Abstract
3 min readAbstract Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is ubiquitously expressed on multiple myeloma (MM) cells. Cevostamab is a novel, first-in-class FcRH5xCD3 T-cell-engaging bispecific antibody that facilitates T-cell-mediated killing of MM cells. In a Phase I dose-escalation and dose-expansion study in patients with late-line RRMM, cevostamab induced deep and durable responses and had manageable safety when administered by intravenous (IV) infusion (Richter et al. ASH 2024). Subcutaneous (SC) dosing could improve patient convenience and optimize healthcare utilization. CAMMA 3 (EUDRACT: 2021-002307-36) is a Phase Ib study evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of SC cevostamab in patients with RRMM. Here, we describe the results from the dose-escalation stage of the study. Methods: Eligible patients were those with RRMM for whom no established therapy was available or appropriate. Prior therapy with bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T-cells was allowed. Cevostamab was administered by SC injection in 28-day cycles. In Cycle (C) 1, cevostamab was given as step-up doses on Day (D) 1 (2 mg) and D8 (10–30 mg) and at target dose on D15 (40–300 mg). Cevostamab was then given at target dose Q2W in C2–6 and Q4W from C7+. Treatment was continued for a total of 13 cycles or until disease progression (PD) or unacceptable toxicity occurred. Results: As of February 24, 2025, 58 patients (median age: 63.5 years, min–max: 33–81; male: 70.7%) had received ≥1 dose of cevostamab; 31.0% had extramedullary disease. The median number of prior lines of therapy was 5 (min–max: 2–11) and 48.3% had received ≥1 prior B-cell maturation antigen (BCMA)-targeted therapy. At data cut-off, the median time on study was 9.4 months (min–max: 0.3–33.6). Among all evaluable patients (n=52), the overall response rate across all tested dose levels was 38.8% and the very good partial response (VGPR) or better rate was 30.6%. Notably, 14.3% achieved a stringent complete response (sCR), 6.1% a complete response (CR), 10.2% a VGPR, and 8.2% a partial response. The median duration of response was 12.3 months (95% confidence interval: 8.3, not estimable). A total of 12 patients who achieved sCR/CR were evaluated for minimal residual disease (MRD) by next-generation sequencing. At the 10−5 threshold, 8 patients were MRD negative, 2 were MRD positive, and 2 had baseline calibration failure. Adverse events (AEs) of any Grade (Gr) in ≥20% of patients were cytokine release syndrome (CRS; 69.0%), injection site reaction (ISR; 58.6%), neutropenia (31.0%), anemia (29.3%), pyrexia (25.9%), and rash (22.4%). CRS primarily occurred in C1 and was mostly low Gr (Gr 1: 34.5%; Gr 2: 32.8%; Gr 3: 1.7%). Patients with CRS were frequently managed with tocilizumab (50.0%), steroids (67.5%), or both agents (32.5%); all events resolved. Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3.4% of patients (Gr 2: 1.7%; Gr 3: 1.7%). Gr 3–4 AEs (39.7% overall) in ≥5% of patients were neutropenia (29.3%), anemia (17.2%; all Gr 3), thrombocytopenia (6.9%), lymphopenia (5.2%), and ISR (5.2%; all Gr 3). Gr 3–4 infections occurred in 12.1% of patients. Most ISRs were low Gr (Gr 1: 32.8%; Gr 2: 20.7%; Gr 3: 5.2%) and the majority occurred in C1. ISR symptoms in ≥10% of patients were injection site erythema (41.4%), pain (13.8%), pruritus (12.1%), and rash (12.1%). Treatment-related AEs leading to cevostamab discontinuation occurred in 3 patients (Gr 2 tumor flare [n=1], Gr 3 ISR [n=1], Gr 3 elevated AST, and Gr 4 elevated ALT [n=1]). Gr 5 (fatal) AEs excluding PD occurred in 3 patients (COVID-19 [n=1], staphylococcal infection [n=1], and fall and subdural hematoma [n=1]); none were considered treatment-related.Conclusions: SC cevostamab monotherapy induces deep and durable responses and has manageable safety in patients with late-line RRMM, many of whom had received prior BCMA-targeted therapies. Efficacy and safety (including CRS) appear generally comparable with that observed with IV cevostamab monotherapy in patients with late-line RRMM, with the exception of the occurrence of low Gr ISRs.
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