PMID- 33735504 OWN - NLM STAT- MEDLINE DCOM- 20211230 LR - 20211230 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 127 IP - 11 DP - 2021 Jun 1 TI - Phase 1b trial of isatuximab, an anti-CD38 monoclonal antibody, in combination with carfilzomib as treatment of relapsed/refractory multiple myeloma. PG - 1816-1826 LID - 10.1002/cncr.33448 [doi] AB - BACKGROUND: Isatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM). METHODS: This phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m(2) intravenously for cycle 1, days 1 and 2, and then 27 mg/m(2) for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity. RESULTS: With a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing. CONCLUSIONS: Treatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM. LAY SUMMARY: This phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months. CI - (c) 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. FAU - Martin, Thomas G AU - Martin TG AUID- ORCID: 0000-0003-1752-5092 AD - Hematology/Oncology, University of California San Francisco Medical Center, San Francisco, California. FAU - Shah, Nina AU - Shah N AUID- ORCID: 0000-0002-1971-8173 AD - Hematology/Oncology, University of California San Francisco Medical Center, San Francisco, California. FAU - Richter, Joshua AU - Richter J AD - Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Vesole, David H AU - Vesole DH AD - Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey. FAU - Wong, Sandy W AU - Wong SW AD - Hematology/Oncology, University of California San Francisco Medical Center, San Francisco, California. FAU - Huang, Chiung-Yu AU - Huang CY AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California. FAU - Madduri, Deepu AU - Madduri D AD - Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Jagannath, Sundar AU - Jagannath S AUID- ORCID: 0000-0003-2934-6518 AD - Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Siegel, David S AU - Siegel DS AD - Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey. FAU - Biran, Noa AU - Biran N AD - Myeloma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey. FAU - Wolf, Jeffrey L AU - Wolf JL AD - Hematology/Oncology, University of California San Francisco Medical Center, San Francisco, California. FAU - Parekh, Samir AU - Parekh S AD - Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Cho, Hearn J AU - Cho HJ AD - Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Munster, Pamela AU - Munster P AD - Hematology/Oncology, University of California San Francisco Medical Center, San Francisco, California. FAU - Richard, Shambavi AU - Richard S AD - Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Ziti-Ljajic, Samira AU - Ziti-Ljajic S AD - Translational Medicine and Early Development, Pharmacokinetic and Drug Metabolism, Pharmacokinetic Unit, Sanofi, Paris, France. FAU - Chari, Ajai AU - Chari A AUID- ORCID: 0000-0002-0405-7480 AD - Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. LA - eng GR - Sanofi/ GR - Amgen/ PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210318 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Oligopeptides) RN - 72X6E3J5AR (carfilzomib) RN - R30772KCU0 (isatuximab) SB - IM MH - Antibodies, Monoclonal/adverse effects MH - *Antibodies, Monoclonal, Humanized/adverse effects MH - Antineoplastic Agents/adverse effects MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Humans MH - *Multiple Myeloma/drug therapy MH - *Oligopeptides/adverse effects MH - Recurrence PMC - PMC8252002 OTO - NOTNLM OT - carfilzomib OT - immunomodulatory OT - isatuximab OT - monoclonal antibody OT - pharmacokinetics OT - proteasome COIS- Thomas G. Martin reports research funding (institutional) from Sanofi, Amgen, Janssen, and Seattle Genetics and consultancy for Roche and