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 McClellan; Jesus G. Berdeja

doi:10.1038/s41408-019-0178-8

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

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

50 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 language	English (US)
Article number	17
Journal	Blood cancer journal
Volume	9
Issue number	2
DOIs	https://doi.org/10.1038/s41408-019-0178-8
State	Published - Feb 1 2019

Funding

A.K.S.: Consulting roles at Celgene, Amgen, Janssen, BMS, and Roche. S.S.: Speakers’ bureau for Celgene and Millennium Pharmaceuticals. R.V.B.: Speaker’s bureau for Celgene, Takeda, BMS, and Amgen. M.R.P.: Speaker’s bureau for Celgene, Exelixis, and Genentech. J.B., K.E.M., K.H., J.M., Q.S.N., Y.X., A.G.P., D.S., D. L., E.W.H., and J.S.M.: Employee of Genentech, Inc. and shareholders of F. Hoffmann La Roche, Ltd. V.R.: Former employee of Genentech, Inc. and shareholders of F. Hoffmann La Roche, Ltd. Current employee of BeiGene, USA. J.G.B.: Research funding from Genentech, Abbvie, Amgen, Bluebird, BMS, Celgene, Constellation, Curis, Janssen, Novartis, Takeda, and Teva. A.Y.K., R.N., A. A.C.K., and S.A. declare that they have no conflict of interest. The authors wish to thank the patients and their families, and the investigators who participated in this study. Writing assistance was provided by Genentech, Inc. This work was supported by Genentech, Inc., South San Francisco, California, USA.

ASJC Scopus subject areas

Hematology
Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41408-019-0178-8

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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), Article 17. https://doi.org/10.1038/s41408-019-0178-8

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title = "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.",

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

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year = "2019",

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doi = "10.1038/s41408-019-0178-8",

language = "English (US)",

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Stewart, AK, Krishnan, AY, Singhal, S, Boccia, RV, Patel, MR, Niesvizky, R, Chanan-Khan, AA, Ailawadhi, S, Brumm, J, Mundt, KE, Hong, K, McBride, J, Shon-Nguyen, Q, Xiao, Y, Ramakrishnan, V, Polson, AG, Samineni, D, Leipold, D, Humke, EW, McClellan, JS & Berdeja, JG 2019, 'Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma', Blood cancer journal, vol. 9, no. 2, 17. https://doi.org/10.1038/s41408-019-0178-8

TY - JOUR

T1 - Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma

AU - Stewart, A. Keith

AU - Krishnan, Amrita Y.

AU - Singhal, Seema

AU - Boccia, Ralph V.

AU - Patel, Manish R.

AU - Niesvizky, Ruben

AU - Chanan-Khan, Asher A.

AU - Ailawadhi, Sikander

AU - Brumm, Jochen

AU - Mundt, Kirsten E.

AU - Hong, Kyu

AU - McBride, Jacqueline

AU - Shon-Nguyen, Quyen

AU - Xiao, Yuanyuan

AU - Ramakrishnan, Vanitha

AU - Polson, Andrew G.

AU - Samineni, Divya

AU - Leipold, Douglas

AU - Humke, Eric W.

AU - McClellan, James Scott

AU - Berdeja, Jesus G.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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

Abstract

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UN SDGs

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