In an era where multiple BCMA-directed therapies are approved across various settings for patients with relapsed/refractory multiple myeloma, the investigational FcRH5 x CD3 bispecific antibody cevostamab (RG6160) could represent an additional approach with a novel target to address treatment challenges in the post-BCMA setting, according to Adam D. Cohen, MD.
“We always love to have more options for our patients. The BCMA-directed therapies are moving earlier and earlier; they're already approved in the second line, and the data in the first line are really looking good,” Cohen said in an interview with OncLive®. “It's likely patients are [soon] going to get a BCMA-directed treatment in their first or second line, but we know that, unfortunately, the majority of those patients may still relapse. We know BCMA loss or mutation can be an issue, particularly with the bispecific [antibodies], so having another target to go to in that setting [would] be great.”
Cevostamab was evaluated as monotherapy in a phase 1 trial (NCT03275103) in patients with heavily pretreated, relapsed/refractory multiple myeloma, and data published in Nature showed that the maximum tolerated dose (MTD) was not reached.1 Across all dose levels (n = 324), the rate of grade 3/4 adverse effects (AEs) was 59.6%, and 60.2% experienced serious AEs. Grade 5 AEs occurred in 4.6% of patients, including 0.9% who had grade 5 treatment-related AEs.
Among all patients evaluable for efficacy (n = 323), the overall response rate (ORR) was 42.1% (95% CI, 36.6%-47.6%), including a very good partial response (VGPR) or better rate of 25.1% (95% CI, 20.2%-30%). In patients treated at the recommended phase 2 dose (RP2D) of 160 mg once per day (n = 167), the ORR was 44.3% (95% CI, 36.5%-52.1%), including a VGPR or better rate of 25.7% (95% CI, 18.8%-32.7%). Among the overall population, the median duration of response (DOR) was 11.2 months (95% CI, 8.3-15.6); at the RP2D, the median DOR was 10.4 months (95% CI, 6.2-15.0).
In the interview, Cohen provided background on the development of cevostamab and the rationale for utilizing FcRH5 as a target in multiple myeloma; broke down the key efficacy and safety findings from the phase 1 trial; and detailed ongoing and future research efforts with the bispecific antibody.
Cohen is a professor of medicine in the Division of Hematology-Oncology at the Hospital of the University of Pennsylvania, a member of the Abramson Cancer Center, as well as director of Myeloma Immunotherapy and co-director of the Amyloidosis Program at the University of Pennsylvania in Philadelphia.
OncLive: What is the rationale for utilizing FcRH5 as a therapeutic target in multiple myeloma?
Cevostamab in R/R Multiple Myeloma: Key Highlights
- In a phase 1 trial, cevostamab monotherapy produced an ORR of 42.1% across all doses and 44.3% at the RP2D.
- Instances of grade 3 or higher CRS were rare, and the RP2D utilizes a triple step-up dosing strategy.
- Cevostamab monotherapy is being further evaluated in the phase 3 CEVOLUTION trial, which is investigating the agent vs investigator’s choice of therapy in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
Cohen: One of the nice things about FcRH5 is that it's highly expressed on plasma cells, which are the precursors that turn into myeloma. Its expression is near ubiquitous on myeloma cells, but other than that, it has very limited expression on other normal cells in the body. There is some expression on mature B cells, but it doesn't seem to have expression on other normal tissue. Therefore, it's a pretty clean safety profile in terms of looking at off-tumor, on-target toxicities. [FcRH5 expression] seems to be limited primarily to the late B-cell and plasma cell lineage.
The other thing [to note] is that [FcRH5] expression seems to be independent of BCMA or GPRC5D [expression, which are] some of the other targets that are being hit in multiple myeloma with some of our currently approved therapies. Even if the myeloma loses expression of those other markers, the FcRH5 expression would not be expected to be affected.
What is the mechanism of action of cevostamab?
Cevostamab is a T-cell–engaging bispecific antibody. One end of the molecule attaches to CD3 on T cells, and the other end [binds] to the FcRH5 protein on the myeloma cells. [This mechanism of action] basically brings the T cells to the myeloma cells [and] activates the T cells, where they can then kill [the myeloma cells]. [In the phase 1 trial], cevostamab was explored as an intravenous [IV] infusion. There are subsequent studies looking at it given subcutaneously, but for this study, it was all given as an IV initially as a 4-hour infusion, and then once it was tolerated, it went down to a 2-hour infusion.
As with all bispecific antibodies, there's step-up dosing that has to occur in order to mitigate the risk of cytokine release syndrome [CRS], as well as neurotoxicity. That was a big part of this phase 1 trial: trying to identify the optimal step-up dosing to limit the risk of particularly high-grade or severe CRS.
How was this phase 1 trial conducted? What patients were enrolled?
This was a typical phase 1 dose-escalation study with small cohorts initially, exploring both step-up dosing and the target dose, those were each escalated independently until the optimal step-up dosing was identified, and then the target dose could be further escalated. There actually were a lot of different step-up schedules and doses that were explored in efforts to to optimize that CRS profile.
After initial activity was seen, there were several expansion cohorts looking at different target doses, trying to get a sense of the preliminary efficacy. The primary objectives of the study were safety, determination of the MTD, and the RP2D. Secondary objectives were ORR and DOR.
[Cevostamab] was given as an IV infusion once every 3 weeks. One unique aspect of this protocol was that it was fixed-duration therapy. [We planned for] patients to get 17 cycles, which was 51 weeks or about 1 year of treatment, and then stop. This [fixed-duration aspect] was very novel at the time this trial was designed back in 2017, when in all the other bispecific antibody trials and almost any trial in late-line myeloma, patients were being treated until progression. There's now been a trend to adopting more fixed-duration therapy, and a lot of it is based on this study.
