Responses per International Myeloma Working Group (IMWG) criteria deepened over time, with patient 1 achieving a complete response at a MRD sensitivity level of 10-6 after month 5; patient 2 achieving a partial response (PR) at a MRD sensitivity level of 10-5 during month 4; patient 3 achieving a PR at a MRD sensitivity level of 10-5 during month 3; and patient 4 achieving a PR at a MRD sensitivity level of 10-5 at the beginning of month 2. Of note, in the first 2 patients with the longest follow-up, MRD-negative bone marrow responses were sustained through 3 months.
CAR T-cell expansion occurred despite the absence of lymphodepleting chemotherapy. All patients experienced a rise in lymphocyte count, with the absolute lymphocyte count increasing to 43 x 109/L in patient 3. Dexamethasone was administered to patients 3 and 4 with prompt resolution and no clinical sequelae. Additionally, CAR-positive T cells were detected in the blood at day 15 at rates of 35%, 22%, 72% and 85%, and comprised a mixture of CD4 and CD8 CAR T-cells. Of note, the highest level of CAR-positive cells was achieved at dose level –1.
“These initial MRD-negative responses and persistent CAR T-cell [expansion may be] prognostic of ongoing clinical responses,” presenting author Phoebe Joy Ho, MBBS, DPhil, a professor at the University of Sydney, shared. “Establishing durability of response [DOR] remains a priority in continued follow-up, and updated results will be presented at future meetings.”
Ho is also a senior staff specialist in hematology, the director of research, and head of the Multiple Myeloma Research Unit and Thalassemia/Haemoglobinopathy Unit at the Institute of Haematology, Royal Prince Alfred Hospital in Sydney, Australia.
Why was KLN-1010 chosen for investigation in this patient population, and what makes its mechanism of action unique?
KLN‑1010 is an envelope-modified, replication-incompetent, self-inactivating modified lentiviral vector gene therapy administered intravenously to generate novel, fully-human anti-BCMA CAR T cells in vivo. Designed as an off-the-shelf therapy, KLN-1010 eliminates the need for preconditioning lymphodepleting chemotherapy, simplifies the logistics of CAR T-cell administration, and may increase T-cell fitness through the absence of ex vivo culture, all of which could improve access to CAR T-cell therapies, Ho explained.
Ho also expanded on preclinical data showing modification of diverse T-cell lineages, antitumor activity, and potent tumor control with KLN-1010.2
“In mouse xenograph models of myeloma, KLN-1010 delivered in vivo led to more profound killing of tumor compared with ex vivo manufactured ciltacabtagene autoleucel [cilta-cel; Carvykti]–like CAR T cells,” Ho reported.1“In the treated mice, while KLN-1010–generated CAR T cells have diverse T-cell developmental phenotypes, there is a higher compilation of central memory and STEM-like CAR T cells. [Furthermore,] in multiple animal models, the vast majority of KLN-1010-generated CAR–positive cells are shown to be T cells.”
How was this phase 1 trial designed?
inMMyCAR is a first-in-human, dose-escalation/-expansion study conducted at 3 different sites in Australia: Peter MacCallum Cancer Center, The Alfred Hospital, and Royal Prince Alfred Hospital. The study plans to enroll approximately 20 patients with relapsed/refractory multiple myeloma who received 3 or more lines of prior therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), or anti-CD38 antibodies. Other eligibility criteria include an ECOG performance status of 0 or 1 and adequate bone marrow or organ function.
In the dose-escalation phase, patients will receive KLN-1010 at 6 x 106 IU/kg (dose level –1), 2 x 107 IU/kg (dose level 1), dose level 2, and dose level 3. This was followed by an expansion cohort in which patients received the recommended phase 2 dose (RP2D) of KLN-1010.
The study’s primary end points are safety, tolerability, and identification of the RP2D. Key secondary end points include CAR T-cell expansion and persistence, overall response rate per IMWG criteria, MRD, DOR, and progression-free survival.
What were the baseline characteristics of the initial 4 patients in this study?
