Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma

Abstract

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.

Fig. 1. Best percent change in either serum M-protein or serum free light chain levels (in patients without detectable M-protein) relative to baseline for all efficacy-evaluable patients.

Two efficacy-evaluable patients are not depicted due to lack of detectable M protein or serum free light chains at baseline; both of these patients had a best response of progressive disease

Fig. 2. FcRH5 expression as measured by clone 10A8 and clone 7D11 in patients at baseline and post-dose.

a Spaghetti plot of baseline and post-dosing flow cytometry data for each patient showing staining intensity—measured as molecules of equivalent soluble fluorochrome (MESF)—by an anti-FcRH5 antibody pair consisting of clone 10A8, a competing and blocking antibody with respect to DFRF4539A, and clone 7D11, a non-competing and non-blocking antibody with respect to DFRF4539A. b Box plot summary of FcRH5 receptor expression and receptor occupancy in patient samples at pre-dose and post-dose timepoints

Fig. 3. Expression of FcRH5 receptors (CD307) and DFRF4539A engagement on plasma cells (CD45^dim/CD38⁺⁺/CD138⁺) in bone marrow aspirates.

a Overlay of isotype control antibody (anti-Her2) and anti-FcRH5 antibody (clone 10A8, a competing and blocking antibody with respect to DFRF4539A) at baseline vs. post-dosing. b Overlay of isotype control antibody (anti-Her2) and anti-FcRH5 antibody (clone 7D11, a non-competing and non-blocking antibody with respect to DFRF4539A) at baseline vs. post-dosing

Fig. 4. Presence of plasma cells (CD45^dim/CD38⁺⁺/CD138⁺) at baseline vs. post-treatment.

a Gating strategy. b Representative patient with plasma cell depletion following dosing with DFRF4539A. c Representative patient without plasma cell depletion following dosing with DFRF4539A