Observational study explores daratumumab resistance mechanisms in primary light-chain amyloidosisSmall study links daratumumab resistance to immune changes in light-chain amyloidosis

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-{gamma} 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.