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

Abstract Introduction: KLN-1010 is an investigational gene therapy administered intravenously to generate a novel, fully human anti-BCMA CAR-T cell in vivo for patients with RRMM. Selective transduction of circulating T cells is achieved through an improved third-generation lentiviral vector (LVV) comprised of a modified vesicular stomatitis virus glycoprotein fusogen co-expressed with an anti-CD3 antibody on the LVV envelope, enabling viral entry through CD3 on T cells rather than the low-density lipoprotein receptor. Designed as an off-the-shelf therapy, KLN-1010 eliminates the need for apheresis, bespoke ex vivo cell manufacturing, or lymphodepleting chemotherapy and may broaden access to CAR-T therapies. Here, we report the results on the initial three patients treated with KLN-1010 from inMMyCAR, the first sponsored multicenter study of an in vivo CAR-T therapy for patients with RRMM. Methods: Eligibility required RRMM with measurable disease, adequate end-organ and bone marrow (BM) function, and at least 3 prior lines of therapy, including a proteosome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. The study design includes a 3+3 dose escalation, with half-log dose increments. Results: Patients (N=3) ranged from age 61-72 and their time from diagnosis was 7.9-9.4 yrs. All had high-risk cytogenetics and 3-4 prior lines of therapy. Two were refractory to a PI, an IMiD, and anti-CD38 therapy. All were naïve to BCMA-targeted therapies; none had extramedullary involvement. Time from consent to infusion was 13-18 days. All patients experienced treatment-emergent adverse events (AEs), primarily around infusion and during CAR-T expansion. Two patients developed infusion-related reaction (IRR) 30-60 min post-infusion that resolved within 6-48 hrs. Tocilizumab was administered prophylactically in the latter two patients after the first IRR was observed. Grade 2 cytokine release syndrome (CRS) was observed in two patients during CAR-T expansion. No immune effector cell-associated neurotoxicity syndrome or delayed neurotoxicity (e.g. parkinsonism or cranial nerve palsies) were noted. Cytopenias were limited: one patient with Grade 3 anemia lasting 1 day (day 15) and one patient with Grade 3/4 neutropenia (only on days 1 and 15). No patients were observed to have Grade ≥3 thrombocytopenia, Grade ≥3 hematologic toxicity, or treatment-emergent infections at month 1. T cell expansion occurred despite no preparative chemotherapy with peak absolute lymphocyte counts (ALC) between days 13-18 at 2.3, 7.37, and 43.1 × 109/L. CAR-positive cells comprised 35%, 22%, and 72% of CD3+ lymphocytes on day 15 with vector transgene copies of 51,647 and 65,873 copies/µg genomic DNA in the two samples analyzed. No clinical sequelae of the lymphocytosis were noted; dexamethasone promptly resolved the lymphocytosis in the patient with the highest ALC. CAR-T cells were detected in the BM and peripheral blood through month 3 and were comprised predominantly of memory-phenotype T cells. All patients experienced an MRD-negative response (10-5 or 10-6 sensitivity) at month 1 by a next-generation flow cytometry or sequencing method. The patient with the longest follow-up to date maintained the MRD negativity (10-6 sensitivity) at month 3. All achieved a partial response at month 1 by IMWG criteria that deepened over time; the best response was a very good partial response (VGPR) at month 3. All remain in response without disease progression. Conclusions: Preliminary results from the first three patients dosed in the inMMyCAR Phase 1 study of KLN-1010 demonstrate that promising clinical activity and manageable toxicities are feasible with an off-the-shelf in vivo CAR-T in MM. Lymphodepletion was not required for in vivo CAR-T cell generation and expansion in the peripheral blood. CRS was consistent with that seen with ex vivo CAR-T therapies, while cytopenias were notably limited and no treatment-emergent infections occurred. Early MRD-negative responses with deepening of IMWG response over time and persistent memory CAR-T cells were observed. Similar outcomes have been associated with durable remissions with ex vivo CAR-T cells in MM. CAR-T cell expansion peaked around day 15; memory-phenotype T cells persisted in the BM and blood through month 3. All patients had an early MRD-negative BM that was sustained for 3 months in the patient with the longest follow up. The study remains ongoing and updated results will be presented.