Combination therapy with cevostamab (BFCR4350A), pomalidomide (Pomalyst), and dexamethasone produced robust efficacy, favorable immune modulation, and reduced high-grade cytokine release syndrome (CRS) risk in patients with heavily pretreated multiple myeloma, according to Shaji Kumar, MD.
Findings from the dose-expansion portion of the phase 1 CAMMA 1 trial (NCT04910568) showed that among patients with relapsed/refractory multiple myeloma who received cevostamab plus pomalidomide and dexamethasone, the overall response rate (ORR) was 86.2% (95% CI, 71.9%-100%) among patients who received cevostamab at 70 mg (n = 29) and 88.0% (95% CI, 73.3%-100%) among those who received the agent at 105 mg (n = 25).1 At these respective target dose levels, the rates of minimal residual disease (MRD)–negative complete response (CR) or better at any time were 46.7% (95% CI, 21.4%-71.9%) and 38.5% (95% CI, 12.0%-64.9%).
Furthermore, biomarker analyses showed that both doses of cevostamab generated rapid, deep, and durable serum BCMA level decreases, which were determined to be consistent with effective tumor reduction levels.2 Additionally, the highest levels of T-cell activation were observed during cycle 1 of cevostamab, and after the addition of pomalidomide, reductions in T-regulatory cells—high levels of which are associated with poor T-cell antitumor activity—were seen at both cevostamab target dose levels.
“The data show no additional safety issues compared with cevostamab alone, but also good efficacy, and we can decrease the [incidence of] higher-grade CRS with triple step-up dosing,” Kumar said in an interview with OncLive®.
In the interview, Kumar discussed the unique mechanism of action of cevostamab, efficacy and safety data with the combination from CAMMA 1, and future directions for the development of increasingly individualized myeloma therapies.
Kumar is leader of Cancer Risk Assessment in the Early Detection and Interception Research Program, a consultant and research chair in the Division of Hematology in the Department of Internal Medicine, and a professor of medicine at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.
Highlights From the Primary Analysis of CAMMA 1
- Cevostamab plus pomalidomide and dexamethasone induced high ORRs of 86.2% (95% CI, 71.9%-100%) at the 70-mg cevostamab dose level and 88.0% (95% CI, 73.3%-100%) at the 105-mg dose level among BCMA-directed therapy–naive patients with relapsed/refractory multiple myeloma.
- In the double step-up dosing cohort, MRD negativity was achieved by 46.7% (95% CI, 21.4%-71.9%) of patients treated at the 70-mg dose and 38.5% (95% CI, 12.0%-64.9%) of patients treated at the 105-mg dose.
- The implementation of a triple step-up dosing regimen provided optimal safety mitigation, reducing the incidence of grade 2 or higher CRS and the use of tocilizumab (Actemra) to less than 10%.
OncLive: What is the rationale for targeting FcRH5within patients with multiple myeloma?
Kumar: Studies have shown that FcRH5 is uniformly present on myeloma cells across the spectrum of plasma cell disorders. It seems like a good target to go after with the different immunotherapy approaches we have. Cevostamab represents the first of the bispecific antibodies targeting FcRH5 on myeloma cells. Close behind are other investigational strategies looking at CAR T-cell therapies targeting FcRH5, as well as antibody-drug conjugate–type approaches, to see whether they can go after similar targets.
What is the mechanism of action of cevostamab, and what differentiates it from other bispecific antibodies that have been investigated in myeloma?
Cevostamab is a CD3 x FcRH5 bispecific antibody that works in a similar way to other T-cell redirection therapies and bispecific antibodies. The [bispecific antibodies] that are approved in myeloma and available in the clinic include teclistamab-cqyv [Tecvayli], elranatamab-bcmm [Elrexfio], and linvoseltamab-gcpt [Lynozyfic]. Those 3 are all BCMA-targeting bispecific antibodies.
Cevostamab is different because it targets FcRH5. It seems that bispecific antibodies, whether they target BCMA, GPRC5D, or FcRH5, broadly elicit similar response rates of approximately 60% to 70%. To some extent, [responses] depend on what treatments patients have received before and whether they have received T-cell redirection therapy against the same antigen before. FcRH5 is a new target and potentially a different approach for patients who have already received a BCMA-targeted bispecific antibody or CAR T-cell therapy.
