Fixed-Duration Cevostamab After CAR T-Cell Therapy Is Well Tolerated in Heavily Pretreated Myeloma

Fixed-duration cevostamab following treatment with B-cell maturation agent (BCMA)–directed CAR T-cell therapy was shown to be feasible and well tolerated in patients with heavily pretreated multiple myeloma, according to data from the phase 2 STEM trial (NCT05801939) presented at the 22nd International Myeloma Society Annual Meeting and Exposition.1

Pre-cevostamab, the complete response (CR)/stringent CR (sCR) rate was 63% (n = 27); it was 81% at day 1 of cycle 8 (n = 22), and 93% at 1-year post CAR T-cell therapy (n = 14). The minimal residual disease (MRD)–negative CR rate pre-cevostamab was 100%; at day 1 of cycle 8 and 1-year post CAR T-cell therapy, MRD-negative rates were 95% and 93%, respectively (Figure).

Regarding progression-free survival and overall survival, the median follow-up was 12 months, but “the vast majority of patients are alive and remain progression-free,” Adam D. Cohen, MD, director of myeloma immunotherapy and an associate professor of medicine at the Hospital of the University of Pennsylvania, shared during the presentation.

What was the rationale for evaluating cevostamab consolidation in the STEM trial?

Although BCMA-directed CAR T-cell therapies are known to have substantial activity in the late-line treatment of patients with multiple myeloma, most patients ultimately experience relapse. Fc receptor–homolog 5 (FcRH5) is a distinct surface antigen expressed independently of BCMA on multiple myeloma cells. Cevostamab, a bispecific antibody targeting both FcRH5 and CD3, has shown clinical activity in heavily pretreated multiple myeloma, including in patients previously exposed to BCMA-directed therapies.

Updated results from a phase 1 dose-escalation and dose-expansion study (GO39775; NCT03275103) showed that treatment with cevostamab monotherapy at the 160-mg target dose led to an overall response rate (ORR) of 44.3% among patients with heavily pretreated relapsed/refractory multiple myeloma (n = 167).2 This comprised a very good partial response or better rate of 25.7% and a partial response rate of 18.6%. Among patients who had received prior BCMA therapy (n = 96) vs those who had not (n = 71), the ORRs were 32.3% and 60.6%, respectively. Of note, MRD negativity was achieved in 11 of 18 evaluable patients, and responses generally occurred early and deepened over time.

Based on these data, investigators hypothesized that introducing cevostamab consolidation after treatment with a BCMA-directed CAR T-cell therapy could reinvigorate persisting CAR-positive T cells against residual BCMA-expressing myeloma while simultaneously eliminating BCMA-low or -negative clones through FcRH5-directed engagement of endogenous T cells.1 Additionally, incorporating MRD-directed, fixed-duration therapy could help mitigate the risk of infections and other treatment-related complications, Cohen explained.

What was the design of the STEM trial?

The single-institution, investigator-initiated STEM trial opened in July 2023, and was designed to enroll up to 30 patients with relapsed/refractory multiple myeloma for a total of 26 evaluable patients. Eligibility criteria included receipt of commercial CAR T-cell therapy between 6 and 10 weeks prior to enrollment; 4 or more prior lines of treatment, including an immunomodulatory drug, proteasome inhibitor, and CD38 antibody; stable disease or better after CAR T-cell therapy; and an ECOG performance status of 0 or 1. Of note, the criterion for 4 or more lines of prior therapy was modified in 2024 to reflect updated labels for idecabtagene vicleucel (ide-cel; Abecma) or ciltacabtagene autoleucel (cilta-cel; Carvykti).

Patients were excluded if they had progressive disease post–CAR T-cell therapy; prior cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome of grade 3 or higher; prior Parkinsonism or autoimmune disease; active infection; or received out-of-specification or experimental CAR T-cell therapy.