Three of the initial 4 patients evaluated in the study received dose level 1. The ages of patients 1, 2, 3, and 4 were 72 years, 62 years, 61 years, and 70 years, respectively. Patients 1 and 4 were male; patients 2 and 3 were female. Patients 1 through 3 had immunoglobulin G (IgG) myeloma with lambda light chains, while patient 4 had kappa light chains. Assessment of high-risk cytogenetics showed that patients had the following mutations: 17p deletions (patients 1, 2, 4), 1q gain (patients 1 and 4), t(4;14) translocations (patients 2, 3), and 1p32 deletions (patient 2). Bone marrow plasma cell percentages were 30%, less than 5%, 10% and 60% in patients 1, 2, 3, and 4, respectively. These patients received 4, 3, 3, and 5 prior lines of therapy, respectively. Patients 1, 3, and 4 were all refractory to PIs, IMiDs, and anti-CD38 antibodies; patient 2 was only refractory to IMiDs and anti-CD38 antibodies. No patients had extramedullary disease, and all patients had previously undergone autologous stem cell transplant.
How did CAR T-cell persistence with KLN-1010 compare with that of ex vivo CAR T-cell therapies?
Moreover, phenotypic evidence showed that KLN-1010–generated CAR T cells were enriched with memory T cells, which are known to be associated with improved expansion, persistence and tumor control, Ho stated. The percentage of CAR-positive T cells in the blood over time peaked at day 15 for all 4 patients, and 2 patients had CAR T-cell persistence up to month 3.
CAR T-cell expansion with KLN-1010 was also commensurate with that of approved ex vivo CAR T-cell therapies at peak expansion; this persistence was observed in both the blood and the bone marrow. In patients 1, 2, and 3, the Cmax of vector copies per µg of genomic DNA was 51,657, 65,873, and 108,730, respectively. In comparison, the Cmax of vector copies per µg of genomic DNA in the phase 1/2 CARTITUDE-1 (NCT03548207) and phase 3 CARTITUDE-4 (NCT04181827) trials were a median of 47,806 (range, 7189-115,234) and 34,891 (range, 935-104,861), respectively.
What should be known about the agent’s safety profile?
Investigators did not observe any instances of immune effector cell–associated neurotoxicity syndrome or delayed neurotoxicity. Moreover, all cases of cytokine release syndrome (CRS) were low-grade, and CRS events were consistent with those seen with ex vivo CAR T-cell therapies. The median onset of CRS was 10 days (range, 10-12), and the median duration was 5.5 days (range, 2-8). Two Grade 1/2 CRS events occurred at dose level 1, and 1 grade 1/2 CRS event occurred at dose level –1. Dexamethasone and tocilizumab (Actemra) were administered as supportive care measures (n = 3 each).
Treatment-emergent adverse effects (TEAEs) occurred in more than 1 patient included Infusion-related reactions (IRR; grade 1/2, n = 2; grade 3 or higher, n = 1 [dose-limiting toxicity]), lymphocytosis (n = 1; n = 1), hypomagnesemia (n = 2; n = 0), and hypokalemia (n = 2, n = 0). Grade 3 or higher TEAEs included febrile neutropenia, IRR, lymphopenia, lymphocytosis, anemia, vasovagal syncope, and pneumonia (n = 1 each).
Cytopenias were also minimal, with only 1 case of grade 4 transient neutropenia reported. Grade 3 or higher anemia and thrombocytopenia occurred in one patient each on study days 15 and 16, respectively, and lasted for 2 days. Two patients experienced grade 3 or higher neutropenia. One grade 1/2 and 1 grade 3 or higher IRR occurred at dose level 1; tocilizumab and steroids were administered as supportive care. One grade 1/2 IRR occurred at dose level –1, and paracetamol was administered as supportive care.
This favorable safety and tolerability profile, which was achieved with an off-the-shelf product, suggests that outpatient administration of KLN-1010 may be feasible, Ho concluded.
Disclosures: Ho reported serving as a consultant for Gilead, Janssen, and Pfizer; receiving research funding from Novartis; and receiving honorarium from GSK.
References
- Harrison S, Ho, PJ, Lim S-L, 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-in-human phase 1 study of KLN-1010: results of a phase 2 trial. Blood. 2025;146(suppl 1):LBA-1. doi:10.1182/blood-2025-LBA-1
- Kelonia Therapeutics to present preclinical data highlighting therapeutic potential of in vivo CAR-T cell therapy in multiple myeloma. News Release. Kelonia Therapeutics. April 2, 2024. Accessed December 9, 2025. https://keloniatx.com/kelonia-therapeutics-to-present-preclinical-data-highlighting-therapeutic-potential-of-in-vivo-car-t-cell-therapy-in-multiple-myeloma/
