Open AccessPhase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma
Author(s) -
A. Keith Stewart,
Amrita Krishnan,
Seema Singhal,
Ralph V. Boccia,
Manish R. Patel,
Rubén Niesvizky,
Asher ChananKhan,
Sikander Ailawadhi,
Jochen Brumm,
Kirsten Mundt,
Kyu Hong,
Jacqueline McBride,
Quyen Shon-Nguyen,
Yuanyuan Xiao,
Vanitha Ramakrishnan,
Andrew G. Polson,
Divya Samineni,
Douglas D. Leipold,
Eric W. Humke,
James Scott McClellan,
Jesús G. Berdeja
Publication year - 2019
Publication title -
blood cancer journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.607
H-Index - 51
ISSN - 2044-5385
DOI - 10.1038/s41408-019-0178-8
Subject(s) - medicine , multiple myeloma , antibody drug conjugate , tolerability , antibody , anemia , pharmacokinetics , adverse effect , refractory (planetary science) , gastroenterology , pharmacology , lenalidomide , drug , immunology , monoclonal antibody , physics , astrobiology
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.