The first-in-human clinical trial of an in vivo CAR T-cell therapy for multiple myeloma has shown encouraging clinical outcomes at an early time point, with a safety profile and ease of administration that indicates the off-the-shelf KLN-1010 could be easily deployable, researchers from Australia reported at the American Society of Hematology 2025 Annual Meeting & Exposition.1
“In inMMyCAR, the phase I first-in-human trial of in vivo KLN-1010, we have shown that lymphodepletion is not required for in vivo CAR T-cell generation and expansion in the peripheral blood,” said Phoebe Joy Ho, MBBS, DPhil, FRACP, FRCPA, FFFc, Professor of Hematology at the University of Sydney and Royal Prince Alfred Hospital in Sydney.
“CAR T-cell expansion peaked around Day 15, and memory phenotype T cells persisted in the marrow and blood through month 3. We note that similar outcomes have been associated with durable remissions with ex vivo CAR T in myeloma. We achieved 100% early MRD [measurable residual disease]–negative responses by month 1, with deepening of responses over time,” Dr. Ho said.
The favorable safety profiles seen with this off-the-shelf product make outpatient therapy feasible, she added.
Audience reaction to the findings was universally positive: “fantastic,” “incredible work,” “practice-changing,” and “takes your breath away” were among the comments made by attendees at the Late-Breaking Abstracts Session.
About the Therapy
KLN-1010 is administered intravenously to generate a fully human anti-BCMA CAR T cell in vivo. Simply put, Dr. Ho explained that by injecting the lentiviral vector, the aim is to generate CAR Ts in vivo, as opposed to the current system where T cells are harvested for manufacturing in the laboratory. Such in vivo CAR T-cell therapy eliminates the need for preconditioning lymphodepletion and simplifies the logistics and cost of delivering CAR T-cell therapy as it is currently done.
This is an improved third-generation lentiviral vector that is comprised of a modified vesicular stomatitis virus glycoprotein (VSV-G) fusogen co-expressed with an anti-CD3 antibody on the lentiviral vector envelope; this enables viral entry through CD3 on the T cells rather than the low-density lipoprotein receptor. Selective transduction of circulating T cells is achieved.
Phase I inMMyCAR Study
Preclinical studies demonstrated superior antimyeloma activity compared with ex vivo–manufactured CAR T cells, along with the generation of less differentiated, memory-like T-cell phenotypes that are associated with improved persistence and tumor eradication. On this basis, a phase I, first-in-human trial was initiated in patients with relapsed or refractory multiple myeloma previously exposed to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody but not to an agent targeting B-cell maturation antigen (BCMA).
The inMMyCAR study is enrolling 20 participants. Dr. Ho presented data from the first four treated participants, all of whom had high-risk cytogenetics.Three of the four patients were treated at 2×107 IU/kg (dose level 1) and one was treated at 6×106 IU/kg (dose level –1); this dose de-escalation was prompted by the high efficacy and favorable safety profile observed with the treatment, she explained.
CAR T Expansion
“CAR T-cell expansion occurred despite the absence of lymphodepletion,” Dr. Ho said. “All patients experienced a rise in lymphocyte count…CAR-positive T cells were detected in the blood on Day 15 at levels of 22% to 85% of CD3-positive T cells, with a mixture of CD4 and CD8 cells of different proportions. Of note, the highest level of 85% was achieved at dose level –1,” she reported.
Phenotypically, in all four patients, KLN-1010 generated CAR Ts that were enriched with less differentiated T cells and with memory CAR T cells, which are known to be associated with improved expansion, persistence, and tumor control associated with durable remission.The Cmax and the persistence of the CAR T cells seen out to 3 months, in both blood and marrow, were commensurate with the available ex vivo products. The level of expansion was 51,000 to 108,000 copies per microgram of DNA.
