Early-line immunotherapy in multiple myeloma: reshaping the treatment paradigm
Abstract
Multiple myeloma (MM) has traditionally been considered to be incurable, despite increasingly effective induction, transplantation, and maintenance strategies. Chimeric antigen receptor (CAR) T-cell therapies and T-cell–redirecting bispecific antibodies have produced deep and durable responses in heavily pretreated disease and are now moving into earlier lines of therapy. The biologic rationale for earlier use includes the potential for greater T-cell fitness, a more permissive bone marrow immune microenvironment, a lower burden of treatment-resistant disease, and the need to deliver effective therapy before attrition prevents patients from receiving effective treatments. Randomized trials have established the superiority of B-cell maturation antigen (BCMA)-directed CAR T-cell therapy and BCMA- or G protein–coupled receptor class C group 5 member D (GPRC5D)-directed bispecific regimens over conventional therapies in early relapse. In contrast, frontline use remains investigational, with predominantly small, nonrandomized studies and limited follow-up. Ongoing studies are evaluating these approaches as induction, consolidation, maintenance, and measurable residual disease (MRD)–directed therapy, as well as potential alternatives to autologous stem cell transplantation. However, moving T-cell–redirecting immunotherapy earlier introduces important biological and clinical challenges, including sustained immune and antigen engagement, antigen escape and distinct toxicities. Optimal sequencing across targets and treatment modalities, as well as the optimal duration of therapy, remain areas of active investigation. The high efficacy of modern anti-CD38–based quadruplets and transplantation also establishes a demanding benchmark against which early-line immunotherapy must be assessed. In this review, we examine the immunological and clinical rationale for earlier treatment, summarize emerging evidence for CAR T-cell therapies and bispecific antibodies in early-relapsed and newly diagnosed myeloma, and discuss their evolving relationship with autologous transplantation. We further highlight the need for prospective sequencing studies, sustained MRD endpoints and fixed-duration/response-adapted strategies to determine whether earlier immunotherapy can provide durable disease control while reducing cumulative treatment exposure.
Related
- Rethinking immunotherapy sequencing in multiple myeloma: a conceptual adaptive immunotherapy sequencing model
- Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation
- Efficacy and specific toxicity profiles of GPRC5D- versus BCMA-targeted bispecific antibodies in relapsed/refractory multiple myeloma: a meta-analysis of clinical trials and real-world studies
- STAT3 inhibition for the induction of immunogenic cell death in multiple myeloma
- Spatial oligonucleotide immuno-reprogramming model (SOIRM): a testable framework linking bone marrow resistance states and oligonucleotide therapeutics in multiple myeloma
BibTeX
@article{darji2026earlyline,
title = {{Early-line immunotherapy in multiple myeloma: reshaping the treatment paradigm}},
author = {Rida Darji and Curtis Marcoux and Mahmoud Gaballa and Aimaz Afrough and Meera Mohan and Krina K. Patel and Oren Pasvolsky},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1981988},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1981988},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Early-line immunotherapy in multiple myeloma: reshaping the treatment paradigm
AU - Rida Darji
AU - Curtis Marcoux
AU - Mahmoud Gaballa
AU - Aimaz Afrough
AU - Meera Mohan
AU - Krina K. Patel
AU - Oren Pasvolsky
PY - 2026
DA - 2026/10/30
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1981988
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1981988
AB - Multiple myeloma (MM) has traditionally been considered to be incurable, despite increasingly effective induction, transplantation, and maintenance strategies. Chimeric antigen receptor (CAR) T-cell therapies and T-cell–redirecting bispecific antibodies have produced deep and durable responses in heavily pretreated disease and are now moving into earlier lines of therapy. The biologic rationale for earlier use includes the potential for greater T-cell fitness, a more permissive bone marrow immune microenvironment, a lower burden of treatment-resistant disease, and the need to deliver effective therapy before attrition prevents patients from receiving effective treatments. Randomized trials have established the superiority of B-cell maturation antigen (BCMA)-directed CAR T-cell therapy and BCMA- or G protein–coupled receptor class C group 5 member D (GPRC5D)-directed bispecific regimens over conventional therapies in early relapse. In contrast, frontline use remains investigational, with predominantly small, nonrandomized studies and limited follow-up. Ongoing studies are evaluating these approaches as induction, consolidation, maintenance, and measurable residual disease (MRD)–directed therapy, as well as potential alternatives to autologous stem cell transplantation. However, moving T-cell–redirecting immunotherapy earlier introduces important biological and clinical challenges, including sustained immune and antigen engagement, antigen escape and distinct toxicities. Optimal sequencing across targets and treatment modalities, as well as the optimal duration of therapy, remain areas of active investigation. The high efficacy of modern anti-CD38–based quadruplets and transplantation also establishes a demanding benchmark against which early-line immunotherapy must be assessed. In this review, we examine the immunological and clinical rationale for earlier treatment, summarize emerging evidence for CAR T-cell therapies and bispecific antibodies in early-relapsed and newly diagnosed myeloma, and discuss their evolving relationship with autologous transplantation. We further highlight the need for prospective sequencing studies, sustained MRD endpoints and fixed-duration/response-adapted strategies to determine whether earlier immunotherapy can provide durable disease control while reducing cumulative treatment exposure.
SN - 1664-3224
ER -