Reshaping the definition of high-risk disease in the immune effector therapy era in multiple myeloma
- 1Division of Hematology, Department of Medicine, Mayo Clinic , , ,
- 2Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute , , ,
Abstract
Multiple myeloma (MM) outcomes have improved with proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and transplantation, yet a subset of patients with high-risk MM (HRMM) continues to relapse early and die prematurely. Immune effector therapies (IET)—B-cell maturation antigen (BCMA)- and G protein–coupled receptor class C group 5 member D (GPRC5D)-directed chimeric antigen receptor T cells (CAR-T) and bispecific antibodies—have transformed the treatment of relapsed/refractory MM. However, their benefit in HRMM remains incompletely defined. This review describes how HRMM is defined in the IET-era distinguishing baseline biological/genomic risk, clinical high-risk phenotypes, and IET-specific adverse predictors. The International Myeloma Society/International Myeloma Working Group consensus integrates adverse cytogenetics and beta-2 microglobulin, whereas functional high-risk disease, extramedullary disease (EMD), plasma cell leukemia (PCL), high tumor burden, inflammation, and prior BCMA exposure identify aggressive disease in relapsed patients. Across pivotal trials, CAR-T therapy, particularly ciltacabtagene autoleucel, and selected bispecific antibodies retain activity in high-risk cytogenetic subgroups, whereas EMD and PCL remain associated with inferior responses and short progression-free survival. Emerging dual-antigen and trispecific engagers, along with novel targets such as FcRH5 and CD70, aim to overcome antigen escape. Prospective, biology-informed studies are needed to achieve durable disease control in HRMM.
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BibTeX
@article{nishimura2026reshaping,
title = {{Reshaping the definition of high-risk disease in the immune effector therapy era in multiple myeloma}},
author = {Yoshito Nishimura and Gunjan Gaur and Francesca Cottini and Saurabh Zanwar},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1956522},
url = {https://europepmc.org/article/PMC/PMC13669832},
note = {CC BY},
}
RIS
TY - JOUR
TI - Reshaping the definition of high-risk disease in the immune effector therapy era in multiple myeloma
AU - Yoshito Nishimura
AU - Gunjan Gaur
AU - Francesca Cottini
AU - Saurabh Zanwar
PY - 2026
DA - 2026/10/01
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1956522
UR - https://europepmc.org/article/PMC/PMC13669832
AB - Multiple myeloma (MM) outcomes have improved with proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and transplantation, yet a subset of patients with high-risk MM (HRMM) continues to relapse early and die prematurely. Immune effector therapies (IET)—B-cell maturation antigen (BCMA)- and G protein–coupled receptor class C group 5 member D (GPRC5D)-directed chimeric antigen receptor T cells (CAR-T) and bispecific antibodies—have transformed the treatment of relapsed/refractory MM. However, their benefit in HRMM remains incompletely defined. This review describes how HRMM is defined in the IET-era distinguishing baseline biological/genomic risk, clinical high-risk phenotypes, and IET-specific adverse predictors. The International Myeloma Society/International Myeloma Working Group consensus integrates adverse cytogenetics and beta-2 microglobulin, whereas functional high-risk disease, extramedullary disease (EMD), plasma cell leukemia (PCL), high tumor burden, inflammation, and prior BCMA exposure identify aggressive disease in relapsed patients. Across pivotal trials, CAR-T therapy, particularly ciltacabtagene autoleucel, and selected bispecific antibodies retain activity in high-risk cytogenetic subgroups, whereas EMD and PCL remain associated with inferior responses and short progression-free survival. Emerging dual-antigen and trispecific engagers, along with novel targets such as FcRH5 and CD70, aim to overcome antigen escape. Prospective, biology-informed studies are needed to achieve durable disease control in HRMM.
SN - 2234-943X
ER -