All patients achieved MRD negativity within 1 month of treatment: the first three achieved MRD-negative disease at 10-6 sensitivity, while the fourth patient, who was treated at dose level –1, had MRD negativity at a sensitivity of 10-5 at month 1. Two patients remained MRD-negative at 3 months, one patient at 10-6 and one at 10-5. Dr. Ho explained the sensitivity at 10-5 was “due to sample cellularity by flow cytometry,” and sequencing is now in progress.
The patient with the longest follow-up (approximately 5 months) achieved a complete response by International Myeloma Working Group (IMWG) criteria. The remaining patients were in partial response, attributed to delayed clearance of paraprotein, with additional evidence of activity demonstrated by marked reductions in involved free light chains and soluble BCMA levels, consistent with a reduction in tumor load, Dr. Ho reported.
Good Tolerability
No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed in these four participants. Three cases of cytokine release syndrome occurred, and all were grade 1 or 2. One case of transient grade 4 neutropenia, attributed to margination, was reported. In addition, one patient developed grade 3 anemia and one developed grade 1 thrombocytopenia. Infusion reactions occurred in three patients, with only one grade 3 event, all resolving promptly with standard management. Compared to ex vivo CAR T-cell therapy, this indicates an improved adverse event profile, according to Dr. Ho.
DISCLOSURE: Dr. Ho had personal disclosures for Gilead, Janssen, GSK, and Pfizer.
REFERENCE
1. Harrison S, Ho PJ, Lim S-L, et al. MRD-negative outcomes following a novel, in vivo gene therapy generating anti-BCMA CAR T-cells in patients with RRMM: preliminary results from inMMyCAR, the first-in-human phase 1 study of KLN-1010. 2025 ASH Annual Meeting & Exposition. Abstract LBA-1.
Presented December 9, 2025.
EXPERT POINT OF VIEW
For her thoughts on the novel CAR T therapy, The ASCO Post interviewed Amrita Krishnan, MD, Professor in the Department of Hematology & Hematopoietic Cell Transplantation, the Nason-Hollingsworth Endowed Chair in Multiple Myeloma, and Director of the Judy and Bernard Briskin Multiple Myeloma Center at City of Hope Orange County, California.
“The findings are very exciting,” Dr. Krishnan said. “It may turn out that they are not exactly product-specific, but more about how future myeloma treatments are continuing to evolve.”She noted that early CAR T trials were focused on response, and once that was demonstrated the concerns became more about toxicity. Now, with efficacy and tolerability becoming fairly well established, “it’s become about balancing efficacy and toxicity and about how we can do even better,” she said.
The data on KLN-1010 indeed appear to show both efficacy and safety for this in vivo CAR T-cell product, she noted. “We saw no high-grade CRS [cytokine release syndrome] and no neurotoxicity, either early or delayed. So far, the safety signal seems very good, and at least comparable if not better than with ex vivo CAR T-cell therapies, though follow-up is still very short,” she observed.
Certainly, she emphasized, an off-the-shelf therapy that requires no apheresis and no lymphodepleting chemotherapy is a big “win” for patients and physicians. Burden of care is reduced, and there is less chance of disease progression prior to the CART administration since there is no delay while waiting for product manufacturing, she said. “In CARTITUDE-4, the initial survival curve dropped because of patients progressing before they actually got their CAR T. In patients with very advanced or aggressive disease, the few weeks of manufacturing time can really matter. The manufacturing time has been one of the real challenges with CAR T.”
The study excluded patients who had not received prior CAR T-cell therapy. Dr. Krishnan commented that based on the strong efficacy signal now observed, hopefully future cohorts will explore efficacy in patients already treated with various BCMA targeted therapies. It is her understanding that future study populations will expand to include U.S. sites.
DISCLOSURE: Dr. Krishnan had personal disclosures for Sanofi, Johnson & Johnson, Adaptive Biotechnologies, Janssen Pharmaceuticals, Bristol Myers Squibb, GSK, Arcellx, AbbVie, and Roche.
REFERENCE
1. Harrison S, Ho PJ, Lim S-L, et al. MRD-negative outcomes following a novel, in vivo gene therapy generating anti-BCMA CAR T-cells in patients with RRMM. 2025ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 9, 2025.
