The GPRC5D (G protein-coupled receptor class C group 5 member D) gene encodes an orphan G protein-coupled receptor of the class C family, a seven-pass transmembrane protein of currently undetermined signal transduction function and endogenous ligand. Its expression profile is characterized by a striking disparity: while it exhibits low or minimal expression in most normal human tissues, clinically significant overexpression is highly restricted to malignant plasma cells in Multiple Myeloma (MM), as well as specific hard keratinized cellular tissues such as the hair follicles, nail beds, and filiform papillae of the tongue ^[1]. This selective high expression in tumor cells has positioned GPRC5D as a critical immunotherapeutic target for MM, with agents like the bispecific T-cell engager talquetamab and CAR T cells showing clinical efficacy in relapsed/refractory disease; however, its restricted expression in normal keratinized tissues results in predictable on-target, off-tumor toxicities including mucocutaneous and nail adverse events ^[2-3]. Furthermore, elevated GPRC5D expression in the bone marrow is often correlated with poor prognosis and high-risk cytogenetic features in MM patients ^[4]. B6-huGPRC5D mouse is a humanized model generated using gene editing technology, in which the sequences from the ATG start codon to the TAA stop codon of the endogenous mouse Gprc5d gene are replaced with the sequences from the ATG start codon to the TAA stop codon of the human GPRC5D gene. This model can be used for studying the pathological mechanisms and therapeutic approaches of Multiple Myeloma (MM), as well as for the development of GPRC5D-targeted drugs.