The population under investigation had very heavily relapsed/refractory myeloma and did not have a good alternative treatment option in the eyes of the investigator. This trial enrolled from 2017 to 2023, and [it was interesting] how the myeloma treatment landscape evolved over that time frame. We had a number of new agents approved during the enrollment of the trial, so that the patient population actually became more and more refractory as the trial went on, and patients really had a large amount of exposure to prior BCMA-directed therapies [and] other T-cell engagers which somewhat impacted the results.
What safety data for cevostamab were reported from the phase 1 trial?
The safety profile is a key aspect of this agent. We certainly did see CRS as expected. It was [77.8%] in all patients. It was [63.3%] in patients at the [triple step-up] dosing recommended schema [n = 30], when doses were given on day 1, 2, and 8 at step-up dosing, and then the full dose at day 9. Grade 3 or higher CRS [was rare at 1.2% for all patients], and it tended to be short lived and easily manageable.
[Possible] immune effector cell–associated neurotoxicity syndrome [ICANs] or neurotoxicity was seen, as seen with other agents. It was [13.8%] of patients [at the 160-mg target dose]. Once you got past that initial step-up dosing, the main toxicities were cytopenias—neutropenia, thrombocytopenia, and anemia—although high grades of that were typically under 30% across all dose levels. Other toxicities included fatigue, cough, and nasal congestion, allergic type reactions...and then a low level of gastrointestinal toxicities [such as] diarrhea and nausea.
What was impressive was the infection profile, which maybe differentiates [cevostamab] from BCMA-targeted treatment. While infections were seen in the majority of patients [52.8%], the high-grade, grade 3 or higher [infection rate] was low [20.7%], and that's despite the fact that IVIG and pneumocystis prophylaxis was not mandated on this trial since it opened in 2017. Only approximately one-third of patients actually received or required IVIG, and this is quite different than what we see with the BCMA-directed therapies.
What were the key efficacy findings from this phase 1 study?
In the entire patient population of 324 patients, the ORR was 42.1%. At the RP2D, which is the 160-mg target dose given every 3 weeks, the ORR was 44.3%. There was a difference based on whether patients had a prior BCMA-directed therapy; over 50% of patients had a prior BCMA-directed therapy. In the group [treated at the RP2D] that was naive to BCMA-directed therapy [n = 71], the ORR was actually 60.6%, and that's somewhat in line with what was described in the original registration studies with the BCMA-directed agents, for instance. The ORRs maybe look a little bit lower than some of those agents in their initial registration studies, but this was definitely a more heavily pretreated group of patients, and that influenced [responses] to some degree.
The other key efficacy end point was DOR. At that RP2D, the median duration of response was 10.4 months. [The median DOR] was 19.7 months in patients who were naive to a prior BCMA-directed therapy. What this shows is maybe a slightly lower ORR in a very heavily pretreated population but still very good efficacy, and these [responses] could be durable, especially since this was a fixed-duration therapy. Many of those patients stopped treatment at 17 cycles and still had ongoing responses, some as far out as 4 years in some of the longest patients with the longest follow-up.
What are the next steps of research for cevostamab? Are there potential combination strategies to explore?
A few of the things that are being developed. There's a trial of subcutaneous administration of this agent, with preliminary data presented at the 2025 ASH Annual Meeting and Exposition showing similar efficacy [vs IV administration].2 That may be an option going forward for a little bit more convenience. [We can also] study the drug going forward in combinations, and there was some nice activity shown in combination with pomalidomide [Pomalyst] and dexamethasone in a somewhat less heavily treated population of patients, with over 80% ORR in some of the preliminary data presented at ASH and EHA in the last year.
Recently, the phase 3 registration trial called CEVOLUTION [NCT07555938], which is comparing cevostamab with pomalidomide and dexamethasone vs physician's choice of standard-of-care regimen for patients [who received] 1 to 3 prior lines of therapy. That's a worldwide study that just recently opened, so we'll see if that sort of allows the drug to get approved.
Going forward, [we'll see cevostamab evaluated] in a lot of other combinations as well. We've been exploring an investigator-initiated [phase 2] study [NCT05801939] at the University of Pennsylvania giving cevastomab after a BCMA-directed CAR T-cell therapy [as] a consolidation approach, starting about 2.5 to 3 months after the CAR T-cell therapy, with the idea that maybe by switching the antigen target, you may be able to eliminate some of that BCMA-low or BCMA-negative reservoir of myeloma that could escape the CAR T cells and perhaps lead to deeper, more durable remissions. We showed some preliminary data at ASH 2025 and are hoping to have updated [data] at ASH [in 2026].
There's also combinations of cevostamab with other bispecific antibodies, immunomodulatory drugs, and other immune-related or -modulating agents. There's a lot of interesting ways that this drug can be used, and we'll hopefully learn over the next few years what the optimal combination strategy is.
References
- Cohen AD, Richter J, Trudel S, et al. FcRH5×CD3 bispecific antibody cevostamab in relapsed or refractory multiple myeloma: a phase 1 trial. Nat Med. Published online July 22, 2026. doi:10.1038/s41591-026-04522-3
- Ho PJ, Quach H, Delimpasi S, et al. Subcutaneous cevostamab demonstrates manageable safety and clinically meaningful activity in relapsed/refractory multiple myeloma (RRMM): First results from the phase Ib CAMMA 3 study. Blood. 2025;146(suppl 1):700. doi:10.1182/blood-2025-700
