2025 Update of Cellular Immunotherapy for Plasma Cell Disorders

Abstract

Despite progression-free survival in multiple myeloma (MM) patients extending to 17 years due to contemporary quadruplet induction therapies, there remains a necessity for novel products in the treatment of high-risk patients. BCMA, GPRC5D, FcRH5, SLAMF7, and TACI are the principal chimeric antigen receptor T (CAR-T) cell target molecules, with dual-target treatments under development to enhance treatment efficacy. Ide-cel and cilta-cel are CAR-T cells directed against BCMA, having received approval from the U.S. Food and Drug Administration for relapsed/refractory MM based on the phase 2 KarMMa and CARTITUDE trials, respectively. Research is currently being conducted on the administration of these products in newly diagnosed patients and for maintenance therapy. Additional anti-BCMA targeted medicines, including LCAR-B38M, completely humanized CAR-T (FHVH-T), P-BCMA-ALLO-1, ALLO-715, and anti-BCMA CAR-NK, provide promising treatment options. Moreover, the anti-CD19 Fast-CAR, designed to shorten production time, and PHE885, which possesses in vivo proliferation capability, are regarded as very efficacious. Arlocel, developed for the significant target GPRC5D, has demonstrated efficacy compared to conventional treatments. The development of academic CAR-T products such as ARI0002h, HBI0101, eque-cel, zevorcel, anito-cel, and Sleeping Beauty (utilizing a non-viral vector) have importance due to their accessibility and cost-effectiveness. Real-world data have demonstrated comparable efficacy and safety outcomes in both academic and commercial CAR-T research. CAR-T cell studies are also being undertaken for smoldering MM and amyloid light-chain (AL) amyloidosis. CAR-PRISMM and CAR-HiRiSMM are regarded as extremely effective and safe therapies for patients with high-risk smoldering MM. NXC-201, which targets BCMA, has been developed for AL amyloidosis. Notwithstanding these promising outcomes, numerous difficulties still confront CAR-T therapy. These factors may be related to the tumor, the patient, and/or the CAR-T product. To overcome these issues, new strategies are being implemented, including combination therapyand the incorporation of gamma-secretase inhibitors. In conclusion, CAR-T treatments have evolved into an effective therapy modality and are anticipated to be utilized in earlier treatment phases in the future. The CRISPR gene editing method contributes to future perspectives.