Target antigen and plasma cell phenotype are critical factors for sensitivity to response-adapted daratumumab therapy
Abstract
Abstract In this response-adapted clinic trial with daratumumab monotherapy for older patients with newly diagnosed multiple myeloma (MM), we identified target antigen expression, a plasma cell phenotype, and an activated immune tumor microenvironment (iTME) as critical features associated with response to CD38 monoclonal antibody therapy. Here, patients achieving a partial response after 2 cycles continued daratumumab, otherwise lenalidomide or bortezomib was added. This strategy resulted in an overall response rate of 97% and low rates of adverse events, with 37% of patients able to continue daratumumab monotherapy. Importantly, we found that higher CD38 expression, plasma cell gene expression programming, and an activated iTME were associated with patients who were able to continue daratumumab therapy alone. In contrast, patients requiring the addition of lenalidomide or bortezomib had increased expression of adhesion, tumor necrosis factor signaling, KRAS signaling, and B-cell programs, as well as an immunosuppressed iTME. Tracking of clonal dynamics illustrated the selection of subclones enriched for de novo resistance gene expression programs after only 2 cycles of daratumumab monotherapy. Upon relapse, daratumumab refractory MM cells were characterized by the expansion of preexisting minor subclones with mixed transcriptomic programs containing the plasma cell phenotype with decreased CD38 expression and maintenance of resistance programs, suggesting development of acquired resistance involves an uncoupling of transcriptional programs present in therapy-naïve tumors. To our knowledge, this is the first study to demonstrate the effectiveness of response-adapted daratumumab treatment and describe critical biomarkers of single-agent daratumumab sensitivity in vulnerable patients with therapy-naïve MM. This trial was registered at www.ClinicalTrials.gov as #NCT04151667.
Article Details
Authors (27)
Mark B. Meads
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Xiaohong Zhao
School of Chemistry and Chemical Engineering/Film Energy Chemistry for Jiangxi Provincial Key Laboratory (FEC)
David Noyes
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Praneeth R. Sudalagunta
Alexandra Achille
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Chaomei Zhang
Rafael R. Canevarolo
Maria Silva
2Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Dario Magaletti
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Daniel DeAvila
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Sonila Toska
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Ashley Oates
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Daniel Lastorino
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Dietrich Werner Idiaquez
4Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Jinming Song
Samer S. Sansil
5Cancer Pharmacokinetics and Pharmacodynamics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Sean J. Yoder
3Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Ariel F. Grajales-Cruz
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Brandon Blue
Naval Research Enterprise Internship Program Student Residing in the Electronics Sciences and Technology Division, United States Naval Research Laboratory
Ciara L. Freeman
7Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Jongphil Kim
6Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Melissa Alsina
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States
Jason Brayer
8Departments of Malignant Hematology and Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Ariosto S. Silva
Xiaofei Song
Molecular Synthesis Center, Key Laboratory of Marine Drugs of Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotherapeutics, School of Medicine and Pharmacy
Kenneth H. Shain
Rachid Baz
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL