Modulating CD38 enzymatic activity during antibody-based immunotherapy in multiple myeloma: a basic science perspective

作者：Alberto L. Horenstein, Kristine A. Frerichs, Angelo C. Faini, Niels W.C.J. van de Donk, Fabio Malavasi · 发表于：Frontiers in Immunology · 年份：2026 · DOI：10.3389/fimmu.2026.1769281 · 被引用次数：1 · 研究领域：Calcium signaling and nucleotide metabolism、Adenosine and Purinergic Signaling、Sirtuins and Resveratrol in Medicine

Introduction Multiple myeloma (MM) develops within a profoundly immunosuppressive bone marrow (BM) microenvironment. CD38, a multifunctional ectoenzyme highly expressed on malignant plasma cells, contributes to this niche by degrading nicotinamide adenine dinucleotide (NAD + ) into ADPR, which fuels adenosine (ADO) production through CD38/CD203a/CD73 enzymatic pathway. CD38_targeting monoclonal antibodies (mAbs), including daratumumab (DARA) and isatuximab (ISA), exert antitumor activity through direct cytotoxicity and immune modulation; however, resistance to these agents remains a major clinical challenge. Understanding how CD38 enzymatic activity and adenosinergic metabolism evolve during therapy is essential for improving treatment efficacy. Methods This study investigates (i) the enzymatic functions of CD38, (ii) the in vitro effects of DARA and ISA on CD38_mediated NAD + degradation in primary MM cells and a representative MM cell line, and (iii) the in vivo dynamics of ADO and its metabolite inosine (INO) in BM and peripheral blood (PB) plasma from MM patients receiving DARA monotherapy. Results In vitro , both DARA and ISA promoted NAD⁺ degradation with accumulation of ADPR. In vivo , ADO concentrations in BM plasma remained consistently in the micromolar range and declined only modestly during treatment, whereas INO progressively increased, leading to a gradual attenuation of the BM -PB gradient. These findings indicate that adenosinergic metabolism remains active du...