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

Alexander 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

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5 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

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ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

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