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.

Emerging immunotherapies in multiple myeloma

“…Another antibody drug conjugate, DFRF4539A, is an anti-FcRH5 (also known as FcRL5) antibody conjugated to monomethyl auristatin and has shown limited activity and high incidence of toxicity in a phase I study; therefore, it was unsuccessful for this disease (table 2). 134135…”

Targeted Therapies for Multiple Myeloma

“…Fc receptor-homolog 5 (FcRH5; also known as FcRL5, IFGP5, CD307 and IRTA2) is a cell surface antigen of unknown function whose expression is restricted to mature B cells, with greater expression on malignant PCs [ 145 , 146 ]. DFRF4539A is an ADC that contains a humanized IgG1 anti-human FcRH5 monoclonal antibody (MFRF3266A) and a potent anti-mitotic agent, monomethyl auristatin E. A phase I study of DFRF4539A in RRMM showed limited clinical activity with 34 of 37 patients demonstrating SD or PD [ 147 ]. Consequently, further investigation of DFRF4539A has ceased.…”

Roles for the FCRL6 Immunoreceptor in Tumor Immunology

“…This microtubule inhibitor becomes active when surface receptors bound by the mAb-conjugate are internalized in target cells. A Phase 1 study of this anti-FCRL5-MMAE drug compound (DFRF4539A) in relapsed and refractory multiple myeloma patients ( n = 39) showed tolerability as a single agent, but demonstrated limited activity and may not be a successful strategy for myeloma ( 39 ). The authors speculated that the low response rates in this study could be due to the unknown threshold for Ab-dependent cytotoxicity activity, shedding of the FCRL5 target, limited internalization, and a less effective role of MMAE in cells with a low proliferative index.…”