GlaxoSmithKline. Nina Shah reports research funding (institutional) from Bluebird Bio, Janssen, Celgene/Bristol-Myers Squibb, Sutro Biopharma, TeneoBio, Poseida, and Nektar and consultancy for and honoraria from Celgene, Janssen, Bluebird Bio, Sutro Biopharma, Genentech, Seattle Genetics, Oncopeptides, Karyopharm, Surface Oncology, Precision Biosciences, GlaxoSmithKline, Nektar, Amgen, Indapta Therapeutics, Bristol-Myers Squibb, CareDx, Kite, Karyopharm, and Sanofi. Joshua Richter reports consultancy and membership on an advisory board for Sanofi. David H. Vesole reports research funding (institutional) from Sanofi and Amgen; stock and other ownership interests in Amgen, AbbVie, Biogen, Celgene/Bristol-Myers Squibb, Gilead Sciences, Johnson & Johnson, Lilly, and Novartis; honoraria from or consultancy for Amgen, Takeda, Celgene, and Pfizer; and membership in speakers' bureaus for Amgen, Celgene/Bristol-Myers Squibb, Janssen Oncology, GlaxoSmithKline, and Takeda. Sandy W. Wong reports research funding (institutional) from Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Roche/Genentech, and Fortis and consultancy or membership on an advisory committee for Amgen and Sanofi. Deepu Madduri reports research funding (institutional) from Janssen and Regeneron; membership in speakers' bureaus for Shire, Legend, Kinevant, and GlaxoSmithKline; honoraria from Janssen, Celgene, and AbbVie; and consultancy for Foundation Medicine and Takeda. Sundar Jagannath reports consultancy for Legend Biotech, Takeda, AbbVie, Celgene, Bristol-Myers Squibb, Karyopharm, Janssen, and Merck and membership on scientific advisory boards for Celgene, Bristol-Myers Squibb, and Sanofi-Aventis. David S. Siegel reports research funding (institutional) from Celgene; stock and other ownership interests in Cellularity; consulting or advisory roles with Amgen, Celgene, Takeda, Janssen Oncology, Bristol-Myers Squibb, Karyopharm Therapeutics, and Merck; and membership in speakers' bureaus for Amgen, Celgene, Takeda, Janssen Oncology, and Bristol-Myers Squibb. Noa Biran reports research funding (institutional) from Merck, Karyopharm Therapeutics, and Bristol-Myers Squibb; honoraria from or consultancy for Bristol-Myers Squibb, Amgen, Celgene, Takeda, and Janssen Oncology; and membership in speakers' bureaus for Takeda, Celgene, Amgen, Janssen, and Bristol-Myers Squibb. Jeffrey L. Wolf reports consultancy for Adaptive Biotech, TeneoBio, Amgen, Bristol-Myers Squibb, Takeda, and Janssen. Samir Parekh reports consultancy for Foundation Medicine and research funding (institutional) from Celgene, Pfizer, and Karyopharm. Hearn J. Cho is employed by the Multiple Myeloma Research Consortium and reports research funding from Takeda, Celgene, and Genentech. Samira Ziti-Ljajic is an employee of Sanofi. Ajai Chari reports consultancy for Secura Bio, Novartis, Amgen, Bristol-Myers Squibb, Celgene, Antengene, Takeda, Janssen, and Karyopharm; has received research funding from Amgen, Array Biopharma, Celgene, GlaxoSmithKline, Janssen, Takeda, Novartis, Oncopeptides, Pharmacyclics, and Seattle Genetics; and is an advisory board member for Amgen, Celgene, Millennium/Takeda, Novartis, Janssen, Karyopharm, Sanofi, GlaxoSmithKline, Secura Bio, and Seattle Genetics. The other authors made no disclosures. EDAT- 2021/03/19 06:00 MHDA- 2021/12/31 06:00 PMCR- 2021/07/02 CRDT- 2021/03/18 17:53 PHST- 2020/11/30 00:00 [revised] PHST- 2020/09/22 00:00 [received] PHST- 2020/12/05 00:00 [accepted] PHST- 2021/03/19 06:00 [pubmed] PHST- 2021/12/31 06:00 [medline] PHST- 2021/03/18 17:53 [entrez] PHST- 2021/07/02 00:00 [pmc-release] AID - CNCR33448 [pii] AID - 10.1002/cncr.33448 [doi] PST - ppublish SO - Cancer. 2021 Jun 1;127(11):1816-1826. doi: 10.1002/cncr.33448. Epub 2021 Mar 18.