P103 | Partial inhibition of NAMPT restores metabolic vulnerability and synergizes with anti-myeloma agents in multiple myeloma

作者：G. Giorgetti · 发表于：Haematologica · 年份：2026 · DOI：10.3324/haematol.2026.s1.160

Introduction. Multiple myeloma (MM) is a metabolically demanding plasma cell malignancy in which resistance to current therapies remains a major clinical challenge. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD⁺ salvage pathway, sustains cellular energetics and redox balance in tumor cells and is frequently upregulated in MM. We previously reported that complete inhibition of NAMPT disrupts NAD⁺ metabolism in malignant and normal cells, leading to dose-limiting toxicities that have hindered clinical development. RPT1F is a novel, first-in-class partial NAMPT inhibitor designed to preserve residual enzymatic activity in healthy cells while selectively disrupting NAD⁺ homeostasis in tumor cells. This study aimed to evaluate the efficacy and mechanistic synergy of RPT1F, alone and in combination with standard anti-MM agents, in preclinical models.Methods. RPT1F was first tested on bone marrow mononuclear cells collected from MM patients to assess selective toxicity toward malignant plasma cells (CD138⁺) versus normal immune subsets (CD138⁻), including NK, NKT, B lymphocytes, and CD8⁺/CD4⁺ T cells. Anti-tumor activity was then evaluated across a panel of genetically and metabolically heterogeneous MM cell lines. Cell viability, apoptosis, NAD⁺/ATP levels, and mitochondrial oxygen consumption rate (OCR) were quantified after 24-hour drug exposure. Combination studies with clinically used anti-MM drugs were performed, and drug synergy was analy...