What was the design of CAMMA 1?
The CAMMA 1 trial is evaluating cevostamab alone or in different combinations. It’s a multi-arm trial exploring the utility of this bispecific antibody in a wide variety of different clinical settings in patients with multiple myeloma. Arm B of this trial investigated the combination of cevostamab with pomalidomide and dexamethasone, using 2 mg of pomalidomide instead of the standard 4-mg dose.1
There was a dose-escalation phase initially, followed by a dose-expansion phase. [The trial enrolled] 29 patients in the 70 mg cevostamab arm and 25 patients in the 105 mg cevostamab arm. These were all heavily treated patients with a median of 2 prior lines of therapy. [The majority of patients were] triple class–exposed, but some were triple class–refractory as well.
What key findings from the CAMMA 1 study were presented at IMS 2025?
Regarding safety, infections were the most common toxicity. This is similar to what we have seen across all bispecific antibodies, though the [rate of] grade 3 and 4 adverse effects [AEs] was a little lower than what we have seen with some of the other bispecific antibodies. There were no treatment-related deaths in this study. [Considering] common toxicities with bispecific antibodies, this study used double and triple step-up dosing approaches. Overall, with the triple step-up dosing in 26 patients, the rates of CRS were decreased.
[Cevostamab plus pomalidomide and dexamethasone] was also effective. The ORR with the 105-mg dose was 88.0% [95% CI, 73.3%-100%], which was better than the approximately 60% [ORR] we have seen with single-agent cevostamab. This included some deep responses, as [36.0%] of patients achieved a stringent CR and [48%] of patients achieved a CR or better.
[Cevostamab is] effective when used in combination regimens, and [in the 105 mg arm, 38.5% (95% CI, 12.0%-64.9%)] of patients got to an MRD-negative state. The responses were durable in this patient population. [Pomalidomide] is a commonly used immunomodulatory drug in the relapsed patient population, so it makes sense to explore that combination. Hopefully, with continued follow-up, we’ll get a better sense of how durable these responses are in this patient population.
If cevostamab plus pomalidomide and dexamethasone continue to show efficacy in clinical research, what role might this triplet regimen have in the myeloma treatment paradigm?
As BCMA-targeted bispecific antibodies are moving into the frontline and early relapsed settings, we are going to explore other combinations, especially in subsequent lines of therapy. If we wanted to explore another T-cell redirection therapy that uses a different antigen target, then [combining it with cevostamab] would make perfect sense. For example, we saw data from the phase 3 MajesTEC-3 trial [NCT05083169] showing that teclistamab plus daratumumab [Darzalex] is effective in that first relapsed setting. If a patient were to be relapsing on that regimen, [cevostamab-based regimens] could be ideal combinations to explore, because we are using a bispecific antibody against different targets and partnering it with another drug that the patient would not have received up until now.
As cellular therapies move forward in the myeloma treatment paradigm, what questions are emerging regarding therapeutic sequencing and individualized treatment selection?
As more therapies become available in this disease, sequencing becomes more challenging. It’s going to be driven by a variety of factors, particularly the data from phase 3 trials, accessibility, the cost of therapy, and the potential for AEs. [This includes] AEs that could induce long-term consequences, like some of the Parkinson-type disorders we see with CAR T cells, for example, or the increased risk of infections or delayed cytopenias. Those will all be factored into that decision-making process.
T-cell redirection therapies are going to continue to move up front. It’s only going to be a matter of time before the bispecific antibodies become a part of initial therapy. Data in frail patients who received single-agent teclistamab were impressive.
We saw data with teclistamab and daratumumab in the first-relapse setting and in patients who had not received prior daratumumab. There are ongoing trials investigating BCMA-targeted bispecific antibodies with daratumumab-containing combinations in that upfront setting. The field is going to evolve relatively rapidly over the next few years, and we will see more of either CAR T-cell therapies or bispecific antibodies being important parts of the upfront setting.
References
- 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.
- Harrison S, Riley CH, Mian H, et al. Tumor clearance, T-cell fitness, and minimal residual disease (MRD) outcomes in patients with relapsed/refractory multiple myeloma (RRMM) treated with cevostamab plus pomalidomide and dexamethasone: biomarker analyses from CAMMA 1 arm B. Blood. 2025;146(suppl 1):252. doi:10.1182/blood-2025-252
