In Vivo CAR T-Cell Therapy Drives Responses and MRD Negativity in R/R Myeloma

Treatment with the in vivo CAR T-cell therapy KLN-1010 led to deep minimal residual disease (MRD)–negative responses in patients with relapsed/refractory myeloma, according to data from the phase 1 inMMyCAR trial (NCT07075185) presented at the 2026 EHA Congress.¹

Findings demonstrated that evaluable patients (n = 18) achieved an overall response rate (ORR) of 100%, including a stringent complete response (sCR) rate of 22%, a CR rate of 6%, a very good partial response (VGPR) rate of 22%, and a PR rate of 50%. Among patients with at least 4 months of follow-up (n = 6), the sCR rate was 67%, and the VGPR rate was 33%.

MRD-negative bone marrow responses at a 10^–5 sensitivity were also observed in 100% of evaluable patients (n = 14).

“There is a favorable safety and tolerability profile with this off-the-shelf product,” lead study author Andrew Spencer, MBBS, FRACP, FRCPA, DM, said in a presentation of the data. “Overall, these are favorable preliminary data, and we continue to enroll [patients] to the study.”

Spencer is head of Malignant Haematology, Transplantation and Cellular Therapies Service and head of Myeloma Research at Monash University in Melbourne, Australia.

What differentiates KLN-1010 from traditional CAR T-cell therapies?

Although traditional CAR T-cell therapy relies on T-cell collection via leukapheresis, manufacturing of the product, and administration to the patient, KLN-1010 uses lentiviral particles for in vivo CAR T-cell generation.

By generating the anti-BCMA CAR T-cells within patients, this strategy eliminates the need for lymphodepletion prior to CAR T-cell infusion. Additionally, this method could expand CAR T-cell therapy access with simplified logistics, increase T-cell fitness, and lower the cost of goods and manufacturing.

How is the inMMyCAR trial being conducted?

The first-in-human phase 1 trial is enrolling patients at least 18 years of age with relapsed/refractory multiple myeloma with measurable disease who have received at least 3 prior lines of therapy that included a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and CD38-directed monoclonal antibody.^1,2 Patients are also required to have an ECOG performance status of 0 or 1, along with adequate bone marrow and end organ function.¹

The dose-escalation portion of the study is being conducted with a 3+3 and backfill design, with investigators evaluating KLN-1010 at doses of 4 x 10⁶ IU/kg, 6 x 10⁶ IU/kg, and 2 x 10⁷ IU/kg. Expansion cohorts will further evaluate the in vivo CAR T-cell therapy at the recommended phase 2 dose (RP2D).

Safety and tolerability, along with determining the RP2D, are serving as the trial’s primary end points. Secondary end points comprise CAR T-cell expansion and persistence, ORR per International Myeloma Working Group criteria, MRD, duration of response, and progression-free survival.

As of the April 21, 2026, data cutoff, 18 patients have been treated across all 3 dose levels. Patients experienced a median time from consent to infusion of 13 days. The median age was 67 years (range, 50-77), and most patients were male (72%). Multiple myeloma subtypes included IgG (61%), IgA (6%), IgM (6%), and light chain (28%). Notably, 72% of patients had high-risk cytogenetics, and 28% of patients had extramedullary disease at baseline. The majority of patients had stage II or III disease (56%) per Revised International Staging System criteria.

Patients had a median bone marrow plasma cell level of 20% (range, 4%-90%), a median absolute lymphocyte count of 1.1 x 10⁹ cells/L (range, 0.2-2.7), and a median CD3-positive count of 732 cells/µL (range, 133-1608). Patients had received a median of 3.5 prior lines of therapy (range, 2-7), and 89% of patients had undergone prior autologous stem cell transplant. Most patients were refractory to a PI (72%), an IMiD (78%), and an anti-CD38 monoclonal antibody (78%); 56% of patients were triple-class refractory.

What is the safety profile of KLN-1010 in relapsed/refractory multiple myeloma?

Safety data showed that instances of cytokine release syndrome (CRS) were consistent with those seen with ex vivo CAR T-cell therapies, and Spencer noted that later onset was supportive of outpatient dosing. No grade 3 or higher CRS was reported across the 3 dose levels. The median time to CRS onset was 13 days (range, 5-14) at the 4 x 10⁶ IU/kg dose (n = 7), 13 days (range, 12-18) at the 6 x 10⁶ IU/kg dose (n = 8), and 9.5 days (range, 9-10) at the 2 x 10⁷ IU/kg dose (n = 3). The median durations of CRS were 3 days (range, 3-5), 3 days (range, 1-8), and 2.5 days (range, 2-3), respectively. The respective rates of grade 1/2 CRS were 100%, 75%, and 67%.

Across all evaluable patients, 1 patient experienced grade 1/2 immune effector cell–associated neurotoxicity syndrome (ICANS), and 1 additional patient had grade 3 or higher ICANS. The grade 3 adverse effect was managed with methylprednisolone and anakinra (Kineret), limiting its duration to 3 days. Not delayed neurotoxicities were reported.

Prior to the use of dexamethasone premedication for the infusion of KLN-1010, 60% of patients (n = 5) experienced any-grade infusion-related reactions, including 1 patient with a grade 3 or higher reaction. With dexamethasone premedication (n = 13), no infusion-related reactions of any grade occurred.

No patients experienced grade 3 or higher infections in the first 3 months following infusion; 1 patient had grade 3 or higher pneumonia that occurred more than 3 months following infusion.

The rates of grade 3 or higher neutropenia, thrombocytopenia, and anemia were 61%, 33%, and 22%, respectively. The respective median times to resolution of these cytopenias were 3 days (range, 1-9), 5.5 days (range, 2-7) and 2 days (range, 1-7).

What additional CAR T expansion/persistence data were shared at EHA 2026?

Spencer also shared that the maximal concentration data for KLN-1010 were consistent with those seen with ex vivo CAR T-cell therapies at peak expansion, with persistence observed in the peripheral blood and bone marrow. At day 15, the median percentage of CAR-positive cells in evaluable patients was 42.3% at the 4 x 10⁶ IU/kg dose (n = 2), 53.1% at the 6 x 10⁶ IU/kg dose (n = 7), and 34.5% at the 2 x 10⁶ IU/Kg dose (n = 3). The respective CD4/CD8 ratios were 0.9, 0.6, and 0.5.

Findings also showed that responses were observed across heterogenous T-cell profiles at baseline, and robust expansion was reported across dose levels and baseline T-cell profiles. T-cell memory phenotypes were also noted across patients, which persisted through month 3.

“We know that with currently available CAR T-cell therapies, there is an association between memory phenotypes and successful disease control. [In this analysis], we can illustrate that out to 3 months, we’ve got stem cell memory cells and central memory cells evident…illustrating that there is some preliminary evidence that this memory phenotype is being generated and persisting in these patients.”

Disclosures: Spencer did not report any financial conflicts of interest.

References

1. Spencer A, Harrison S, Lim S-L, 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: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S185.
2. A study to evaluate a novel gene therapy in patients with relapsed and refractory multiple myeloma (inMMyCAR). ClinicalTrials.gov. Updated April 24, 2026. Accessed June 11, 2026. https://clinicaltrials.gov/study/NCT07075185