PMID- 30718503 OWN - NLM STAT- MEDLINE DCOM- 20191230 LR - 20200309 IS - 2044-5385 (Electronic) IS - 2044-5385 (Linking) VI - 9 IP - 2 DP - 2019 Feb 4 TI - Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. PG - 17 LID - 10.1038/s41408-019-0178-8 [doi] LID - 17 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. FAU - Stewart, A Keith AU - Stewart AK AD - Division of Hematology-Oncology, Mayo Clinic, Phoenix, AZ, USA. Stewart.Keith@mayo.edu. FAU - Krishnan, Amrita Y AU - Krishnan AY AD - Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Medical Center, Duarte, CA, USA. FAU - Singhal, Seema AU - Singhal S AD - Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. FAU - Boccia, Ralph V AU - Boccia RV AD - Center for Cancer and Blood Disorders, Bethesda, MD, USA. FAU - Patel, Manish R AU - Patel MR AD - Florida Cancer Specialists, Sarasota, FL, USA. AD - Sarah Cannon Research Institute, Nashville, TN, USA. FAU - Niesvizky, Ruben AU - Niesvizky R AD - Multiple Myeloma Center, New York Presbyterian Hospital-Cornell Medical Center, New York, NY, USA. FAU - Chanan-Khan, Asher A AU - Chanan-Khan AA AD - Division of Hematology & Oncology, Mayo Clinic, Jacksonville, FL, USA. FAU - Ailawadhi, Sikander AU - Ailawadhi S AD - Division of Hematology & Oncology, Mayo Clinic, Jacksonville, FL, USA. FAU - Brumm, Jochen AU - Brumm J AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Mundt, Kirsten E AU - Mundt KE AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Hong, Kyu AU - Hong K AD - Genentech, Inc., South San Francisco, CA, USA. FAU - McBride, Jacqueline AU - McBride J AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Shon-Nguyen, Quyen AU - Shon-Nguyen Q AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Xiao, Yuanyuan AU - Xiao Y AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Ramakrishnan, Vanitha AU - Ramakrishnan V AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Polson, Andrew G AU - Polson AG AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Samineni, Divya AU - Samineni D AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Leipold, Douglas AU - Leipold D AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Humke, Eric W AU - Humke EW AD - Genentech, Inc., South San Francisco, CA, USA. FAU - McClellan, James Scott AU - McClellan JS AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Berdeja, Jesus G AU - Berdeja JG AD - Sarah Cannon Research Institute, Nashville, TN, USA. LA - eng GR - P50 CA186781/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190204 PL - United States TA - Blood Cancer J JT - Blood cancer journal JID - 101568469 RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Biomarkers) RN - 0 (FCRL5 protein, human) RN - 0 (Immunoconjugates) RN - 0 (Receptors, Fc) SB - IM MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents, Immunological/administration & dosage/adverse effects/pharmacokinetics/*therapeutic use MH - Biomarkers MH - Drug Monitoring MH - Drug Resistance, Neoplasm MH - Female MH - Follow-Up Studies MH - Humans MH - Immunoconjugates/administration & dosage/adverse effects/pharmacokinetics/*therapeutic use MH - Immunophenotyping MH - Male MH - Middle Aged MH - Multiple Myeloma/*drug therapy/*pathology MH - Receptors, Fc/*antagonists & inhibitors MH - Recurrence MH - Retreatment MH - Treatment Outcome PMC - PMC6362066 COIS- 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. EDAT- 2019/02/06 06:00 MHDA- 2019/12/31 06:00 PMCR- 2019/02/04 CRDT- 2019/02/06 06:00 PHST- 2018/04/20 00:00 [received] PHST- 2018/08/17 00:00 [accepted] PHST- 2018/08/06 00:00 [revised] PHST- 2019/02/06 06:00 [entrez] PHST- 2019/02/06 06:00 [pubmed] PHST- 2019/12/31 06:00 [medline] PHST- 2019/02/04 00:00 [pmc-release] AID - 10.1038/s41408-019-0178-8 [pii] AID - 178 [pii] AID - 10.1038/s41408-019-0178-8 [doi] PST - epublish SO - Blood Cancer J. 2019 Feb 4;9(2):17. doi: 10.1038/s41408-019-0178-8.