KLN-1010 In Vivo CAR Achieves 100% MRD Negativity in R/R Myeloma

KLN-1010, an in vivo gene therapy approach to generating anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells, yielded a 100% overall response rate (ORR) and universal minimal residual disease (MRD) negativity at 1 month, according to preliminary phase 1 data presented at the European Hematology Association (EHA) 2026 Congress in Stockholm, Sweden.

Andrew Spencer, MBBS, MD, of the Alfred Hospital–Monash University Australian Centre for Blood Diseases in Melbourne, Australia, presented results from 18 patients treated in the inMMyCar trial (NCT07075185), evaluating KLN-1010, a modified lentiviral vector engineered to generate anti-BCMA CAR T cells in vivo following a single intravenous infusion.

“We're demonstrating that lymphodepletion is not required for in vivo CAR T generation, expansion, and persistence in this population and that this has occurred in a heterogeneous, immunologically speaking, patient population,” Spencer said. “I think overall [these are] very favorable preliminary data.”

Mechanism and Rationale

KLN-1010 is an envelope-modified, replication-incompetent, self-inactivating lentiviral vector. Its VSV-G fusogen has been mutated to eliminate binding to LDL-expressing cells while maintaining transduction efficiency, and CD3 single-chain variable fragment (scFv) retargeting directs the vector specifically to T cells, avoiding liver uptake and drug sinks. The vector carries a proprietary, fully human anti-BCMA CAR construct incorporating 4-1BB costimulatory and CD3ζ signaling domains.

The in vivo approach eliminates the weeks-long ex vivo manufacturing process required for conventional CAR T-cell therapies, removes the need for lymphodepleting chemotherapy, and substantially reduces cost. Spencer noted that the median time from consent to treatment in the trial was 13 days, a window he said would likely be shorter outside the clinical trial context given the simplified logistics.

Trial Design and Patient Characteristics

The inMMyCar trial uses a 3+3 dose-escalation design with backfill, enrolling patients with relapsed/refractory multiple myeloma after 3 or more prior lines of therapy including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody, with ECOG performance status of 0 or 1 and adequate bone marrow and organ function. Three dose levels were evaluated: 2 × 10⁷ IU/kg, 6 × 10⁶ IU/kg, and 4 × 10⁶ IU/kg. The study enrolled initially at 3 Australian sites and has since expanded to US centers including City of Hope, Emory University Hospital, Massachusetts General Hospital, Providence Portland Medical Center, and Stanford University.

Among the 18 patients treated, median age was 67 years (range, 50-77), 72% were male, and 72% had high-risk cytogenetics. Extramedullary disease was present in 28% at baseline, and median bone marrow plasma cell percentage was 20% (range, 4%-90%). The disease stage was ISS stage 2 or 3 in 56% of patients. Patients received a median of 3.5 prior lines of therapy (range, 2-7), 89% had undergone prior autologous stem cell transplant, and 56% were triple-class refractory. Median absolute lymphocyte count was 1.1 × 10⁹ cells/L (range, 0.2-2.7), and median CD3+ count was 732 cells/µL (range, 133-1608), reflecting marked immunological heterogeneity at study entry.

Efficacy: Universal Response and Sustained MRD Negativity

With a median follow-up of 2.8 months, all 18 patients achieved a response by International Myeloma Working Group (IMWG) criteria, with an ORR of 100% including 50% with very good partial response (VGPR) or better. Among patients with at least 4 months of follow-up (n = 6), responses deepened over time, with 67% achieving stringent complete response (sCR). In the 14 patients for whom 1-month MRD results were available, all were MRD-negative at the 10⁻⁵ sensitivity threshold. MRD-negative bone marrow responses were sustained through 6 months, and the earliest-treated patients are now in ongoing response at and beyond 9 months post-dosing. Consistent declines in soluble BCMA and serum free light chain levels were observed across the evaluable population.

Spencer showed representative clinical responses included FDG-PET negativity at sites of both intramedullary and extramedullary disease at 1 month post-treatment in a 68-year-old patient with gain 1q who achieved VGPR and MRD negativity, and complete clearance of CD138+/BCMA+ plasma cells on bone marrow biopsy in a 72-year-old patient with 30% baseline bone marrow plasma cell involvement who achieved sCR and MRD negativity.

CAR T Expansion and Persistence Across Diverse Immune Profiles

Peak vector transgene copy numbers were comparable across all three dose levels, with median C~max~ values of 65,873, 71,021, and 110,032 vector copies/µg genomic DNA at the 2 × 10⁷, 6 × 10⁶, and 4 × 10⁶ IU/kg dose levels, respectively. Median CAR+ cells by flow cytometry at day 15 were 34.5%, 53.1%, and 42.3% at the three dose levels. CAR T persistence was observed in both peripheral blood and bone marrow through 6 months.

“Importantly, these levels are consistent or in line with ex vivo CAR T-cell therapies that we currently use,” said Spencer.

In 13 patients with complete translational data, responses were achieved regardless of baseline T-cell phenotype, including wide variation in absolute lymphocyte count, CD3+ count, PD-1+ CD8 fraction, TIM-3+ CD8 fraction, and CD4/CD8 ratio. The R² for the correlation between baseline PD-1+ CD8 cell proportion and in vivo expansion (vector copy area under the curve) was 0.0006947, indicating no meaningful relationship. Stem cell memory and central memory phenotypes were observed in both the CD4+ and CD8+ CAR T compartments and persisted through month 3. “We know that with currently available CAR T therapies that there is an association between memory phenotypes and successful disease control,” said Spencer. “There is some preliminary evidence that this memory phenotype is being generated and persisting in these patients.”

Safety: Outpatient Delivery Feasible

Although cytokine release syndrome (CRS) occurred in the majority of patients, no grade 3 or higher CRS events were observed across any dose level. CRS onset was later than that typically seen with ex vivo CAR T-cell therapies, with median time to onset of 9.5 days (range, 9-10) at the 2 × 10⁷ IU/kg dose level and 13 days (range, 12-18 and 5-14) at the 2 lower dose levels, and median duration of 2.5 to 3 days. All CRS events were grade 1 to 2 and manageable with standard supportive care, including dexamethasone and tocilizumab (Actemra) per institutional protocol.

Two patients experienced immune effector cell–associated neurotoxicity syndrome (ICANS): 1 with lower-grade ICANS that resolved coincident with CRS after 3 days, and 1with grade 3 ICANS managed with methylprednisolone and anakinra (Kineret) that resolved to grade 2 within 3 days and fully resolved within 9 days without sequelae. No delayed neurotoxicity including parkinsonism, cranial nerve palsy, or peripheral neuropathy was observed in any patient.

Infusion-related reactions (IRRs) occurred in 3 of 5 patients (60%) treated without premedication; after implementation of dexamethasone premedication, no IRRs were observed in the subsequent 13 patients. Grade or higher 3 cytopenias were limited and brief: neutropenia occurred in 61% with a median time to resolution of 3 days (range, 1-9); thrombocytopenia in 33% with median resolution of 5.5 days (range, 2-7); and anemia in 22% with median resolution of 2 days (range, 1-7). One grade 3 or higher infection (pneumonia) was observed among 8 patients in the late post-treatment period; no grade 3 or higher infections occurred within the first 3 months.

Based on the off-the-shelf administration, lack of need for lymphodepletion, and limited number of adverse events, the investigators deemed KLN-1010 to have a favorable safety profile for outpatient dosing. Enrollment in the inMMyCar trial is ongoing.

“[KLN-1010] has a favorable safety and tolerability profile, which may enable ambulatory care delivery of this, which has significant implications,” Spencer emphasized.

REFERENCE

Spencer A, Harrison S, Lim SL, et al. Successful in vivo CAR-T generation and MRD clearance with KLN-1010 across diverse baseline T-cell phenotypes in relapsed/refractory multiple myeloma. Presented at the European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S185.