Single-Cell Analysis Reveals Inflammatory-Immunosuppressive Niches Associated with Suboptimal Response to Daratumumab-Based Therapy in AL Amyloidosis

Systemic light-chain amyloidosis is caused by plasma cell clones that secrete misfolded free light chains. Although daratumumab is used for first-line therapy, mechanisms underlying suboptimal response remain unclear. We generated a bone marrow single-cell atlas from 30 patients treated with a first-line daratumumab-based regimen. Suboptimal responders were defined as not achieving a very good partial response within six cycles. In the t(11;14) subgroup, amyloidogenic plasma cells from suboptimal responders exhibited lower baseline protein-translation and cell-cell adhesion programs than those from good responders. The bone marrow of suboptimal responders exhibited increased baseline (i) prostaglandin E2-EP2/EP4 signaling with myeloid-derived suppressor cell-like CD14+ monocytes expressing PTGS2; and (ii) non-classical MHC class I signaling between plasma cells and the microenvironment. Following treatment, myeloid and NK-cell dysfunction, T-cell exhaustion, and IFN gamma; responses were more pronounced in suboptimal responders than in good responders. This atlas reveals inflammatory-immunosuppressive bone marrow niches that underpinned suboptimal response.