Rethinking immunotherapy sequencing in multiple myeloma: a conceptual adaptive immunotherapy sequencing model
- 1Department of Hemato-Oncology, Al-Quds University School of Medicine
Abstract
Background: Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs) have transformed treatment for relapsed/refractory multiple myeloma (RRMM). Contemporary guidelines increasingly incorporate prior antigen-directed exposure, disease kinetics, patient fitness, toxicity, access, and patient preference. However, a prospectively validated framework that jointly operationalizes immune fitness, tumor antigen status, and treatment feasibility for sequencing T-cell–redirecting therapies is not available.
Main body: This Perspective introduces the Adaptive Immunotherapy Sequencing Model (AISM), an author-proposed framework for research and multidisciplinary discussion. AISM proposes that sequencing should be studied in relation to two evolving biological domains: the capacity of the host T-cell compartment to support therapy and the probability that the relevant tumor antigen remains therapeutically actionable. The model uses provisional 0–10 research constructs for T-cell fitness and antigen-escape risk to make these domains explicit. AISM hypothesizes that, for eligible patients with early RRMM and feasible access, referral for BCMA-directed CAR-T before prolonged exposure to T-cell–redirecting BsAbs may preserve a potentially favorable treatment option. It also recognizes that off-the-shelf BsAbs may be necessary when disease tempo, frailty, access, or patient preference make CAR-T impracticable. After prior BCMA-directed therapy, an antigen-switching approach is biologically plausible, but antigen loss is not universal and other mechanisms of resistance must be considered.
Conclusions: AISM provides a testable framework for prospective comparative studies. Such studies should evaluate whether biologically informed sequencing improves progression-free survival (PFS), while also assessing overall survival, toxicity, infections, treatment-free time, feasibility, and patient-reported outcomes.
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BibTeX
@article{khalili2026rethinking,
title = {{Rethinking immunotherapy sequencing in multiple myeloma: a conceptual adaptive immunotherapy sequencing model}},
author = {Aliaa Khalili},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1897153},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1897153/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Rethinking immunotherapy sequencing in multiple myeloma: a conceptual adaptive immunotherapy sequencing model
AU - Aliaa Khalili
PY - 2026
DA - 2026/10/15
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1897153
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1897153/full
AB - Background: Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs) have transformed treatment for relapsed/refractory multiple myeloma (RRMM). Contemporary guidelines increasingly incorporate prior antigen-directed exposure, disease kinetics, patient fitness, toxicity, access, and patient preference. However, a prospectively validated framework that jointly operationalizes immune fitness, tumor antigen status, and treatment feasibility for sequencing T-cell–redirecting therapies is not available. Main body: This Perspective introduces the Adaptive Immunotherapy Sequencing Model (AISM), an author-proposed framework for research and multidisciplinary discussion. AISM proposes that sequencing should be studied in relation to two evolving biological domains: the capacity of the host T-cell compartment to support therapy and the probability that the relevant tumor antigen remains therapeutically actionable. The model uses provisional 0–10 research constructs for T-cell fitness and antigen-escape risk to make these domains explicit. AISM hypothesizes that, for eligible patients with early RRMM and feasible access, referral for BCMA-directed CAR-T before prolonged exposure to T-cell–redirecting BsAbs may preserve a potentially favorable treatment option. It also recognizes that off-the-shelf BsAbs may be necessary when disease tempo, frailty, access, or patient preference make CAR-T impracticable. After prior BCMA-directed therapy, an antigen-switching approach is biologically plausible, but antigen loss is not universal and other mechanisms of resistance must be considered. Conclusions: AISM provides a testable framework for prospective comparative studies. Such studies should evaluate whether biologically informed sequencing improves progression-free survival (PFS), while also assessing overall survival, toxicity, infections, treatment-free time, feasibility, and patient-reported outcomes.
SN - 1664-3224
ER -