Primary light-chain amyloidosis (pAL) is caused by plasma cell (PC) clones that secrete misfolded free light chains that deposit. Anti-CD38 antibody daratumumab is the first-line therapy, while ∼10–30% of patients exhibit suboptimal responses (<very good partial response, VGPR), and baseline predictors and resistance mechanisms remain under investigation. We generated a single-cell bone marrow atlas with B cell receptor and transcriptome sequencing from a cohort of 30 patients with pAL treated with daratumumab–bortezomib–dexamethasone, including 11 paired pre-/post-treatment samples. Among 27 outcome-evaluable patients, 10 demonstrated suboptimal responses before cycle 6 or the start of subsequent therapy. Among patients with t(11;14), compared with good responders, suboptimal responders’ amyloidogenic PCs exhibited lower baseline protein-translation and cell-cell-adhesion gene expression programs, but higher endoplasmic reticulum stress programs. With treatment, mitotic programs were upregulated and gave rise to additional pathogenic PC states. Suboptimal responders also demonstrated two PC–centered immune processes that were enhanced relative to baseline: (i) an inflammatory PTGES2/3–PTGER2/4 axis driven by PTGS2 expressing myeloid-derived suppressor cell–like CD38⁻ CD14⁺ monocytes that expanded with treatment; and (ii) an immunosuppressive non-classical MHC I axis, in which PCs exerted inhibitory interactions (HLA-E–KLRK1, HLA-G–LILRB1, HLA-F–LILRB1). Consistent with these cell-cell interactions, myeloid cells and NK cells showed functional impairment, while T cells were more exhausted; all three cell types exhibited increased interferon-γ responses in suboptimal versus good responders. This atlas reveals amyloidogenic PCs’ resistance to daratumumab and an inflammatory–immunosuppressive niche driven by prostaglandin and non-classical MHC I, underpinning suboptimal responses.

The authors have declared no competing interest.

This study was funded by the National Natural Science Foundation of China (Grant No. 82470202 for LJ), the CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2025-I2M-XHXX-010 for SKN), the National High Level Hospital Clinical Research Funding (Grant No. 2025-PUMCH-A-182 for SKN), and the Research Initiative for Post-Marketing Clinical Studies of Innovative Pharmaceuticals (Grant No. WKZX2024CX105204 for LJ).

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This study was approved by the Ethics Review Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and written informed consent was obtained from all participants (Approval No. JS-3455).

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