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

A. Keith Stewart, Amrita Y. Krishnan, Seema Singhal, Ralph V. Boccia, Manish R. Patel, Ruben Niesvizky, Asher A. Chanan-Khan, Sikander Ailawadhi, Jochen Brumm, Kirsten E. Mundt, Kyu Hong, Jacqueline McBride, Quyen Shon-Nguyen, Yuanyuan Xiao, Vanitha Ramakrishnan, Andrew G. Polson, Divya Samineni, Douglas Leipold, Eric W. Humke, James Scott McClellanJesus G. Berdeja

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article number17
JournalBlood cancer journal
Volume9
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Stewart, A. K., Krishnan, A. Y., Singhal, S., Boccia, R. V., Patel, M. R., Niesvizky, R., Chanan-Khan, A. A., Ailawadhi, S., Brumm, J., Mundt, K. E., Hong, K., McBride, J., Shon-Nguyen, Q., Xiao, Y., Ramakrishnan, V., Polson, A. G., Samineni, D., Leipold, D., Humke, E. W., ... Berdeja, J. G. (2019). Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. Blood cancer journal, 9(2), [17]. https://doi.org/10.1038/s41408-019-0178-8