At ASH 2025, investigators reported early results from the first-in-human phase 1 inMMyCAR study evaluating KLN-1010, an investigational in vivo gene therapy designed to generate anti B-cell maturation antigen CAR T cells directly in patients with relapsed and refractory multiple myeloma.
First In Human Study
KLN-1010 is administered intravenously and uses a third-generation lentiviral vector engineered to selectively transduce circulating T cells via CD3, rather than the low-density lipoprotein receptor. The approach is intended to function as an off-the-shelf CAR T therapy, removing the need for apheresis, ex vivo manufacturing or lymphodepleting chemotherapy.
The multicentre, sponsored study enrolled patients with relapsed and refractory multiple myeloma who had received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug and an anti CD38 monoclonal antibody. All patients had measurable disease, adequate organ function and high-risk cytogenetics, and were naïve to BCMA targeted therapies.
The first three treated patients were aged 61 to 72 years, with 7.9 to 9.4 years from diagnosis and three to four prior lines of therapy. Two were triple class refractory. Time from consent to infusion ranged from 13 to 18 days.
Early Safety And Expansion
All patients experienced treatment emergent adverse events, mainly around infusion and CAR T expansion. Two developed infusion related reactions within 30 to 60 minutes, resolving within 6 to 48 hours. Following this, tocilizumab was given prophylactically in subsequent patients.
Grade 2 cytokine release syndrome occurred in two patients during expansion. No immune effector cell associated neurotoxicity syndrome or delayed neurological toxicity was observed. Cytopenias were limited, with brief grade 3 anaemia in one patient and transient grade 3 or 4 neutropenia in another. No grade 3 or higher thrombocytopenia or treatment emergent infections were reported at one month.
Despite the absence of lymphodepletion, robust T cell expansion occurred, peaking around days 13 to 18. CAR positive cells represented up to 72% of CD3 positive lymphocytes, with no clinical sequelae from lymphocytosis.
Rapid MRD Negative Responses
All three patients achieved minimal residual disease negative bone marrow responses at one month, at sensitivities of 10⁻⁵ or 10⁻⁶ by next generation flow cytometry or sequencing. The patient with the longest follow up maintained MRD negativity at month three.
By International Myeloma Working Group criteria, all achieved partial responses at one month that deepened over time, with a best response of very good partial response at month three. CAR T cells persisted in blood and bone marrow through three months and showed a predominantly memory phenotype.
Investigators concluded that these preliminary data support the feasibility of off-the-shelf in vivo CAR T therapy in multiple myeloma, with manageable toxicity and early MRD negative responses. The study is ongoing, with further updates expected.
Reference
Harrison S et al. Minimal residual disease (MRD)-negative outcomes following a novel, in vivo gene therapy generating anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells in patients with relapsed and refractory multiple myeloma (RRMM): Preliminary results from inMMyCAR, the first-inhuman phase 1 study of KLN-1010. ASH Annual Meeting; December 12-15 2025.