Eligible patients were given ide-cel and cilta-cel as standard-of-care therapy and enrolled onto the STEM trial at 10 to 12 weeks post treatment. Cevostamab was administered intravenously at 3.6 mg on cycle 1 day 1 and 132 mg on cycle 1 day 8 and thereafter, every 3 weeks for 8 cycles. On both infusion days, patients were required to be hospitalized for 48 hours. Patients were then assessed for an MRD-negative CR. If they achieved it, they were observed; if they did not, they went back to treatment with cevostamab every 3 weeks for 8 cycles. Notably, all patients received intravenous immunoglobulin, antiviral, and anti–pneumocystis jirovecii pneumonia prophylaxis.

The study’s primary end point was MRD negative CR rate at 12 months post CAR T-cell therapy.

What were the baseline characteristics of patients in the STEM Trial?

At the interim analysis cutoff date of June 27, 2025, a total of 27 patients were treated on the study. Of these patients, 18 completed therapy, 2 discontinued treatment due to toxicities and disease progression (n = 1 each), and 7 were still receiving treatment.

The median age among all patients was 64 years (range, 33-80), 74% of patients were male, and 78% were White. The median time from diagnosis to study participation was 4.6 years (range, 1.2-20.1). Extramedullary disease was noted in 19% of patients. Cytogenetics included t(4;14), t(14;16), or 17p deletions (44%); gain or amp 1q (59%); and 1p deletions (22%). Additionally, 74% had at least 1 of the listed mutations, and 41% had 2 or more listed mutations.

A total of 93% of patients received cilta-cel, and 7% received ide-cel. The median number of prior lines of CAR T-cell therapy was 4 (range, 2-10). Notably, 74% of patients were triple-class refractory.

What key safety findings were reported with cevostamab?

Hematologic adverse effects (AEs) of any grade and grade 3/4, respectively, included lymphopenia (74%; 67%), neutropenia (74%; 44%), thrombocytopenia (41%; 22%), anemia (26%; 0%), and febrile neutropenia (4%; 4%). Any grade and grade 3/4 nonhematologic AEs included cough (59% vs 0%), infections (52%; 15%), rash (44%; 0%), upper respiratory infection (37%; 0%), nasal congestion (33%; 0%), diarrhea (33%; 0%), increased aspartate aminotransferase levels (33%; 7%), increased alanine aminotransferase levels (26%; 4%), increased creatinine levels (26%; 0%), infusion reactions (19%; 0%), and CRS (15% vs 0%).

A total of 4 patients experienced unusual immune-related AEs such as grade 2 enterocolitis in cycle 4, grade 3 ataxia/gait disturbance/peripheral neuropathy in cycle 8, grade 3 transaminitis and grade 1 autoimmune hepatitis in cycle 1, grade 4 immune thrombocytopenia in cycle 8. Prior to any AEs, 3 of the 4 patients had a preceding infection. All unusual immune-related AEs were resolved.

“To date, over 90% of evaluable patients [are] sustaining MRD-negative CR at 1-year post-CAR T[-cell therapy]. Enrollment [in the trial] is complete; treatment and follow-up are ongoing,” Cohen concluded.

Disclosures: Cohen reported serving on a consulting advisory board for AbbVie, Arcellx, AstraZeneca, Bristol Myers Squibb, Caribou, Genentech/Roche, GSK, Ichnos, iTeos, Janssen, Kite, Legend, Moderna, Pfizer, Prothena, Regeneron, Sanofi; receiving research support from Genentech, GSK, Janssen, and Novartis; and having intellectual property licensed by his institution to Novartis.

References

1. Cohen A, Susanibar-Adaniya S, Garfall A, et al. Phase 2 study of cevostamab consolidation following BCMA CAR T cell therapy: preliminary safety and efficacy data from the “STEM” (sequential T cell-engagement for myeloma) trial. Clin Lymphoma Myeloma Leuk. 2025;25(2):S366. doi:10.1016/S2152-2650(25)04010-8
2. Richter J, Thomas SK, Krishnan AY, et al. Cevostamab in patients with heavily pretreated relapsed/refractory multiple myeloma: updated results from an ongoing phase I study demonstrate clinically meaningful activity and manageable safety and inform the doses and regimen for combination studies. Blood. 2024;144(suppl 1):1021. doi:10.1182/blood-2024-199542