Cevostamab-Based Combos Could Represent Next Bispecific Antibody Approach in R/R Myeloma

The FcRH5 x CD3 bispecific antibody cevostamab (RG6160; BFCR4350A) could be part of the next wave of bispecific antibodies to impact the multiple myeloma treatment paradigm, with this agent displaying the potential to be integrated as part of combination strategies, according to Joshua Richter, MD.

At the 22nd Annual International Myeloma Society (IMS) Meeting and Exposition, investigators presented data from the phase 1 CAMMA 1 study (NCT04910568), which demonstrated that in patients with relapsed/refractory multiple myeloma who were naïve to BCMA-directed therapy, cevostamab given at a target dose of 70 mg (n = 29) in combination with pomalidomide (Pomalyst) and dexamethasone elicited an overall response rate (ORR) was 86.2% (95% CI, 71.9%-100%).1 When cevostamab was given in the same combination at a dose of 105 mg (n = 25), the ORR was 88.0% (95% CI, 73.3%-100%).

In an interview with OncLive®, Richter broke down the implications of the data from CAMMA 1 and detailed the next steps of investigation for cevostamab-based therapies in multiple myeloma.

Richter is an associate professor of medicine at The Tisch Cancer Institute and director of Multiple Myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai in New York, New York.

OncLive: What is the rationale for targeting FcRH5 in the development of therapies for multiple myeloma?

Richter: Right now in multiple myeloma, there are a lot of different targets, but there are 3 leading candidates for bispecific [antibody] targets: BCMA, GPRC5D, and FcRH5. For [agents targeting] BCMA, we already have a number of [bispecific antibodies] FDA approved, including teclistamab-cqyv [Tecvayli], elranatamab-bcmm [Elrexfio], and linvoseltamab-gcpt [Lynozyfic]. BCMA is a great target, but BCMA is expressed on other things besides plasma cells, including some B cells. One of the downsides is the infection rate for BCMA-based therapies can be quite high.

GPRC5D is another great target that's expressed on plasma cells, and this is the target of the bispecific antibody talquetamab-tgvs [TALVEY]. The problem is GPRC5D is expressed on other non-hematopoietic tissue, such as the squamous epithelium of the hands and feet, the oropharynx, and the olivary nucleus. This leads to some off-tumor, on-target [adverse] effects [AEs] such as desquamating rash, dysgeusia, anorexia, and ataxia.

FcRH5, in many ways to me, is the Goldilocks [target]. It doesn't have those same off-tumor, on-target toxicities of GPRC5D, but the infection rate is lower than [targeting] BCMA. FcRH5 is emerging as a hot target where we can find the balance of achieving deep and durable remissions without some of the major AEs.

Why is cevostamab being evaluated as part of combination strategies in relapsed/refractory multiple myeloma?

As we start to look into combination strategies with bispecific antibodies, you're going to see a lot of studies like CAMMA 1 that start incorporating immunomodulatory drugs [IMiDs], like lenalidomide [Revlimid] or pomalidomide. We saw this in the phase 1 MonumenTAL-2 trial [NCT05050097] when we combined talquetamab and pomalidomide.

The interesting thing [in CAMMA 1] is that when we're using pomalidomide with cevostamab, we're not necessarily using pomalidomide for its direct anti-myeloma activity. We're using it for its immunomodulatory effect, remembering that the main mechanism of action of cevostamab is T-cell redirection. IMiDs modulate the immune system and augment T-cell response. The [goal] of adding lower-dose pomalidomide with cevostamab are that we're enhancing the T-cell activity against the myeloma cells, not just relying on pomalidomide to fight the myeloma by itself.

We're really excited about these combinations. One of the things we have to be aware of is that as we augment T-cell response, some of the T-cell–specific toxicities, such as cytokine release syndrome [CRS], may be heightened. In the CAMMA 1 study, they did see [any-grade] CRS rates that were high overall, [including 78.6% with double step-up dosing (n = 28) and 53.8% with triple step-up dosing (n = 26)].

However, we do recognize that one of the things we're starting to do in standard of care is giving prophylactic tocilizumab [Actemra] to reduce the rates of CRS, and so far, we haven't seen any decline in responses. From the original phase 1 study [NCT03275103] of cevostamab, Suzanne Trudel, MSc, MD, [of Princess Margaret Cancer Centre in Toronto, Canada], presented the prophylactic tocilizumab data with cevostamab, and it showed a marked reduction in rates of CRS and better response rates, probably because we're able to keep people on time with dosing.2

What are the next steps for investigating cevostamab?

More data are needed, but ultimately, [data from CAMMA 1] are leading to the [phase 3] Cevolution study, which will be the registrational study to open up in [2026].3 [Cevolution] will be combining cevostamab with pomalidomide and comparing it against other pomalidomide-based triplets in early-relapse multiple myeloma.

The next phase for cevostamab is pushing forward toward approval. At the moment, it doesn't seem that monotherapy is going to be the road to approval, [but] combination strategies [seem more likely], and some of the more important ones that we're seeing are going to be in the Cevolution study, combining with pomalidomide. There have been some amazing data presented by Adam D. Cohen, MD, of Penn Medicine, using cevostamab as a consolidated approach after CAR T-cell therapy. Additionally, be on the lookout for some very interesting combination studies [with cevostamab], potentially with other bispecific antibodies, that are going to be rolling out in 2026.

References

1. Mian HS, Riley CH, Popat R, et al. Cevostamab plus pomalidomide (pom) and dexamethasone (dex) in relapsed/refractory multiple myeloma (RRMM): phase I dose-expansion results from the CAMMA 1 study. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-14.
2. Trudel S, Bahlis N, Spencer A, et al. Pretreatment with tocilizumab prior to the CD3 bispecific cevostamab in patients with relapsed/refractory multiple myeloma (RRMM) showed a marked reduction in cytokine release syndrome incidence and severity. Blood. 2022;140(suppl 1):1363-1365. doi:10.1182/blood-2022-159381
3. Roche Pharma Day 2025. Roche. September 22, 2025. Accessed November 25, 2025. https://assets.roche.com/f/176343/x/059c686d27/20250922_pharma-day-2025_vf_online.pdf