The inMMyCAR Phase 1 study evaluated KLN-1010, a groundbreaking in vivo gene therapy that creates anti-BCMA CAR-T cells directly inside the patient's body for treating relapsed and refractory multiple myeloma, eliminating the need for cell collection (apheresis), custom manufacturing, or chemotherapy preparation. Four patients aged 61-72 years with high-risk disease and 3-5 prior treatment lines received KLN-1010, with treatment ready in just 13-18 days from consent to infusion compared to typical 4-6 week manufacturing timelines for traditional CAR-T. All four patients achieved minimal residual disease (MRD) negativity at month 1 (sensitivity of 1 in 100,000 or 1 in 1,000,000 cancer cells), with the longest followed patient maintaining MRD negativity at 3 months and all patients experiencing deepening responses over time to at least partial response, with best response being complete response at month 5. The safety profile showed manageable side effects including two patients with Grade 2 cytokine release syndrome, brief infusion reactions resolved within 6-48 hours, minimal blood count drops, no brain toxicity or delayed neurological problems like Parkinsonism, and notably no infections at one month, demonstrating that CAR-T cells can be successfully generated and expanded without preparative chemotherapy.

Key Points:

• Revolutionary Off-the-Shelf Approach: KLN-1010 is given as a single intravenous infusion that creates CAR-T cells directly in the body, eliminating the 4-6 week wait for custom cell manufacturing, the need for cell collection procedures, and chemotherapy preparation that weakens the immune system
• Rapid Treatment Timeline: Patients received treatment in just 13-18 days from consent to infusion, dramatically faster than the typical 4-6 week manufacturing time plus additional weeks for scheduling with traditional CAR-T therapy
• Universal MRD Negativity: All four patients (100%) achieved MRD-negative status at 1 month with ultra-sensitive testing (detecting 1 cancer cell among 100,000-1,000,000 normal cells), with one patient maintaining this deep response at 3 months
• Deepening Responses Over Time: All patients achieved at least partial response at month 1 that continued improving, with best response reaching complete response at month 5, and all patients remaining in response without cancer progression
• Effective CAR-T Generation Without Chemotherapy: Despite receiving no preparative chemotherapy, patients showed robust CAR-T cell expansion peaking around days 13-18, with CAR-positive cells making up 22-85% of T cells on day 15 and persisting through month 3
• Favorable Safety Profile: No severe (Grade 3 or higher) blood count drops except brief episodes of 2-3 days, no brain-related side effects (ICANS) or delayed neurological problems, no infections at month 1, and only three patients experiencing manageable Grade 1-2 cytokine release syndrome
• Manageable Infusion Reactions: Three patients developed infusion reactions 30-60 minutes after treatment that resolved within 6-48 hours; preventive medication (tocilizumab) successfully prevented reactions in subsequent patients
• High-Risk Patient Population: All patients had aggressive disease features (high-risk genetics, 7.2-9.4 years since diagnosis, 3-5 prior treatment lines), with three patients resistant to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies, yet all responded to treatment

Conclusion:

The inMMyCAR Phase 1 study of KLN-1010 represents a potential paradigm shift in CAR-T therapy by demonstrating that highly effective anti-BCMA CAR-T cells can be generated directly inside patients' bodies without the traditional hurdles of cell collection, weeks-long manufacturing delays, or immune-weakening chemotherapy preparation. All four initial patients achieved remarkable MRD-negative responses within one month that continued deepening over time, with one patient maintaining ultra-sensitive MRD negativity at three months, outcomes historically associated with durable remissions in traditional CAR-T studies. The safety profile was notably favorable, with minimal blood count drops, no treatment-related infections, no brain toxicity or delayed neurological complications like Parkinsonism that can occur with traditional CAR-T, and manageable cytokine release syndrome comparable to standard therapies. By reducing treatment timeline from 4-6 weeks to under 3 weeks, eliminating complex manufacturing logistics, and avoiding preparative chemotherapy, KLN-1010 has the potential to dramatically broaden access to CAR-T therapy for multiple myeloma patients worldwide, particularly those who might deteriorate during the typical waiting period or cannot tolerate intensive chemotherapy preparation, while the persistence of memory-type CAR-T cells through three months suggests the possibility of durable disease control.

Authors:

Simon Harrison, Phoebe Joy Ho, Sueh-Li Lim, Stephanie Talam, Hannah Pahl, Dharmesh Dingar, Scott Currence, Travis Quigley, and Andrew Spencer. Presented at ASH 2025 (Abstract LBA-1).