiority study with pomalidomide [Pomalyst] plus low-dose dexamethasone, which is a very highly active [regimen].

Although, nominally, the progression-free survival [PFS] was better [with belantamab mafodotin at 11.2 months] vs 7.0 months, it was not statistically superior. That was the FDA-required confirmatory trial that they were going to use to obtain [regular] approval. In this case, they have temporarily taken it off the market, although it is still currently being explored in ongoing clinical studies.² Hopefully, we will have it back available as an FDA-approved agent in the future.

What have been the implications of the FDA approval of the BMCA/CD3-targeted bispecific antibody teclistamab for heavily pretreated patients?

This is the first in what is hopefully many approvals in a class of BCMA-targeted agents and other targets using a platform called bispecific T-cell engagers. This is [similar to] a monoclonal antibody in that one side targets BCMA. However, it is a dual-targeted bispecific monoclonal antibody, and the second half of the molecule targets the CD3 receptor on T cells. The T-cells then [bring the agent] directly in proximity to the myeloma cells and causes their destruction.

The main adverse effect, as you would expect with CAR T-cell therapies and any T cell–based product is cytokine release syndrome [CRS]. Monitoring and managing [CRS] early [is important]. However, what is particularly nice about this and other T-cell engaging products are the high responses and depth of responses. [We even see] minimal residual disease [MRD]–negative responses, which are unheard of at this stage of patients and the number of lines they have seen to this point. This is a phenomenal platform using a highly effective target that has produced incredible results for patients that had very few good options to choose from.

What are some of the unmet needs that still exist for patients with penta-refractory multiple myeloma?

Not every patient is necessarily a candidate for these [BCMA-targeted] therapies. [These treatments] are still high in intensity with CRS and the monitoring for that. [This applies for] both [teclistamab] and CAR T-cell therapies. That is why I am hopeful that belantamab mafodotin will get reapproved at some point, because that would still give us the BCMA target to use without having those same risks of CRS.

One of the other drawbacks currently between the CAR T-cell therapies, teclistamab, and other agents in the pipeline and in various stages of FDA submission is that many of them also target the BCMA molecule. There are data to say that you can see responses, but those eye-popping overall response rates go down for patients that have had exposure to a prior BCMA-targeted therapy. That is where having bispecific antibodies, CAR T-cell therapies, or other options that utilize different targets rather than BCMA will only further expand the field from here.

Are there any other limitations for the use of BCMA-targeted therapies in this patient population?

With CAR T-cell therapy, the waitlist and the manufacture times have been a problem. There have been some real-world, single-center studies to say that from an intention-to-treat standpoint, if you include patients that were on the waitlist and did not make it to getting a CAR T-cell therapy, the overall response rate [is lower]. That is part of the big difference between the CAR T-cell therapies and bispecific antibodies; you do not have that time bias of [needing] to survive long enough to get the CAR T-cell therapy.

The other big limitation right now is the cost of both CAR T-cell therapies and the bispecifics. [Teclistamab] was basically priced to match, or be slightly above, what the CAR T-cell therapies were. In a best-case scenario for responders, they could be on these products for a couple years at a cost exceeding half a million dollars per year, which is well above what the current market can sustain, especially as we get more and more patients with multiple myeloma into this setting. More survivors of multiple myeloma means more patients on these drugs with an ever-increasing cost. Furthermore, the next wave of studies, naturally, wil try to bring these [agents] earlier into lines of therapy before the T cells have been exposed to other therapies. If you are trying to bring these therapies into earlier [settings] and then combining them with other [agents], the compound cost of all of that [will approach] a breaking point, if we are not already there.

References

1. FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed March 30, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline. November 22, 2022. Accessed March 30, 2023. https://us.gsk.com/en-us/media/press-releases/