Background: BCMA-targeted CAR T cells have unprecedented activity in relapsed/refractory multiple myeloma (RRMM), but the majority of patients (pts) relapse. Mechanisms of resistance include lack of persistence or poor function of CAR T cells, as well as BCMA-low or -negative residual tumor cells. FcRH5 is a MM antigen with expression independent of BCMA. Cevostamab (cevo) is an FcRH5-targeted, T cell-engaging bispecific antibody with demonstrated activity in RRMM, including in patients with prior BCMA-directed therapies (Richter et al, ASH 2024, #1021). We hypothesized that fixed-duration cevo following BCMA-targeted CAR T cells would be feasible, tolerable and improve sustained minimal residual disease (MRD)-negative complete response (CR) rates, potentially leading to more durable responses.

Methods: This is an ongoing single-institution, investigator-initiated study (NCT05801939), with funding from Genentech/Roche. RRMM pts who received standard of care CAR T cells (ide-cel or cilta-cel) 8-10 weeks prior to enrollment, with stable disease or better, receive cevo at a step-up dose of 3.6 mg intravenously (IV) on Cycle 1 Day 1 (C1D1), followed by full target dose starting on C1D8, then every 3 weeks for total of 8 cycles. If pts are in MRD-negative CR after 8 cycles (Adaptive Clonoseq assay, at 10-5 sensitivity), they stop therapy and are observed. If not, they get another 8 cycles of cevo, and then are observed. Primary endpoint is frequency of MRD-negative CR at 12 months post-CAR T cell therapy. All pts receive IVIG.

Results: Twenty-seven pts (20M and 7F; median age 64 (33-80); 21 White, 6 Black) have enrolled. Twenty (74%) had high risk cytogenetics (t(4;14), t(14;16), -17p, -1p, or +1q), with 11 (41%) having ≥2 high risk features; 5 (19%) had extramedullary disease. Median number of prior lines was 4 (2-10), with 74% triple-class refractory, 11% prior BCMA therapy, and 11% prior talquetamab. Twenty-five (93%) received cilta-cel and 2 (7%) ide-cel. Reponses at enrollment (post-CAR T cells) were 63% CR/sCR, 15% VGPR, 18% PR, 4% SD; 25 of 27 pts were evaluable for MRD, with 100% MRD-negative at 10-5. During a safety run-in, 3 pts started cevo 8-10 weeks post-CAR T cells, at a target dose of 160 mg, and during C1 all had grade (G) 1 or 2 allergic-type symptoms (rash, arthralgias, cough and/or bronchospasm) which resolved with anti-histamines and topical or systemic steroids. For this reason, the study was modified to start cevo 10-12 weeks post-CAR T cells and change target dose to 132 mg. As of 6/27/25 data cut-off, no dose-limiting toxicities (DLT) have occurred. CRS occurred in 4 (15%) pts (3 G1, 1 G2) and infusion reactions in 19% (all G1/2); no ICANS or HLH was seen. Median number of cycles is 8, and 6 (22%) pts have had dose reductions from 132 to 90mg. Common treatment-emergent adverse events (TEAE's), regardless of attribution, include lymphopenia (74%, G3/4 67%), neutropenia (74%, G3/4 44%), cough (59%, G3/4 0%), rash 44% (G3/4 0%), thrombocytopenia 41% (G3/4 22%), upper respiratory infection 37% (G3/4 0%), nasal congestion 33% (G3/4 0%), and AST increase 33% (G3/4 7%). Infections were seen in 52% (G3/4 in 15%). Notable immune-related AE's include colitis G1, neuropathy with ataxia G3, ITP G4 (n=2, 1 with prior history), autoimmune hepatitis G1) – all resolved.

So far, 22 pts are response-evaluable after 8 cycles, with 81% in stringent CR, 9% in VGPR, 5% in SD; 21/22 (95%) were MRD-negative at 10-5, and 20/22 (91%) at 10-6 (1 pt had PD after C4, counted as MRD+). Only 3 pts to date have required the 2nd 8 cycles of cevo. Fourteen pts are evaluable at 1 year post-CAR T cells, with 93% in MRD-negative (at 10-5) sCR, 79% at 10-6. With median follow-up of 12 months (range 3-25) post-CAR T cells, estimated 12-month PFS and OS are both 95%. Preliminary correlative analyses demonstrate detectable CAR+ T cells (by both qPCR and flow) at enrollment in 2 of 5 pts tested to date; both had modest re-expansion of CAR T cells during C1 of cevo, with persistence out to 1 year.Conclusions: To date, cevostamab consolidation starting 10-12 weeks post-CAR T cell infusion at 3.6mg single step-up and 132mg q3wk target dose appears feasible and well-tolerated in heavily-pretreated RRMM, with low rates of non-hematologic G3/4 TEAE's, including infections. Preliminary efficacy appears promising, with over 90% showing sustained MRD-negative CR at 1 year. Analyses and follow-up are ongoing.

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2025
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