RVd and CyBorD therapies remodel B-cell maturation signaling and alter immune and clonal architecture in multiple myeloma

Background: Multiple myeloma (MM) features plasma cell (PC) heterogeneity and alterations in B-cell differentiation and immune regulation. Although lenalidomide/bortezomib/dexamethasone (RVd) and cyclophosphamide/bortezomib/dexamethasone (CyBorD) are clinically effective, their precise impacts on PC/B‐cell maturation remain unclear. Methods: We performed CyTOF profiling on bone marrow samples from RVd- (n = 47) and CyBorD-treated MM patients (n = 15), each compared to untreated cohort (n = 43). Within each therapeutic arm, responders (RVd, n = 35; CyBorD, n = 5) were compared to non-responders (RVd, n = 12; CyBorD, n = 10). Results: RVd and CyBorD therapies exerted distinct immune modulation patterns, differentially affecting PC, early B-cell stages, and naive T cells. Evaluation of transcriptional B-cell regulators in B-cell lymphopoiesis revealed that both regimens decreased IRF4, CXCR4, and FGFR3 while upregulating Pax-5 across B‐cell stages and PC. RVd uniquely upregulated MYD88 and c-Myc and decreased sXBP1; its responders further suppressed BLIMP-1 and FGFR3. In contrast, CyBorD elevated sXBP1, BLIMP-1, and Notch-1 while reducing c-Myc in the B and PC subsets. Both therapies increased the expression of the stemness factor KLF4 and variably modulated NANOG; CyBorD altered Nestin and RARα2 in responder PCs, whereas RVd suppressed OCT3/4. Shared immunophenotypic aberrations included decreased MMSET, CD200, and CD52, and increased CD47, CD81, and CD44 in B‐cell compartments. In PC, both regimens elevated CD338 while reducing CD47, CD319, and CD138. RVd responders further downregulated CD56, CD269, and CD329, and increased CD243. Conclusions: These shared and divergent modulations elucidate the molecular underpinnings of RVd and CyBorD efficacy and inform precision regimen selection.